WO2005110478A2

WO2005110478A2 - Combination therapy for treating fibrotic disorders

Info

Publication number: WO2005110478A2
Application number: PCT/US2005/012579
Authority: WO
Inventors: Lawrence M. Blatt
Original assignee: Intermune, Inc.
Priority date: 2004-04-13
Filing date: 2005-04-13
Publication date: 2005-11-24
Also published as: WO2005110478A3

Abstract

The present invention provides methods of treating fibrotic diseases, including pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), pulmonary fibrosis from a known etiology, liver fibrosis, cardiac fibrosis, and renal fibrosis. The methods generally involve administering to an individual with a fibrotic disease (i) pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist and (ii) a TGF-ß antagonist or an endothelin receptor antagonist concurrently, in an amount effective to ameliorate the clinical course of the disease. The invention also provides a method of treating a fibrotic disorder by administering to an individual (i) pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist and (ii) a TGF-ß antagonist or an endothelin receptor antagonist in synergistically effective amounts to ameliorate the clinical course of the disease.

Description

COMBINATION THERAPY FOR TREATING FIBROTIC DISORDERS

FIELD OF THE INVENTION [0001] This invention is in the field of fibrosis, and particularly, lung fibrosis, liver fibrosis and renal fibrosis.

BACKGROUND OF THE INVENTION

[0002] Current data indicate that fibrosis is not a static process; extracellular matrix is constantly being laid down and resorbed and tl e progressive accumulation of fibrous tissue is thought to represent a relative imbalance between pro-fibrotic processes and anti-fibrotic processes. If these processes are not properly regulated, the pathologic and progressive accumulation of collagen in the extracellular space as a result of a disordered wound healing process leads to replacement of normal cells by dense fibrous bands of protein, and results in fibrotic disease with disordered function in the affected organ (for example, impairment of respiratory function, impaired circulatory function via fibrotic changes in arterial walls, fibrotic degeneration of renal and liver function, degenerative musculoskeletal function, fibrotic degeneration of cardiac muscle or skeletal muscle, fibrotic degenerative changes in neuronal tissues in the central nervous system as well as the peripheral nervous system, etc.).

[0003] Pulmonary fibrosis can be caused by a number of different conditions, including sarcoidosis, hypersensitivity pneumonitis, collagen vascular disease, and inhalant exposure. The diagnosis of these conditions can usually be made by careful history, physical examination, chest radiography, including a high resolution computer tomographic scan (HRCT), and transbronchial biopsies. However, in a significant number of patients, no underlying cause for the pulmonary fibrosis can be found. These conditions of unknown etiology have been termed idiopathic interstitial pneumonias or idiopathic pulmonary fibrosis. Histologic examination of tissue obtained at open lung biopsy allows classification of these patients into several categories, including Usual Interstitial Pneumonia (UIP), Desquamative Interstitial Pneumonia (DIP), and Non-Specific Interstitial Pneumonia (NSIP).

[0004] The logic of dividing idiopathic interstitial pneumonias into these categories is based not only on histology, but also on the different response to therapy and prognosis for these different entities. DIP is associated with smoking and the prognosis is good, with more than 70% of these patients responding to treatment with corticosteroids. NSIP patients are also frequently responsive to steroids and prognosis is good, with 50% of patients surviving to 15 years. In contrast, the UIP histologic pattern is associated with a poor response to therapy and a poor prognosis, with survival of only 3-5 years.

[0005] Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia and is characterized by the UIP pattern on histology. IPF has an insidious onset, but once symptoms appear, there is a relentless deterioration of pulmonary function and death within 3-5 years after diagnosis. The mean age of onset is 60-65 and males are affected approximately twice as often as females. Prevalence estimates are 13.2-20.2 per 100,000. The annual incidence is estimated to be 7.4-10.7 per 100,000 new cases per year.

[0006] Published evidence suggests that less than 20% of patients with IPF respond to steroids. In patients who have failed treatment with steroids, cytotoxic drugs such as azathioprine or cyclophosphamide are sometimes added to the steroid treatment. However, a large number of studies have shown little or no benefit of these drugs. There are currently no drugs approved for treatment of IPF.

[0007] Liver fibrosis occurs as a result of a chronic toxic insult to the liver, such as chronic hepatitis C virus (HCV) infection, autoimmune injury, and chronic exposure to toxins such as alcohol. Chronic toxic insult leads to repeated cycles of hepatocyte injury and repair accompanied by chronic inflammation. Over a variable period of time, abnormal extracellular matrix progressively accumulates as a consequence of the host's wound repair response. Left unchecked, this leads to increasing deposition of fibrous material until liver architecture becomes distorted and the liver's regenerative ability is compromised. The progressive accumulation of scar tissue within the liver finally results in the histopathologic picture of cirrhosis, defined as the formation of fibrous septae throughout the liver with the formation of micronodules.

[0008] Renal fibrosis is a complication of kidney injury and can contribute to organ failure. Tubulointerstitial and glomerular fibrosis is a morphologic hallmark of chronic, progressive renal disease and is thought to be the final common mechanism leading to end-stage renal disease. There are multiple etiologies of renal fibrosis. In particular, Type I and II diabetes mellitus are common causes of renal fibrosis. In addition, there are toxic, drug-induced, metabolic, structural, genetic, and infectious causes of chronic renal insufficiency related to renal fibrosis. In a number of pathologic conditions, the etiology is unknown. Of particular clinical relevance, the rate of decline of the glomerular filtration rate in patients with chronic renal disease correlates strongly with the extent of tubulointerstitial and glomerular injury. Tubulointerstitial fibrosis is also a component of age-related structural changes in otherwise normal kidneys and is a hallmark of chronic allograft nephropathy (chronic allograft rejection), the most common cause of kidney transplant failure in the first decade after transplantation. Accumulation of proteins, such as fibronectin and various collagens, in the interstitium of the kidney is thought to be a fundamental process in development of tubulointerstitial scarring. Increased synthesis, decreased degradation, or both can underlie interstitial protein accumulation. During fibrosis, interstitial fibroblasts proliferate and are primarily responsible for increased production of interstitial proteins. Currently, there are no drugs that adequately treat renal fibrosis.

[0009] In addition to fibrotic disorders of the lung, liver and kidney, many other organs and tissues are susceptible to fibrotic degeneration. In particular, cardiac injury from hypoxia or ischemia, toxins, infectious agents, genetic etiologies, and structural disorders can lead to an inappropriate chronic wound healing process that results in fibrosis of cardiac tissue.

[0010] There is a need in the art for methods of treating fibrotic disorders. The present invention addresses this need. Literature

[0011] WO 01/34180; Ziesche et al. (1999) N. Engl. J. Med. 341:1264-1269; du Bois (1999) N. Engl. J. Med. 341:1302-1304; U.S. Patent No. 6,294,350; EP 795,332; King (2000) N Engl. J. Med. 342:974-975; Ziesche and Block (2000) Wien. Klin Wochenschr. 112:785-790; Raghu et al. (1999) Am. J. Respir. Crit. Care Med. 159:1061-1069; Stern et al. (2001) Chest 120:213- 219; Gay et al. (1998) Am. J. Respir. Crit. Care Med. 157:1063-1072; Dayton et al. (1993) Chest 103:69-73.

[0012] Al-Bayati et al. (2002) Biochem. Pharmacol. 64:517-525; Shihab et al. (2002) Am. J. Transplant. 2: 111 - 119; Yu et al. (2002) Curr. Opinion Pharmacol. 2: 177- 181 ; U.S . Patent Νos. 5,310,562; 5,518,729; 5,716,632; and 6,090,822.

[0013] METAVIR (1994) Hepatology 20:15-20; Brunt (2000) Hepatol. 31:241-246; Alpini (1997) J. Hepatol. 27:371-380; Baroni et al. (1996) Hepatol. 23 :1189-1199 ; Czaja et al. (1989) Hepatol. 10:795-800; Grossman et al. (1998) J Gastroenterol Hepatol. 13:1058-1060; Rockey and Chung (1994) J. Invest. Med. 42:660-670; Sakaida et al. (1998) J. Hepatol. 28 :471-479 ; Shi et al. (1997) Proc. Natl. Acad. Sci. USA 94:10663-10668; Baroni et al. (1999) Liver 19:212-219; Lortat- Jacob et al. (1997) J. Hepatol. 26:894-903; Llorent et al. (1996) J. Hepatol. 24:555-563.

SUMMARY OF THE INVENTION [0014] The present invention provides methods of treating fibrotic diseases, including pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), pulmonary fibrosis from a known etiology, liver fibrosis, cardiac fibrosis, and renal fibrosis. The methods generally involve administering to an individual with a fibrotic disease (i) pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and (ii) a TGF-β antagonist or an endothelin receptor antagonist concurrently, in an amount effective to ameliorate the clinical course of the disease. The invention also provides a method of treating a fibrotic disorder by administering to an individual (i) pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and (ii) a TGF-β antagonist or an endothelin receptor antagonist in synergistically effective amounts to ameliorate the clinical course of the disease.

FEATURES OF THE INVENTION

[0015] In one aspect, the invention features a method of treating a fibrotic disorder in an individual, the method comprising administering to the individual a combined dosage of pirfenidone (or a pirfenidone analog) and a TGF-β antagonist that is effective in the treatment of the fibrotic disorder in the individual. In some embodiments, the TGF-β antagonist is GLEEVEC™ imatinib mesylate.

[0016] In another aspect, the invention features a method of treating a fibrotic disorder in an individual comprising administering to the individual a combined dosage of pirfenidone (or a pirfenidone analog) and a TGF-β antagonist effective in the treatment of the fibrotic disorder in the individual, and further comprising co-administering to the individual an amount of a Type II interferon receptor agonist that augments the anti-fibrotic effect of the pirfenidone (or pirfenidone analog) and TGF-β antagonist combination therapy in the treatment of the individual. In some embodiments, the TGF-β antagonist is GLEEVEC™. In other embodiments, the Type II interferon receptor agonist is IFN-γ. In additional embodiments, the TGF-β antagonist is GLEEVEC™ and the Type II interferon receptor agonist is IFN-γ.

[0017] In another aspect, the invention features a method of treating a fibrotic disorder in an individual comprising administering to the individual a combined dosage of pirfenidone (or a pirfenidone analog) and a TGF-β antagonist effective in the treatment of the fibrotic disorder in the individual, and further comprising co-administering to the individual an amount of a TNF antagonist that augments the anti-fibrotic effect of tl e pirfenidone (or pirfenidone analog) and TGF-β antagonist combination therapy in the treatment of the individual. In some embodiments, the TGF-β antagonist is GLEEVEC™. In other embodiments, the TNF antagonist is etanercept, infliximab or adalimumab. In additional embodiments, the TGF-β antagonist is GLEEVEC™ and the TNF antagonist is etanercept, infliximab or adalimumab. [0018] In another aspect, the invention features a method of treating a fibrotic disorder in an individual comprising administering to the individual a combined dosage of pirfenidone (or a pirfenidone analog) and a TGF-β antagonist effective in the treatment of the fibrotic disorder in the individual, and further comprising co-administering to the individual an amount of an endothelin receptor antagonist that augments the anti-fibrotic effect of the pirfenidone (or pirfenidone analog) and TGF-β antagonist combination therapy in the treatment of the individual. In some embodiments, the TGF-β antagonist is GLEEVEC™. In other embodiments, the endothelin receptor antagonist is TRACLEER™ bosentan. In additional embodiments, the TGF-β antagonist is GLEEVEC™ and the endothelin receptor antagonist is TRACLEER™.

[0019] In another aspect, the invention features a method of treating a fibrotic disorder in an individual comprising administering to the individual a combined dosage of pirfenidone (or a pirfenidone analog) and a TGF-β antagonist effective in the treatment of the fibrotic disorder in the individual, and further comprising co-administering to the individual a combined dosage of a Type II interferon receptor agonist and a TNF antagonist that augments the anti-fibrotic effect of the pirfenidone (or pirfenidone analog) and TGF-β antagonist combination therapy in the treatment of the individual. In some embodiments, the TGF-β antagonist is GLEEVEC™. In other embodiments, the Type II interferon receptor agonist is IFN-γ. In still other embodiments, the TNF antagonist is etanercept, infliximab or adalimumab. In additional embodiments, the TGF-β antagonist is GLEEVEC™, the Type II interferon receptor agonist is IFN-γ, and the TNF antagonist is etanercept, infliximab or adalimumab.

[0020] In another aspect, the invention features a method of treating a fibrotic disorder in an individual comprising administering to the individual a combined dosage of pirfenidone (or a pirfenidone analog) and a TGF-β antagonist effective in the treatment of the fibrotic disorder in the individual, and further comprising co-administering to the individual a combined dosage of a Type II interferon receptor agonist and an endothelin receptor antagonist that augments the anti-fibrotic effect of the pirfenidone (or pirfenidone analog) and TGF-β antagonist combination therapy in the treatment of the individual. In some embodiments, the TGF-β antagonist is GLEEVEC™. In other embodiments, the Type II interferon receptor agonist is IFN-γ. In still other embodiments, the endothelin receptor antagonist is TRACLEER™. In additional embodiments, the TGF-β antagonist is GLEEVEC™, the Type II interferon receptor agonist is IFN-γ, and the endothelin receptor antagonist is TRACLEER™.

[0021] In another aspect, the invention features a method of treating a fibrotic disorder in an individual comprising administering to the individual a combined dosage of pirfenidone (or a pirfenidone analog) and a TGF-β antagonist effective in the treatment of the fibrotic disorder in the individual, and further comprising co-administering to the individual a combined dosage of a TNF antagonist and an endothelin receptor antagonist that augments the anti-fibrotic effect of the pirfenidone (or pirfenidone analog) and TGF-β antagonist combination therapy in the treatment of the individual. In some embodiments, the TGF-β antagonist is GLEEVEC™. In other embodiments, the TNF antagonist is etanercept, infliximab or adalimumab. In still other embodiments, the endothelin receptor antagonist is TRACLEER™. In additional embodiments, the TNF antagonist is etanercept, infliximab or adalimumab, the TGF-β antagonist is GLEEVEC™, and the endothelin receptor antagonist is TRACLEER™.

[0022] In another aspect, the invention features a method of treating a fibrotic disorder in an individual comprising administering to the individual a combined dosage of pirfenidone (or a pirfenidone analog) and a TGF-β antagonist effective in the treatment of the fibrotic disorder in the individual, and further comprising co-administering to the individual a combined dosage of a Type II interferon receptor agonist, a TNF antagonist and an endothelin receptor antagonist that augments the anti-fibrotic effect of the pirfenidone (or pirfenidone analog) and TGF-β antagonist combination therapy in the treatment of the individual. In some embodiments, the TGF-β antagonist is GLEEVEC™. In other embodiments, the Type II interferon receptor agonist is IFN-γ. In still other embodiments, the TNF antagonist is etanercept, infliximab or adalimumab. In yet other embodiments, the endothelin receptor antagonist is TRACLEER™. In additional embodiments, the TGF-β antagonist is GLEEVEC™, the Type II interferon receptor agonist is IFN-γ, the TNF antagonist is etanercept, infliximab or adalimumab, and the endothelin receptor antagonist is TRACLEER™.

[0023] In another aspect, the invention features a method of treating a fibrotic disorder in an individual, the method comprising administering to the individual a combined dosage of pirfenidone (or a pirfenidone analog) and an endothelin receptor antagonist that is effective in the treatment of the fibrotic disorder in the individual. In some embodiments, the endothelin receptor antagonist is TRACLEER™.

[0024] In another aspect, the invention features a method of treating a fibrotic disorder in an individual comprising administering to the individual a combined dosage of pirfenidone (or a pirfenidone analog) and an endothelin receptor antagonist effective in the treatment of the fibrotic disorder in the individual, and further comprising co-administering to the individual an amount of a Type II interferon receptor agonist that augments the anti-fibrotic effect of the pirfenidone (or pirfenidone analog) and endothelin receptor antagonist combination therapy in the treatment of the individual. In some embodiments, the endothelin receptor antagonist is TRACLEER™. In other embodiments, the Type II interferon receptor agonist is IFN-γ. In additional embodiments, the endothelin receptor antagonist is TRACLEER™ and the Type II interferon receptor agonist is IFN-γ.

[0025] In another aspect, the invention features a method of treating a fibrotic disorder in an individual comprising administering to the individual a combined dosage of pirfenidone (or a pirfenidone analog) and an endothelin receptor antagonist effective in the treatment of the fibrotic disorder in the individual, and further comprising co-administering to the individual an amount of a TNF antagonist that augments the anti-fibrotic effect of the pirfenidone (or pirfenidone analog) and endothelin receptor antagonist combination therapy in the treatment of the individual. In some embodiments, the endothelin receptor antagonist is TRACLEER™. In other embodiments, the TNF antagonist is etanercept, infliximab or adalimumab. In additional embodiments, the endothelin receptor antagonist is TRACLEER™ and the TNF antagonist is etanercept, infliximab or adalimumab.

[0026] In another aspect, the invention features a method of treating a fibrotic disorder in an individual comprising administering to the individual a combined dosage of pirfenidone (or a pirfenidone analog) and an endothelin receptor antagonist effective in the treatment of the fibrotic disorder in the individual, and further comprising co-administering to the individual a combined dosage of a Type II interferon receptor agonist and a TNF antagonist that augments the anti-fibrotic effect of the pirfenidone (or pirfenidone analog) and endothelin receptor antagonist combination therapy in the treatment of the individual. In some embodiments, the endothelin receptor antagonist is TRACLEER™. In other embodiments, the Type II interferon receptor agonist is IFN-γ. In still other embodiments, the TNF antagonist is etanercept, infliximab or adalimumab. In additional embodiments, the endothelin receptor antagonist is TRACLEER™, the Type II interferon receptor agonist is IFN-γ, and the TNF antagonist is etanercept, infliximab or adalimumab.

[0027] In another aspect, the invention features a method of treating a fibrotic disorder in an individual comprising administering to the individual a combined dosage of a Type II interferon receptor agonist and a TGF-β antagonist concurrently, in an amount effective to ameliorate the clinical course of the disease, e.g., reducing the disease burden, slowing the progression of the disease, or reducing morbidity or mortality in the clinical outcome of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the TGF-β antagonist is Gleevec™.

[0028] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, a TGF-β antagonist, and a third agent that is a TNF antagonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the TGF-β antagonist is Gleevec™. In some embodiments, the TNF antagonist is selected from etanercept, infliximab or adalimumab. In other embodiments, the TNF antagonist is a SAPK inhibitor.

[0029] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, a TGF-β antagonist, and a Type I or III interferon receptor agonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the TGF-β antagonist is Gleevec™. In some of these embodiments, the Type I interferon receptor agonist is IFN-α. In some of these embodiments, the IFN-α is a pegylated IFN-α, such as monoPEG (30 kD, linear)-ylated consensus IFN-α, PEGASYS® peginterferon alfa-2a, or PEG-LNTRON® peginterferon alfa-2b. In other embodiments, the IFN-α is an unpegylated IFN-α, such as INFERGEN® interferon alfacon-1, ROFERON® interferon alfa-2a, or INTRON-A® interferon alfa-2b.

[0030] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, a TGF-β antagonist, pirfenidone or a pirfenidone analog, and a Type I or III interferon receptor agonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the TGF-β antagonist is Gleevec™. In some embodiments, the Type I interferon receptor agonist is IFN-α. In some of these embodiments, the IFN-α is a pegylated IFN-α, such as monoPEG (30 kD, linear)-ylated consensus IFN-α, PEGASYS® peginterferon alfa-2a, or PEG-INTRON® peginterferon alfa-2b. In other embodiments, the IFN-α is an unpegylated IFN-α, such as INFERGEN® interferon alfacon-1, ROFERON® interferon alfa-2a, or INTRON-A® interferon alfa-2b.

[0031] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, a TGF-β antagonist, a Type I or III interferon receptor agonist, and a fourth agent that is a TNF antagonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the TGF-β antagonist is Gleevec™. In some embodiments, the Type I interferon receptor agonist is IFN-α. In some of these embodiments, the IFN-α is a pegylated IFN-α, such as monoPEG (30 kD, linear)-ylated consensus IFN-α, PEGASYS® peginterferon alfa-2a, or PEG-INTRON® peginterferon alfa-2b. In other embodiments, the IFN-α is an unpegylated IFN-α, such as INFERGEN® interferon alfacon-1, ROFERON® interferon alfa-2a, or INTRON-A® interferon alfa-2b. In some embodiments, the TNF antagonist is etanercept, infliximab or adalimumab. In other embodiments, the TNF antagonist is a SAPK inhibitor.

[0032] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, a TGF-β antagonist, an endothelin receptor antagonist, and a Type I or III interferon receptor agonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the TGF-β antagonist is Gleevec™. In some embodiments, the endothelin receptor antagonist is Tracleer™. In some embodiments, the Type I interferon receptor agonist is IFN-α. In some of these embodiments, the IFN-α is a pegylated IFN-α, such as monoPEG (30 kD, linear)- ylated consensus IFN-α, PEGASYS® peginterferon alfa-2a, or PEG-INTRON® peginterferon alfa-2b. In other embodiments, the IFN-α is an unpegylated IFN-α, such as INFERGEN® interferon alfacon-1, ROFERON® interferon alfa-2a, or INTRON-A® interferon alfa-2b.

[0033] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, TGF- β antagonist, a Type I or III interferon receptor agonist, pirfenidone or a pirfenidone analog, and a fifth agent that is a TNF antagonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the TGF-β antagonist is Gleevec™. In some embodiments, the Type I interferon receptor agonist is IFN-α. In some of these embodiments, the IFN-α is a pegylated IFN-α, such as monoPEG (30 kD, linear)-ylated consensus IFN-α, PEGASYS® peginterferon alfa-2a, or PEG-INTRON® peginterferon alfa-2b. In other embodiments, the IFN-α is an unpegylated IFN-α, such as INFERGEN® interferon alfacon-1, ROFERON® interferon alfa-2a, or INTRON-A® interferon alfa-2b. In some embodiments, the TNF antagonist is etanercept, infliximab or adalimumab. In other embodiments, the TNF antagonist is a SAPK inliibitor.

[0034] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, TGF- β antagonist, a Type I or III interferon receptor agonist, an endothelin receptor antagonist, and a fifth agent that is a TNF antagonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the TGF-β antagonist is Gleevec™. In some embodiments, the endothelin receptor agonist is Tracleer™. In some embodiments, the Type I interferon receptor agonist is IFN-α. In some of these embodiments, the IFN-α is a pegylated IFN-α, such as monoPEG (30 kD, linear)-ylated consensus IFN-α, PEGASYS® peginterferon alfa-2a, or PEG-INTRON® peginterferon alfa-2b. In other embodiments, the IFN-α is an unpegylated IFN-α, such as INFERGEN® interferon alfacon-1, ROFERON® interferon alfa-2a, or INTRON-A® interferon alfa-2b. In some embodiments, the TNF antagonist is etanercept, infliximab or adalimumab. In other embodiments, the TNF antagonist is a SAPK inhibitor.

[0035] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, TGF- β antagonist, a Type I or III interferon receptor agonist, an endothelin receptor antagonist, and pirfenidone or a pirfenidone analog, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the TGF-β antagonist is Gleevec™. In some embodiments, the endothelin receptor agonist is Tracleer™. In some embodiments, the Type I interferon receptor agonist is IFN-α. In some of these embodiments, the IFN-α is a pegylated IFN-α, such as monoPEG (30 kD, linear)-ylated consensus IFN-α, PEGASYS® peginterferon alfa-2a, or PEG-INTRON® peginterferon alfa-2b. In other embodiments, the IFN-α is an unpegylated IFN-α, such as INFERGEN® interferon alfacon-1, ROFERON® interferon alfa-2a, or INTRON-A® interferon alfa-2b.

[0036] In another aspect, the invention provides a combination therapy for treating fibrosis in an individual, the method comprising administering a Type II interferon receptor agonist, TGF- β antagonist, a Type I or III interferon receptor agonist, an endothelin receptor antagonist, pirfenidone or a pirfenidone analog, and a sixth agent that is a TNF antagonist, in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the TGF-β antagonist is Gleevec™. In some embodiments, the endothelin receptor agonist is Tracleer™. In some embodiments, the Type I interferon receptor agonist is IFN-α. In some of these embodiments, the IFN-α is a pegylated IFN-α, such as monoPEG (30 kD, linear)-ylated consensus IFN-α, PEGASYS® peginterferon alfa-2a, or PEG-INTRON® peginterferon alfa-2b. In other embodiments, the IFN-α is an unpegylated IFN-α, such as INFERGEN® interferon alfacon-1, ROFERON® interferon alfa-2a, or INTRON-A® interferon alfa-2b. In some embodiments, the TNF antagonist is etanercept, infliximab or adalimumab. In other embodiments, the TNF antagonist is a SAPK inhibitor. [0037] In another aspect, the invention features a method of treating a fibrotic disorder in an individual comprising administering to the individual a combined dosage of Type II interferon receptor agonist and an endothelin receptor antagonist that is effective in the treatment of the fibrotic disorder in the individual. In some embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the endothelin receptor antagomst is TRACLEER™.

[0038] In another aspect, the invention features a method of treating a fibrotic disorder in an individual comprising administering to the individual a combined dosage of Type II interferon receptor agonist, an endothelin receptor antagonist, and a TNF antagonist in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the endothelin receptor antagonist is TRACLEER™. In some embodiments, the TNF antagonist is etanercept, infliximab or adalimumab.

[0039] In another aspect, the invention features a method of treating a fibrotic disorder in an individual comprising administering to the individual a combined dosage of Type II interferon receptor agonist, an endothelin receptor antagonist, and a TGF-β antagonist in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the endothelin receptor antagonist is TRACLEER™. In some embodiments, the TGF-β antagonist is Gleevec™.

[0040] In another aspect, the invention features a method of treating a fibrotic disorder in an individual comprising administering to the individual a combined dosage of Type II interferon receptor agonist, an endothelin receptor antagonist, a TNF antagonist, and a TGF-β antagonist in combined amounts effective to ameliorate the clinical course of the disease. In some embodiments, the Type II interferon receptor agonist is IFN-γ. In some embodiments, the endothelin receptor antagonist is TRACLEER™. In some embodiments, the TNF antagonist is etanercept, infliximab or adalimumab. In some embodiments, the TGF-β antagonist is Gleevec™.

BRIEF DESCRIPTION OF THE DRAWING [0041] Figure 1 depicts the fold induction of collagen synthesis by fibroblasts in the presence of one or more of endothelin- 1 (ET1 or E), interleukin-4 (IL-4, or I), transforming growth factor-beta (TGF or T), and interferon-gamma (IFNg). DEFINITIONS

[0042] A "fibrotic condition," "fibroproliferative condition," "fibrotic disease," "fibroproliferative disease," "fibrotic disorder," and "fibroproliferative disorder" are used interchangeably herein to refer to a condition, disease or disorder that is characterized by dysregulated proliferation or activity of fibroblasts and/or pathologic or excessive accumulation of collagenous tissue. Typically, any such disease, disorder or condition is amenable to treatment by administration of a compound having anti-fibrotic activity. Fibrotic disorders include, but are not limited to, pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis from a known etiology, liver fibrosis, and renal fibrosis. Other exemplary fibrotic conditions include musculoskeletal fibrosis, cardiac fibrosis, post- surgical adhesions, scleroderma, glaucoma, and skin lesions such as keloids.

[0043] As used herein, the term "hepatic fibrosis," used interchangeably herein with "liver fibrosis," refers to the growth of scar tissue in the liver that can occur in the context of a chronic hepatitis infection.

[0044] The terms "individual," "host," "subject," and "patient" are used interchangeably herein, and refer to a mammal, including, but not limited to, primates, including simians and humans; murines, mammalian farm animals, mammalian sport animals, and mammalian pets.

[0045] As used herein, the term "liver function" refers to a normal function of the liver, including, but not limited to, a synthetic function, including, but not limited to, synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'-nucleosidase, γ- glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; a hemodynamic function, including splanchnic and portal hemodynamics; and the like.

[0046] As used herein, the terms "treatment," "treating," and the like, refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse affect attributable to the disease. "Treatment," as used herein, covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development or reducing its progression; (c) relieving the disease, i.e., causing regression of the disease; and (d) reducing morbidity or mortality in the clinical outcome of the disease.

[0047] As used herein, the term "pirfenidone" means 5 -methyl- l-phenyl-2-(lH)-pyridone.

[0048] As used herein, the term "pirfenidone analog" means any compound of Formula I, IIA or IIB below.

[0049] A "specific pirfenidone analog," and all grammatical variants thereof, refers to, and is limited to, each and every pirfenidone analog shown in Table 1.

[0050] As used herein, the term "TGF-β antagonist" refers to any agent that decreases the level of TGF-β synthesis, any agent that blocks or inhibits the binding of TGF-β to a TGF-β receptor, and any agent that blocks or inhibits TGF-β receptor-mediated signal transduction. Unless otherwise expressly stated, every reference to a "TGF-β antagonist" herein will be understood to mean a TGF-β antagonist other than pirfenidone or a pirfenidone analog.

[0051] As used herein, the term "endothelin receptor antagonist" refers to any agent that blocks or inhibits the binding of endothelin to an endothelin receptor, and any agent that blocks or inhibits endothelin receptor-mediated signal transduction.

[0052] As used herein, the term "a Type II interferon receptor agonist" refers to any naturally- occurring or non-naturally-occurring ligand of a human Type II interferon receptor which binds to and causes signal transduction via the receptor. Type II interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like.

[0053] The term "dosing event" as used herein refers to administration of an antiviral agent to a patient in need thereof, which event may encompass one or more releases of an antiviral agent from a drug dispensing device. Thus, the term "dosing event," as used herein, includes, but is not limited to, installation of a continuous delivery device (e.g., a pump or other controlled release injectible system); and a single subcutaneous injection followed by installation of a continuous delivery system.

[0054] "Continuous delivery" as used herein (e.g. , in the context of "continuous delivery of a substance to a tissue") is meant to refer to movement of drug to a delivery site, e.g. , into a tissue in a fashion that provides for delivery of a desired amount of substance into the tissue over a selected period of time, where about the same quantity of drug is received by the patient each minute during the selected period of time. [0055] "Controlled release" as used herein (e.g. , in the context of "controlled drug release") is meant to encompass release of substance at a selected or otherwise controllable rate, interval, and/or amount, which is not substantially influenced by the environment of use. "Controlled release" thus encompasses, but is not necessarily limited to, substantially continuous delivery, and patterned delivery (e.g., intermittent delivery over a period of time that is interrupted by regular or irregular time intervals).

[0056] "Patterned" or "temporal" as used in the context of drug delivery is meant delivery of drug in a pattern, generally a substantially regular pattern, over a pre-selected period of time (e.g., other than a period associated with, for example a bolus injection). "Patterned" or "temporal" drug delivery is meant to encompass delivery of drug at an increasing, decreasing, substantially constant, or pulsatile, rate or range of rates (e.g., amount of drug per unit time, or volume of drug formulation for a unit time), and further encompasses delivery that is continuous or substantially continuous, or chronic.

[0057] The term "controlled drug delivery device" is meant to encompass any device wherein the release (e.g., rate, timing of release) of a drug or other desired substance contained therein is controlled by or determined by the device itself and not substantially influenced by the environment of use, or releasing at a rate that is reproducible within the environment of use.

[0058] By "substantially continuous" as used in, for example, the context of "substantially continuous infusion" or "substantially continuous delivery" is meant to refer to delivery of drug in a manner that is substantially uninterrupted for a pre-selected period of drug delivery, where the quantity of drug received by the patient during any 8 hour interval in the pre-selected period never falls to zero. Furthermore, "substantially continuous" drug delivery can also encompass delivery of drug at a substantially constant, pre-selected rate or range of rates (e.g., amount of drug per unit time, or volume of drug formulation for a unit time) that is substantially uninterrupted for a pre-selected period of drug delivery.

[0059] By "substantially steady state" as used in the context of a biological parameter that may vary as a function of time, it is meant that the biological parameter exhibits a substantially constant value over a time course, such that the area under the curve defined by the value of the biological parameter as a function of time for any 8 hour period during the time course (AUCs_hr) is no more than about 20% above or about 20% below, and preferably no more than about 15% above or about 15% below, and more preferably no more than about 10% above or about 10%) below, the average area under the curve of the biological parameter over an 8 hour period during the time course (AUC₈h_r average)- The AUC₈h_r average is defined as the quotient (q) of the area under the curve of the biological parameter over the entirety of the time course (AUCtotai) divided by the number of 8 hour intervals in the time course (t_totaiι/3days), i-e., q = (AUCtotai)/ (ttotaiι/3days)- For example, in the context of a serum concentration of a drug, the serum concentration of the drug is maintained at a substantially steady state during a time course when the area under the curve of serum concentration of the drug over time for any 8 hour period during the time course (AUC_8hr) is no more than about 20% above or about 20% below the average area under the curve of serum concentration of the drug over an 8 hour period in the time course (AUC₈h_r average), i-e-, the AUC₈j,_r is no more than 20% above or 20% below tl e AUC₈h_r a_verage for the serum concentration of the drug over the time course.

[0060] The term "therapeutically effective amount" is meant an amount of a therapeutic agent, or a rate of delivery of a therapeutic agent, effective to facilitate a desired therapeutic effect. The precise desired therapeutic effect will vary according to the condition to be treated, the formulation to be administered, and a variety of other factors that are appreciated by those of ordinary skill in the art.

[0061] In many embodiments, the effective amounts of (i) pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist and (ii) TGF-β antagonist or an endothelin receptor antagonist, are synergistic amounts. As used herein, a "synergistic combination" or a "synergistic amount" of (i) pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist and (ii) TGF-β antagonist or an endothelin receptor antagonist, is a combination or amount that is more effective in the therapeutic or prophylactic treatment of a fibrotic disorder than the incremental improvement in treatment outcome that could be predicted or expected from a merely additive combination of (i) the therapeutic or prophylactic benefit of the pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist when administered at that same dosage as a monotherapy and (ii) the therapeutic or prophylactic benefit of the TGF- β antagonist or an endothelin receptor antagonist when administered at the same dosage as a monotherapy.

[0062] In some embodiments of the invention, a selected amount of pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and a selected amount of TGF-β antagonist or endothelin receptor antagonist are effective when used in combination or triple therapy for a fibrotic disease, but the selected amount of the pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, or the selected amount of TGF-β antagonist or endothelin receptor antagonist is ineffective when used in monotherapy for the disease, or combination(s) of any two of the foregoing drugs are ineffective when used in double therapy for the disease.

[0063] Thus, the invention encompasses: (1) regimens in which a selected amount of pirfenidone, pirfenidone analog, or Type II interferon receptor agonist enhances the therapeutic benefit of a selected amount of TGF-β antagonist or endothelin receptor antagonist when used in combination therapy for a disease, where the selected amount of pirfenidone, pirfenidone analog or Type II interferon receptor agonist provides no therapeutic benefit when used in monotherapy for the disease; (2) regimens in which a selected amount of a TGF-β antagonist or endothelin receptor antagonist enhances the therapeutic benefit of a selected amount of pirfenidone, pirfenidone analog or a Type II interferon receptor agonist when used in combination therapy for a disease, where the selected amount of TGF-β antagonist or endothelin receptor antagonist provides no therapeutic benefit when used in monotherapy for the disease; and (3) regimens in which a selected amount of pirfenidone, pirfenidone analog or Type II interferon receptor agonist and a selected amount of TGF-β antagonist or endothelin receptor antagonist provide a therapeutic benefit when used in combination therapy for a disease, where each of the selected amounts of the pirfenidone, pirfenidone analog or Type II interferon receptor agonist and TGF-β antagonist or endothelin receptor antagonist, respectively, provide no therapeutic benefit when used in monotherapy for the disease. [0064] As used herein, a "synergistically effective amount" or "synergistically effective combination" of pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and TGF-β antagonist or an endothelin receptor antagonist, and its grammatical equivalents, shall be understood to include any regimen encompassed by any of (l)-(3) above.

[0065] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0066] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between tl e upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0067] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

[0068] It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pirfenidone analog" includes a plurality of such analogs and reference to "the dose" includes reference to one or more doses and equivalents thereof known to those skilled in the art, and so forth. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only," and the like in com ection with the recitation of claim elements, or use of a "negative" limitation.

[0069] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.

DETAILED DESCRIPTION OF THE INVENTION

[0070] The present invention provides methods for treating a fibrotic disorder in an individual having a fibrotic disorder. Of particular interest in many embodiments is treatment of humans.

[0071] The method generally involves administering an effective amount of pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist and a TGF-β antagonist or endothelin receptor antagonist. The methods provide for treatment of fibrotic diseases, including those affecting the lung such as idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, liver fibrosis or cirrhosis, cardiac and renal fibrosis. The etiology may be due to any acute or chronic insult including toxic, metabolic, genetic and infectious agents.

[0072] Fibrosis is generally characterized by the pathologic or excessive accumulation of collagenous connective tissue. Fibrotic disorders include, but are not limited to, collagen disease, interstitial lung disease, human fibrotic lung disease (e.g., obliterative bronchiolitis, idiopathic pulmonary fibrosis, pulmonary fibrosis from a known etiology, tumor stroma in lung disease, systemic sclerosis affecting the lungs, Hermansky-Pudlak syndrome, coal worker's pneumoconiosis, asbestosis, silicosis, chronic pulmonary hypertension, AIDS-associated pulmonary hypertension, sarcoidosis, and the like), fibrotic vascular disease, arterial sclerosis, atherosclerosis, varicose veins, coronary infarcts, cerebral infarcts, myocardial fibrosis, musculoskeletal fibrosis, post-surgical adhesions, human kidney disease (e.g., nephritic syndrome, Alport' s syndrome, HIV-associated nephropathy, polycystic kidney disease, Fabry's disease, diabetic nephropathy, chronic glomerulonephritis, nephritis associated with systemic lupus, and the like), cutis keloid formation, progressive systemic sclerosis (PSS), primary sclerosing cholangitis (PSC), liver fibrosis, liver cirrhosis, renal fibrosis, pulmonary fibrosis, cystic fibrosis, chronic graft versus host disease, scleroderma (local and systemic), Grave's opthalmopathy, diabetic retinopathy, glaucoma, Peyronie's disease, penis fibrosis, urethrostenosis after the test using a cystoscope, inner accretion after surgery, scarring, myelofibrosis, idiopathic retroperitoneal fibrosis, peritoneal fibrosis from a known etiology, drug-induced ergotism, fibrosis incident to benign or malignant cancer, fibrosis incident to microbial infection (e.g., viral, bacterial, parasitic, fungal, etc.), Alzheimer's disease, fibrosis incident to inflammatory bowel disease (including stricture formation in Crohn's disease and microscopic colitis), fibrosis induced by chemical or environmental insult (e.g., cancer chemotherapy, pesticides, radiation (e.g., cancer radiotherapy), and the like), and the like.

[0073] In some embodiments, effective amounts of a pirfenidone, pirfenidone analog or Type II interferon receptor agonist and a TGF-β antagonist or endothelin receptor antagonist are amounts that, when administered in combination therapy, are effective to reduce fibrosis or reduce the rate of progression of fibrosis by at least about 10%, at least about 15%, at least about 20%), at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared with the degree of fibrosis in the individual prior to treatment with the combination therapy or compared to the rate of progression of fibrosis that would have been experienced by the patient in the absence of the subject therapy.

[0074] In some embodiments, effective amounts of pirfenidone, pirfenidone analog or Type II interferon receptor agonist and a TGF-β antagonist or endothelin receptor antagonist are amounts that, when administered in combination therapy, are effective to increase, or are - effective to reduce the rate of deterioration of, at least one function of the organ affected by fibrosis (e.g., lung, liver, kidney, etc.) by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, or at least about 50%, or more, compared to the basal level of organ function in the individual prior to treatment with the combination therapy or compared to the rate of deterioration in organ function that would have been experienced by the individual in the absence of the subject therapy.

[0075] Methods of measuring the extent of fibrosis in a given organ, and methods of measuring the function of any given organ, are well known in the art.

[0076] The therapy of the invention is effective in reducing clinical symptoms, reducing morbidity or mortality, or reducing risk of death. These clinical outcomes are readily determined by those skilled in the art. Clinical outcome parameters for fibrotic disorders are readily measured by known assays.

[0077] In some embodiments, the present invention provides methods of treating a fibrotic condition that involve administering a synergistic combination of pirfenidone, pirfenidone analog or Type II interferon receptor agonist and a TGF-β antagonist or endothelin receptor antagonist.

[0078] The invention also provides a method for treatment of a fibrotic disease, such as IPF, liver fibrosis or renal fibrosis, in an individual comprising administering to the individual a combination of pirfenidone, pirfenidone analog or Type II interferon receptor agonist and a TGF-β antagonist or endothelin receptor antagonist that is effective for prophylaxis or therapy of fibrotic disease in the individual, e.g., increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual, while reducing the incidence or severity of one or more side effects that would ordinarily arise from treatment with an effective amount of pirfenidone, pirfenidone analog or Type II interferon receptor agonist or a TGF-β antagonist or endothelin receptor antagonist alone. Idiopathic Pulmonary Fibrosis

[0079] The present invention provides methods of treating idiopathic pulmonary fibrosis (IPF). The methods generally involve administering to an individual having IPF effective amounts of pirfenidone, pirfenidone analog or Type II interferon receptor agonist, and a TGF-β antagonistor an endothelin receptor antagonist.

[0080] In some embodiments, a diagnosis of IPF is confirmed by the finding of usual interstitial pneumonia (UIP) on histopathological evaluation of lung tissue obtained by surgical biopsy. The criteria for a diagnosis of IPF are known. Ryu et al. (1998) Mayo Clin. Proc. 73:1085-1101.

[0081] In other embodiments, a diagnosis of IPF is a definite or probable IPF made by high resolution computer tomography (HRCT). In a diagnosis by HRCT, the presence of the following characteristics is noted: (1) presence of reticular abnormality and/or traction bronchiectasis with basal and peripheral predominance; (2) presence of honeycombing with basal and peripheral predominance; and (3) absence of atypical features such as micronodules, peribronchovascular nodules, consolidation, isolated (non-honeycomb) cysts, ground glass attenuation (or, if present, is less extensive than reticular opacity), and mediastinal adenopathy (or, if present, is not extensive enough to be visible on chest x-ray). A diagnosis of definite IPF is made if characteristics (1), (2), and (3) are met. A diagnosis of probable IPF is made if characteristics (1) and (3) are met.

[0082] In some embodiments, "effective amounts" of pirfenidone, pirfenidone analog or Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are any combined dosage that is effective to decrease disease progression by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, or more, compared with a placebo control or an untreated control.

[0083] Disease progression is the occurrence of one or more of the following: (1) a decrease in predicted FVC of 10% or more; (2) an increase in A-a gradient of 5 mm Hg or more; (3) a decrease of 15% or more in single breath DL_C0. Whether disease progression has occurred is determined by measuring one or more of these parameters on two consecutive occasions 4 to 14 weeks apart, and comparing the value to baseline.

[0084] Thus, e.g., where an untreated or placebo-treated individual exhibits a 50% decrease in FVC over a period of time, an individual administered with an effective combination of pirfenidone, pirfenidone analog or Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist exhibits a decrease in FVC of 45%, about 42%, about 40%, about 37%, about 35%, about 32%, about 30%, or less, over the same time period.

[0085] In some embodiments, "effective amounts" of pirfenidone, pirfenidone analog or Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are any combined dosage that is effective to increase progression-free survival time, e.g., the time from baseline (e.g., a time point from 1 day to 28 days before beginning of treatment) to death or disease progression is increased by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3 -fold, at least about 4-fold, at least about 5 -fold, or more, compared a placebo-treated or an untreated control individual. Thus, e.g., in some embodiments effective amounts of pirfenidone, pirfenidone analog or a Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are any combined dosage that is effective to increase the progression-free survival time by at least about 1 week, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 8 months, at least about 10 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, or longer, compared to a placebo-treated or untreated control.

[0086] In some embodiments, effective amounts of pirfenidone, pirfenidone analog or Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are any combined dosage that is effective to increase at least one parameter of lung function, e.g., effective amounts of pirfenidone, pirfenidone analog or Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are any combined dosage that increases at least one parameter of lung function by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3 -fold, at least about 4-fold, at least about 5 -fold, or more, compared to an untreated individual or a placebo-treated control individual. In some of these embodiments, a determination of whether a parameter of lung function is increased is made by comparing the baseline value with the value at any time point after the beginning of treatment, e.g., 48 weeks after the beginning of treatment, or between two time points, e.g., about 4 to about 14 weeks apart, after the beginning of treatment.

[0087] In some embodiments, effective amounts of pirfenidone, pirfenidone analog or Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are any combined dosage that is effective to increase the FVC by at least about 10% at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3 -fold, at least about 4-fold, at least about 5 -fold, or more compared to baseline on two consecutive occasions 4 to 14 weeks apart.

[0088] In some of these embodiments, effective amounts of pirfenidone, pirfenidone analog or Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are any combined dosage that results in a decrease in alveolaπarterial (A-a) gradient of at least about 5 mm Hg, at least about 7 mm Hg, at least about 10 mm Hg, at least about 12 mm Hg, at least about 15 mm Hg, or more, compared to baseline.

[0089] In some of these embodiments, effective amounts of pirfenidone, pirfenidone analog or Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are any combined dosage that increases the single breath DL_C0 by at least about 15%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 2-fold, at least about 3- fold, at least about 4-fold, at least about 5-fold, or more, compared to baseline. DL_C0 is the lung diffusing capacity for carbon monoxide, and is expressed as mL CO/mm Hg/second.

[0090] Parameters of lung function include, but are not limited to, forced vital capacity (FVC); forced expiratory volume (FEVi); total lung capacity; partial pressure of arterial oxygen at rest; partial pressure of arterial oxygen at maximal exertion.

[0091] Lung function can be measured using any known method, including, but not limited to spirometry.

[0092] The subject methods are suitable for the treatment of individuals diagnosed as having IPF. The methods are also suitable for treatment of individuals having IPF who were treated with corticosteroids within the previous 24 months, and who failed to respond to such corticosteroid therapy. IPF patients who are particularly amenable to treatment with the subject methods are characterized by an initial FVC that is at least about 55% of the predicted normal FVC. Also suitable for treatment are IPF patients characterized by an initial FVC that is at least about 60%, or from about 55% to about 70%, of the predicted normal FVC. The percent of predicted normal FVC are based on normal FVC values that are known in the art. See, e.g., Crapo et al, (1981) Am. Rev. Respir. Dis., 123:659-664. FVC is measured using standards methods of spirometry.

[0093] Other IPF patients suitable for treatment with the subject methods are characterized by an initial carbon monoxide diffusing capacity (DLco) ≥ 25%, or > 30%, or > 35%, of predicted normal DLco-

[0094] Also suitable for treatment with the subject methods are IPF patients characterized by (1) an initial DLco ≥ 35% of predicted normal DLco and (2) an initial FVC that is at least about 55%o of the predicted normal FVC.

[0095] Additionally suitable for treatment with the subject methods are IPF patients characterized by (1) an initial DLco ≥ 0% of predicted normal DLco and (2) an initial FVC that is at least about 55% of the predicted normal FVC. Liver Fibrosis

[0096] The present invention provides methods of treating liver fibrosis, including reducing clinical liver fibrosis, reducing the likelihood that liver fibrosis will occur, and reducing a parameter associated with liver fibrosis. The methods generally involve administering an effective combination of pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist to an individual in need thereof. Of particular interest in many embodiments is treatment of humans.

[0097] Liver fibrosis is a precursor to the complications associated with liver cirrhosis, such as portal hypertension, progressive liver insufficiency, and hepatocellular carcinoma. A reduction in liver fibrosis thus reduces the incidence of such complications. Accordingly, the present invention further provides methods of reducing the likelihood that an individual will develop complications associated with cirrhosis of the liver.

[0098] The present methods generally involve administering therapeutically effective amounts of pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist. As used herein, "effective amounts" of pirfenidone, pirfenidone analog or Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are any combined dosage that is effective in reducing liver fibrosis or reducing the rate of progression of liver fibrosis; and/or that is effective in reducing the likelihood that an individual will develop liver fibrosis; and/or that is effective in reducing a parameter associated with liver fibrosis; and/or that is effective in reducing a disorder associated with cirrhosis of the liver.

[0099] The invention also provides a method for treatment of liver fibrosis in an individual comprising administering to the individual amounts of pirfenidone, pirfenidone analog or Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist that are effective for prophylaxis or therapy of liver fibrosis in the individual, e.g., increasing the probability of survival, reducing the risk of death, ameliorating the disease burden or slowing the progression of disease in the individual.

[00100] Whether treatment with a combination of pirfenidone, pirfenidone analog or Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist is effective in reducing liver fibrosis can be determined by any of a number of well-established techniques for measuring liver fibrosis and liver function. Whether liver fibrosis is reduced is determined by analyzing a liver biopsy sample. An analysis of a liver biopsy comprises assessments of two major components: necroinflammation assessed by "grade" as a measure of the severity and ongoing disease activity, and the lesions of fibrosis and parenchymal or vascular remodeling as assessed by "stage" as being reflective of long-term disease progression. See, e.g., Brunt (2000) Hepatol. 31:241-246; and METAVIR (1994) Hepatology 20:15-20. Based on analysis of the liver biopsy, a score is assigned. A number of standardized scoring systems exist which provide a quantitative assessment of the degree and severity of fibrosis. These include the METAVIR, Knodell, Scheuer, Ludwig, and Ishak scoring systems. [00101] The METAVIR scoring system is based on an analysis of various features of a liver biopsy, including fibrosis (portal fibrosis, centrilobular fibrosis, and cirrhosis); necrosis (piecemeal and lobular necrosis, acidophilic retraction, and ballooning degeneration); inflammation (portal tract inflammation, portal lymphoid aggregates, and distribution of portal inflammation); bile duct changes; and the Knodell index (scores of periportal necrosis, lobular necrosis, portal inflammation, fibrosis, and overall disease activity). The definitions of each stage in the METAVIR system are as follows: score: 0, no fibrosis; score: 1, stellate enlargement of portal tract but without septa formation; score: 2, enlargement of portal tract with rare septa formation; score: 3, numerous septa without cirrhosis; and score: 4, cirrhosis.

[00102] Knodell's scoring system, also called the Hepatitis Activity Index, classifies specimens based on scores in four categories of histologic features: I. Periportal and/or bridging necrosis; II. Intralobular degeneration and focal necrosis; III. Portal inflammation; and IV. Fibrosis. In the Knodell staging system, scores are as follows: score: 0, no fibrosis; score: 1, mild fibrosis (fibrous portal expansion); score: 2, moderate fibrosis; score: 3, severe fibrosis (bridging fibrosis); and score: 4, cirrhosis. The higher the score, the more severe the liver tissue damage. Knodell (1981) Hepatol. 1:431.

[00103] In the Scheuer scoring system scores are as follows: score: 0, no fibrosis; score: 1, enlarged, fibrotic portal tracts; score: 2, periportal or portal-portal septa, but intact architecture; score: 3, fibrosis with architectural distortion, but no obvious cirrhosis; score: 4, probable or definite cirrhosis. Scheuer (1991) J Hepatol. 13:372.

[00104] The Ishak scoring system is described in Ishak (1995) J Hepatol. 22:696-699. Stage 0, No fibrosis; Stage 1, Fibrous expansion of some portal areas, with or without short fibrous septa; stage 2, Fibrous expansion of most portal areas, with or without short fibrous septa; stage 3, Fibrous expansion of most portal areas with occasional portal to portal (P-P) bridging; stage 4, Fibrous expansion of portal areas with marked bridging (P-P) as well as portal-central (P-C); stage 5, Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); stage 6, Cirrhosis, probable or definite .

[00105] The benefit of anti-fibrotic therapy can also be measured and assessed by using tl e Child-Pugh scoring system which comprises a multicomponent point system based upon abnormalities in serum bilirubin level, serum albumin level, prothrombin time, the presence and severity of ascites, and the presence and severity of encephalopathy. Based upon tlie presence and severity of abnormality of these parameters, patients may be placed in one of three categories of increasing severity of clinical disease: A, B, or C. [00106] In some embodiments, therapeutically effective amounts of pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are any combined dosage that effects a change of one unit or more in the fibrosis stage based on pre- and post-therapy liver biopsies. In particular embodiments, therapeutically effective amounts of pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagomst reduce liver fibrosis by at least one unit in the METAVIR, the Knodell, the Scheuer, the Ludwig, or the Ishak scoring system.

[00107] Secondary, or indirect, indices of liver function can also be used to evaluate the efficacy of treatment with the subject therapy. Morphometric computerized semi-automated assessment of the quantitative degree of liver fibrosis based upon specific staining of collagen and/or serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Secondary indices of liver function include, but are not limited to, serum transaminase levels, prothrombin time, bilirubin, platelet count, portal pressure, albumin level, and assessment of the Child-Pugh score.

[00108] In another embodiment, effective amounts of pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are any combined dosage that is effective to increase an index of liver function by at least about 10%), at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the index of liver function in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such indices of liver function, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings.

[00109] In another embodiment, effective amounts of pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are any combined dosage effective to slow the decline in an index of liver function by at least about 10%, at least about 20%, at least about 25%, at least about 30%,-at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the decline in the index of liver function that would occur in an untreated individual, or in a placebo-treated individual.

[00110] Serum markers of liver fibrosis can also be measured as an indication of the efficacy of a subject treatment method. Serum markers of liver fibrosis include, but are not limited to, hyaluronate, N-terminal procollagen III peptide, 7S domain of type IV collagen, C-terminal procollagen I peptide, and laminin. Additional biochemical markers of liver fibrosis include α- 2-macroglobulin, haptoglobin, gamma globulin, apolipoprotein A, and gamma glutamyl transpeptidase.

[00111] In another embodiment, therapeutically effective amounts of pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are any combined dosage that is effective to reduce the rate of increase in the serum level of a marker of liver fibrosis by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to the rate of increase in the level of the marker that would occur in an untreated individual, or in a placebo-treated individual. Those skilled in the art can readily measure such serum markers of liver fibrosis, using standard assay methods, many of which are commercially available, and are used routinely in clinical settings. Methods of measuring serum markers include immunological-based methods, e.g., enzyme- linked immunosorbent assays (ELISA), radioimmunoassays, and the like, using antibody specific for a given serum marker.

[00112] Quantitative tests of functional liver reserve can also be used to assess the efficacy of treatment with the subject therapy. These include: indocyanine green clearance (ICG), galactose elimination capacity (GEC), aminopyrine breath test (ABT), antipyrine clearance, monoethylglycine-xylidide (MEG-X) clearance, and caffeine clearance.

[00113] As used herein, a "complication associated with cirrhosis of the liver" refers to a disorder that is a sequellae of decompensated liver disease, i.e., or occurs subsequently to and as a result of development of liver fibrosis, and includes, but is not limited to, development of ascites, variceal bleeding, portal hypertension, jaundice, progressive liver insufficiency, encephalopathy, hepatocellular carcinoma, liver failure requiring liver transplantation, and liver-related mortality.

[00114] In another embodiment, therapeutically effective amounts of pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are any combined dosage that is effective in reducing the incidence of (e.g., the likelihood that an individual will develop) a disorder associated with cirrhosis of the liver by at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, or at least about 80%, or more, compared to an untreated individual, or in a placebo-treated individual.

[00115] Whether combination therapy with pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist is effective in reducing the incidence of a disorder associated with cirrhosis of the liver can readily be determined by those skilled in the art.

[00116] Reduction in liver fibrosis increases liver function. Thus, the invention provides methods for increasing liver function, generally involving administering therapeutically effective amounts of pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist. Liver functions include, but are not limited to, synthesis of proteins such as serum proteins (e.g., albumin, clotting factors, alkaline phosphatase, aminotransferases (e.g., alanine transaminase, aspartate transaminase), 5'- nucleosidase, γ-glutaminyltranspeptidase, etc.), synthesis of bilirubin, synthesis of cholesterol, and synthesis of bile acids; a liver metabolic function, including, but not limited to, carbohydrate metabolism, amino acid and ammonia metabolism, hormone metabolism, and lipid metabolism; detoxification of exogenous drugs; ahemodynamic function, including splanchnic and portal hemodynamics; and the like.

[00117] Whether a liver function is increased is readily ascertainable by those skilled in the art, using well-established tests of liver function. Thus, synthesis of markers of liver function such as albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase, bilirubin, and the like, can be assessed by measuring the level of these markers in the serum, using standard immunological and enzymatic assays. Splanchnic circulation and portal hemodynamics can be measured by portal wedge pressure and/or resistance using standard methods. Metabolic functions can be measured by measuring the level of ammonia in the serum.

[00118] Whether serum proteins normally secreted by the liver are in the normal range can be determined by measuring the levels of such proteins, using standard immunological and enzymatic assays. Those skilled in the art know the normal ranges for such serum proteins. The following are non-limiting examples. The normal range of alanine transaminase is from about 7 to about 56 units per liter of serum. The normal range of aspartate transaminase is from about 5 to about 40 units per liter of serum. Bilirubin is measured using standard assays. Normal bilirubin levels are usually less than about 1.2 mg/dL. Serum albumin levels are measured using standard assays. Normal levels of serum albumin are in the range of from about 35 to about 55 g/L. Prolongation of prothrombin time is measured using standard assays. Normal prothrombin time is less than about 4 seconds longer than control. [00119] In another embodiment, therapeutically effective amounts of pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are any combined dosage that is effective to increase liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more. For example, therapeutically effective amounts of pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are any combined dosage that is effective to reduce an elevated level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to reduce the level of the serum marker of liver function to within a normal range. Therapeutically effective amounts of pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are also any combined dosage effective to increase a reduced level of a serum marker of liver function by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or more, or to increase the level of the serum marker of liver function to within a normal range. Renal Fibrosis

[00120] Renal fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM) components. Overproduction of transforming growth factor-beta (TGF-β) is believed to underlie tissue fibrosis caused by excess deposition of ECM, resulting in disease. TGF-β' s fibrogenic action results from simultaneous stimulation of matrix protein synthesis, inhibition of matrix degradation and enhanced integrin expression that facilitates ECM assembly.

[00121] The present invention provides methods of treating renal fibrosis. The methods generally involve administering to an individual having renal fibrosis effective amounts of pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist. As used herein, "effective amounts" of pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are any combined dosage that is effective in reducing renal fibrosis; and/or is effective in reducing the rate of progression of renal fibrosis; and/or that is effective in reducing the likelihood that an individual will develop renal fibrosis; and/or that is effective in reducing a parameter associated with renal fibrosis; and/or that is effective in reducing a disorder associated with fibrosis of the kidney. [00122] In one embodiment, effective amounts of pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are any combined dosage that is sufficient to reduce renal fibrosis, or reduce the rate of progression of renal fibrosis, by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the degree of renal fibrosis in the individual prior to treatment, or compared to the rate of progression of renal fibrosis that would have been experienced by the patient in the absence of treatment.

[00123] Whether fibrosis is reduced in the kidney is determined using any known method. For example, histochemical analysis of kidney biopsy samples for the extent of ECM deposition and/or fibrosis is performed. Other methods are known in the art. See, e.g., Masseroli et al. (1998) Lab. Invest. 78:511-522; U.S. Patent No. 6,214,542.

[00124] In some embodiments, effective amounts of pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are any combined dosage that is effective to increase kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, compared to the basal level of kidney function in the individual prior to treatment.

[00125] In some embodiments, effective amounts of pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, and a TGF-β antagonist or endothelin receptor antagonist are any combined dosage that is effective to slow the decline in kidney function by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%), at least about 45%, at least about 50%, compared to the decline in kidney function that would occur in the absence of treatment.

[00126] Kidney function can be measured using any known assay, including, but not limited to, plasma creatinine level (where normal levels are generally in a range of from about 0.6 to about 1.2 mg/dL); creatinine clearance (where the normal range for creatinine clearance is from about 97 to about 137 mL/minute in men, and from about 88 to about 128 mL/minute in women); the glomerular filtration rate (either calculated or obtained from inulin clearance or other methods), blood urea nitrogen (where the normal range is from about 7 to about 20 mg/dL); and urine protein levels. Pirfenidone and Analogs Thereof

[00127] Pirfenidone (5-methyl-l-phenyl-2-(lH)-pyridone) and pirfenidone analogs are used in certain combination therapies of the invention. Pirfenidone

Pirfenidone analogs I.

II.A II.B

Descriptions for Substituents R_1? R₂, X

[00128] Ri: carbocyclic (saturated and unsaturated), heterocyclic (saturated or unsaturated), alky Is (saturated and unsaturated). Examples include phenyl, benzyl, pyrimidyl, naphthyl, indolyl, pyrrolyl, furyl, thienyl, imidazolyl, cyclohexyl, piperidyl, pyrrolidyl, morpholinyl, cyclohexenyl, butadienyl, and the like.

[00129] Ri can further include substitutions on the carbocyclic or heterocyclic moieties with substituents such as halogen, nitro, amino, hydroxyl, alkoxy, carboxyl, cyano, thio, alkyl, aryl, heteroalkyl, heteroaryl and combinations thereof, for example, 4-nitrophenyl, 3-chlorophenyl, 2,5-dinitrophenyl, 4-methoxyphenyl, 5-methyl-pyrrolyl, 2, 5-dichlorocyclohexyl, guanidinyl- cyclohexenyl and the like.

[00130] R₂: alkyl, carbocylic, aryl, heterocyclic. Examples include: methyl, ethyl, propyl, isopropyl, phenyl, 4-nitrophenyl, thienyl and the like.

[00131] X: may be any number (from 1 to 3) of substituents on the carbocyclic or heterocyclic ring. The substituents can be the same or different. Substituents can include hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, halo, nitro, carboxyl, hydroxyl, cyano, amino, thio, alkylamino, haloaryl and the like. [00132] The substituents may be optionally further substituted with 1-3 substituents from the group consisting of alkyl, aryl, nitro, alkoxy, hydroxyl and halo groups. Examples include: methyl, 2,3-dimethyl, phenyl, p-tolyl, 4-chlorophenyl, 4-nitrophenyl, 2,5-dichlorophenyl, furyl, thienyl and the like.

[00133] Specific Examples include those shown in Table 1 : Table 1 IA IIB

[00134] U.S. Pat. Nos. 3,974,281; 3,839,346; 4,042,699; 4,052,509; 5,310,562; 5,518,729; 5,716,632; and 6,090,822 describe methods for the synthesis and formulation of pirfenidone and pirfenidone analogs in pharmaceutical compositions suitable for use in the metliods of the present invention. TGF-β Antagonists

[00135] TGF-β antagonists suitable for use in a subject treatment method include agents that decrease the level of TGF-β synthesis, agents that block or inhibit the binding of TGF-β to a TGF-β receptor, and agents that block or inhibit TGF-β-receptor-mediated signal transduction. As used herein, the term "TGF-β" includes any TGF-β subtype, including TGF-β 1, TGF-β2, and TGF-β3. Suitable TGF-β antagonists include, but are not limited to, antibodies specific for TGF-β (including antibodies specific for a particular TGF-β subtype; and antibodies cross- reactive with two or more TGF-β subtypes); antibodies to TGF-β receptor; soluble TGF-β receptor; decorin; and agents that inhibit TGF-β signaling.

[00136] Suitable TGF-β antagonists include antibodies specific for TGF-β. Antibodies specific for TGF-β are known in the art. See, e.g., U.S. Patent Nos. 5,783,185, 5,772,998, 5,674,843, 5,571,714, 5,462,925, and 5,426,098; WO 97/13844; and U.S. Patent Publication Nos 20030064069 and 20030091566. Non-limiting examples of suitable anti-TGF-β antibodies include CAT- 152 (lerdelibumab; Trabio™; Cambridge Antibody Technology), a human anti- TGF-β2 monoclonal antibody; CAT- 192 (metelimumab; Cambridge Antibody Technology), a human anti-TGF-βl monoclonal antibody; and GC-1008 (Genzyme Corp.), a pan-specific human monoclonal antibody to TGF-β 1, TGF-β2, and TGF-β3.

[00137] Suitable TGF-β antagonists include soluble TGF-β receptors. Soluble TGF-β receptors typically lack most or all of the transmembrane portion of a naturally-occurring TGF-β receptor, such that the protein is not membrane bound, yet retains TGF-β binding. Soluble TGF-β receptors include soluble fusion proteins comprising a portion of a TGF-β receptor fused in-frame to a heterologous (non-TGF-β receptor) protein (a "fusion partner"). Non- limiting examples of fusion partners are immunoglobulin Fc, poly-histidine, and the like. Soluble TGF-β receptors have been described in the art. See, e.g., Wang et al. (1999) Thorax 54:805-812; George et al. (1999) Proc. Natl Acad. Sci. USA 96:12719-12724; Muraoka et al. (2002) J. Clin. Invest. 109:1551-1559; and Yata et al. (2002) Hepatology 35:1022-1030.

[00138] TGF-β antagonists include Gleevec™. Gleevec™ (also known as STI-571, or CGP57148B) has the chemical name 4-[(4-methyl-l-piperazinyl)methyl]-N-[4-methyl-3-[[4- (3-pyridinyl)-2-pyrimidinyl]amino-phenyl]benzamide methanesulfonate is commonly known as imatinib mesylate and sold under the trademark Gleevec™. Gleevec™ is a 2- phenylaminopyrimidine that targets the ATP -binding site of the kinase domain of Bcr-Abl tyrosine kinase (see, e.g. Druker et al. (1996) Nature Med. 2, 561; and Buchdunger et al. (1993) Proc. Natl. Acad. Sci. USA 92:2558-2562). [00139] In certain embodiments, the agents are pyrimidine derivatives as described in U.S. Patent No. 5,521,184, the disclosure of which is herein incorporated by reference. In these embodiments, of interest are N-phenyl-2-pyrimidine-amine derivatives of formula (III):

(III)

[00140] wherein

[00141] Rr is 4-pyrazinyl, 1 -methyl- lH-pyrrolyl, amino- or amino-lower alkyl-substituted phenyl wherein the amino group in each case is free, alkylated or acylated, IH-indolyl or 1H- imidazolyl bonded at a five-membered ring carbon atom, or unsubstituted or lower alkyl- substituted pyridyl bonded at a ring carbon atom and unsubstituted or substituted at the nitrogen atom by oxygen, R₂> and R₃> are each independently of the other hydrogen or lower alkyl, one or two of the radicals Rψ, R₅>, R_#, Rv and R₈> are each nitro, fluoro-substituted lower alkoxy or a radical of formula (IN):

-Ν(R₉.)— C(=X)— (Y)_k— Rio (IV)

[00142] wherein

[00143] R_9' is hydrogen or lower alkyl,

[00144] X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl- hydroximino,

[00145] Y is oxygen or the group NH,

[00146] k is 0 or l and

[00147] Rio is an aliphatic radical having at least 5 carbon atoms, or an aromatic, aromatic- aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, heterocyclic or heterocyclic-aliphatic radical,

[00148] and the remaining radicals Rψ, R₅>, Re_', Rr and R₈> are each independently of the others hydrogen, lower alkyl that is unsubstituted or substituted by free or alkylated amino, piperazinyl, piperidinyl, pyrrolidinyl or by morpholinyl, or lower alkanoyl, trifluoromethyl, free, etfierified or esterifed hydroxy, free, alkylated or acylated amino or free or esterified carboxy, [00149] and salts of such compounds having at least one salt-forming group.

[00150] In these embodiments:

[00151] 1 -Methyl- lH-pyrrolyl is preferably 1 -methyl- lH-pyrrol-2-yl or 1 -methyl- lH-pyrrol-3- yi-

[00152] Amino- or amino-lower alkyl-substituted phenyl Ri wherein the amino group in each case is free, alkylated or acylated, is phenyl substituted in any desired position (ortho, meta or para) wherein an alkylated amino group is preferably mono- or di-lower alkylamino, for example dimethylamino, and the lower alkyl moiety of amino-lower alkyl is preferably linear Ci -C₃ alkyl, such as especially methyl or ethyl. IH-Indolyl bonded at a carbon atom of the five-membered ring is lH-indol-2-yl or lH-indol-3- yl.

[00153] Unsubstituted or lower alkyl-substituted pyridyl bonded at a ring carbon atom is lower alkyl-substituted or preferably unsubstituted 2-, or preferably 3- or 4-pyridyl, for example 3- pyridyl, 2-methyl-3 -pyridyl, 4-methyl-3 -pyridyl or 4-pyridyl. Pyridyl substituted at the nitrogen atom by oxygen is a radical derived from pyridine N-oxide, i.e., N-oxido-pyridyl, e.g. N-oxido-4-pyridyl.

[00154] Fluoro-substituted lower alkoxy is lower alkoxy carrying at least one, but preferably several, fluoro substituents, especially trifluoromethoxy or preferably 1,1,2,2-tetrafluoro- ethoxy.

[00155] When X is oxo, thio, imino, N-lower alkyl-imino, hydroximino or O-lower alkyl- hydroximino, the group C=X is, in the above order, a radical C=O, C=S, C=N-H, C=N-lower alkyl, C=N-OH or CN-O-lower alkyl, respectively. X is preferably oxo.

[00156] k is preferably 0, i.e., the group Y is not present.

[00157] Y, if present, is preferably the group NH.

[00158] The term "lower" within the scope of this text denotes radicals having up to and including 7, preferably up to and including 4 carbon atoms.

[00159] Lower alkyl Rr, R_2', R_3' and R₉> is preferably methyl or ethyl.

[00160] An aliphatic radical Rio having at least 5 carbon atoms preferably has not more than 22 carbon atoms, generally not more than 10 carbon atoms, and is such a substituted or preferably unsubstituted aliphatic hydrocarbon radical, that is to say such a substituted or preferably unsubstituted alkynyl, alkenyl or preferably alkyl radical, such as C₅ -C₇ alkyl, for example n- pentyl. An aromatic radical Rio has up to 20 carbon atoms and is unsubstituted or substituted, for example in each case unsubstituted or substituted naphthyl, such as especially 2-naphthyl, or preferably phenyl, the substituents preferably being selected from cyano, unsubstituted or hydroxy-, amino- or 4-methyl-piperazinyl-substituted lower alkyl, such as especially methyl, trifluoromethyl, free, etherified or esterified hydroxy, free, alkylated or acylated amino and free or esterified carboxy. In an aromatic-aliphatic radical Rι₀ the aromatic moiety is as defined above and the aliphatic moiety is preferably lower alkyl, such as especially Ci -C₂ alkyl, which is substituted or preferably unsubstituted, for example benzyl. A cycloaliphatic radical R₁₀ has especially up to 30, more especially up to 20, and most especially up to 10 carbon atoms, is mono- or poly-cyclic and is substituted or preferably unsubstituted, for example such a cycloalkyl radical, especially such a 5- or 6-membered cycloalkyl radical, such as preferably cyclohexyl. In a cycloaliphatic-aliphatic radical R₁₀ the cycloaliphatic moiety is as defined above and the aliphatic moiety is preferably lower alkyl, such as especially Ci -C₂ alkyl, which is substituted or preferably unsubstituted. A heterocyclic radical R₁₀ contains especially up to 20 carbon atoms and is preferably a saturated or unsaturated monocyclic radical having 5 or 6 ring members and 1-3 hetero atoms which are preferably selected from nitrogen, oxygen and sulfur, especially, for example, thienyl or 2-, 3- or 4-pyridyl, or a bi- or tri-cyclic radical wherein, for example, one or two benzene radicals are annellated (fused) to the mentioned monocyclic radical. In a heterocyclic-aliphatic radical R₁₀ the heterocyclic moiety is as defined above and the aliphatic moiety is preferably lower alkyl, such as especially C_\ -C₂ alkyl, which is substituted or preferably unsubstituted.

[00161] Etherified hydroxy is preferably lower alkoxy. Esterified hydroxy is preferably hydroxy esterified by an organic carboxylic acid, such as a lower alkanoic acid, or a mineral acid, such as a hydrohalic acid, for example lower alkanoyloxy or especially halogen, such as iodine, bromine or especially fluorine or chlorine.

[00162] Alkylated amino is, for example, lower alkylamino, such as methylamino, or di-lower alkylamino, such as dimethylamino. Acylated amino is, for example, lower alkanoylamino or benzoylamino.

[00163] Esterified carboxy is, for example, lower alkoxycarbonyl, such as methoxycarbonyl.

[00164] A substituted phenyl radical may carry up to 5 substituents, such as fluorine, but especially in the case of relatively large substituents is generally substituted by only from 1 to 3 substituents. Examples of substituted phenyl that may be given special mention are 4-chlorophenyl, pentafluoro-phenyl, 2-carboxy-phenyl, 2-methoxy-phenyl, 4-fluorophenyl, 4-cyano- phenyl and 4-methyl-phenyl.

[00165] Salt-forming groups in a compound of formula (III) are groups or radicals having basic or acidic properties. Compounds having at least one basic group or at least one basic radical, for example a free amino group, a pyrazinyl radical or a pyridyl radical, may form acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulfuric acid or a phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example aliphatic mono- or di-carboxylic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid or oxalic acid, or amino acids such as arginine or lysine, aromatic carboxylic acids, such as benzoic acid, 2-phenoxy-benzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4- aminosalicylic acid, aromatic-aliphatic carboxylic acids, such as mandelic acid or cinnamic acid, heteroaromatic carboxylic acids, such as nicotinic acid or isonicotinic acid, aliphatic sulfonic acids, such as methane-, ethane- or 2-hydroxyethane-sulfonic acid, or aromatic sulfonic acids, for example benzene-, p-toluene- or naphthalene-2-sulfonic acid. When several basic groups are present mono- or poly-acid addition salts may be formed.

[00166] Compounds of formula (III) having acidic groups, for example a free carboxy group in the radical Rio, may form metal or ammonium salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, or ammonium salts with ammonia or suitable organic amines, such as tertiary monoamines, for example triethylamine or tri-(2-hydroxyethyl)-amine, or heterocyclic bases, for example N-ethylpiperidine or N,N'- dimethyl-piper azine . Compounds of formula (III) having both acidic and basic groups can form internal salts.

[00167] Of particular interest in these embodiments is a pyrimidine derivative in which Rr is 3- pyridyl, R₂>, R₃-, R_5', Re_', and R₈* are each hydrogen, is methyl, and R_7' is a group of formula (IV) in which R_9' is hydrogen, X is oxo, k is 0, and R₁₀ is 4-[(4-methyl-l- piperazinyl)methyl]phenyl. The mesylate salt of this compound having the chemical name 4- [(4-methyl-l-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino- phenyl]benzamide methanesulfonate is now commonly known as imatinib mesylate and sold under the trademark Gleevec™. Endothelin Receptor Antagonists

[00168] Endothelin antagonists suitable for use in the present invention include agents that decrease the level of endothelin synthesis, agents that block or inhibit the binding of endothelin to an endothelin receptor, and agents that block or inhibit endothelin receptor-mediated signal transduction. As used herein, the term "endothelin antagonist" refers to any agent that decreases the level of endothelin synthesis, any agent that blocks or inhibits the binding of endothelin to an endothelin receptor, and any agent that blocks or inhibits endothelin receptor- mediated signal transduction. In some embodiments, an endothelin receptor antagonist is selective for endothelin A (ETA) receptors. In some embodiments, an endothelin receptor antagonist is selective for endothelin B (ETB) receptors. In other embodiments, an endothelin receptor antagonist is an antagonist of both ETA and ETB receptors.

[00169] Specific examples of endothelin antagonists useful in the present invention include, but are not limited to, atrasentan (ABT-627; Abbott Laboratories), Neletri™ (tezosentan; Actelion Pharmaceuticals, Ltd.), sitaxsentan (ICOS-Texas Biotechnology), enrasentan (GlaxoSmithKline), darusentan (LU135252; Myogen) BMS-207940 (Bristol-Myers Squibb), BMS-193884 (Bristol-Myers Squibb), BMS-182874 (Bristol-Myers Squibb), J-104132 (Banyu Pharmaceutical), VML 588/Ro 61-1790 (Vanguard Medica), T-0115 (Tanabe Seiyaku), TAK- 044 (Takeda), BQ-788 (Banyu Pharmaceutical), BQ123, YM-598 (Yamanouchi Pharma), PD 145065 (Parke-Davis), A- 127722 (Abbott Laboratories), A- 192621 (Abbott Laboratories), A- 182086 (Abbott Laboratories), TBC3711 (ICOS-Texas Biotechnology), BSF208075 (Myogen), S-0139 (Shionogi), TBC2576 (Texas Biotechnology), TBC3214 (Texas Biotechnology), PD 156707 (Parke-Davis), PD 180988 (Parke-Davis), ABT-546 (Abbott Laboratories), ABT-627 (Abbott Laboratories), SB247083 (GlaxoSmithKline), SB 209670 (GlaxoSmithKline); and an endothelin receptor antagonists discussed in the art, e.g., Davenport and Battistini (2002) Clinical Science 103:15-35, Wu-Wong et al. (2002) Clinical Science 103:1075-1115, and Luescher and Barton (2000) Circulation 102:2434-2440.

[00170] A suitable endothelin receptor antagonist is TRACLEER™ (bosentan; manufactured by Actelion Pharmaceuticals, Ltd.). TRACLEER™ is an orally active dual endothelin receptor antagonist, and blocks the binding of endothelin to both of its receptors endothelin receptor A and endothelin receptor B.

[00171] TRACLEER™ belongs to a class of highly substituted pyrimidine derivatives, with no chiral centers. It is designated chemically as 4-tert-butyl-Ν-[6-(2-hydroxy-ethoxy)-5-(2- metlιoxy-phenoxy)-[2,2 ]-bipyrimidin-4-yl]-benzenesulfonamide monohydrate and has the following structural formula:

[00172] TRACLEER™ treatment is in some embodiments initiated at a dose of 62.5 mg bid orally for 4 weeks, followed by a maintenance dose of 125 mg bid orally. Type II interferon receptor agonists

[00173] Type II interferon receptor agonists include any naturally occurring or non-naturally- occurring ligand of a human Type II interferon receptor that binds to and causes signal transduction via the receptor. Type II interferon receptor agonists include interferons, including naturally-occurring interferons, modified interferons, synthetic interferons, pegylated interferons, fusion proteins comprising an interferon and a heterologous protein, shuffled interferons; antibody specific for an interferon receptor; non-peptide chemical agonists; and the like.

[00174] A specific example of a Type II interferon receptor agonist is IFN-gamma and variants thereof. While the present invention exemplifies use of an IFN-gamma polypeptide, it will be readily apparent that any Type II interferon receptor agonist can be used in a subject method. Interferon-Gamma

[00175] The nucleic acid sequences encoding IFN-gamma polypeptides may be accessed from public databases, e.g., Genbank, journal publications, and the like. While various mammalian IFN-gamma polypeptides are of interest, for the treatment of human disease, generally the human protein will be used. Human IFN-gamma coding sequence may be found in Genbank, accession numbers X13274; V00543; and NM_000619. The corresponding genomic sequence may be found in Genbank, accession numbers J00219; M37265; and V00536. See, for example. Gray et al. (1982) Nature 295:501 (Genbank X13274); and Rinderknecht et al. (1984) J.B.C. 259:6790.

[00176] IFN-γlb (Actimmune®; human interferon) is a single-chain polypeptide of 140 amino acids. It is made recombinanfly in E.coli and is unglycosylated (Rinderknecht et al. 1984, J. Biol. Chem. 259:6790-6797). Recombinant IFN-gamma as discussed in U.S. Patent No. 6,497,871 is also suitable for use herein.

[00177] The IFN-gamma to be used in the methods of the present invention may be any of natural IFN-gamma, recombinant IFN-gamma and the derivatives thereof so far as they have an IFN-γ activity, particularly human IFN-gamma activity. Human IFN-gamma exhibits the antiviral and anti-proliferative properties characteristic of the interferons, as well as a number of other immunomodulatory activities, as is known in the art. Although IFN-gamma is based on the sequences as provided above, the production of the protein and proteolytic processing can result in processing variants thereof. The unprocessed sequence provided by Gray et al., supra, consists of 166 amino acids (aa). Although the recombinant IFN-gamma produced in E. coli was originally believed to be 146 amino acids, (commencing at amino acid 20) it was subsequently found that native human IFN-gamma is cleaved after residue 23, to produce a 143 aa protein, or 144 aa if the terminal methionine is present, as required for expression in bacteria. During purification, the mature protein can additionally be cleaved at the C terminus after reside 162 (referring to the Gray et al. sequence), resulting in a protein of 139 amino acids, or 140 amino acids if the initial methionine is present, e.g. if required for bacterial expression. The N-terminal methionine is an artifact encoded by the rnRNA translational "start" signal AUG that, in the particular case of E. coli expression is not processed away. In other microbial systems or eukaryotic expression systems, methionine may be removed.

[00178] For use in the subject methods, any of the native IFN-gamma peptides, modifications and variants thereof, or a combination of one or more peptides may be used. IFN-gamma peptides of interest include fragments, and can be variously truncated at the carboxyl terminus relative to the full sequence. Such fragments continue to exhibit the characteristic properties of human gamma interferon, so long as amino acids 24 to about 149 (numbering from the residues of the unprocessed polypeptide) are present. Extraneous sequences can be substituted for the amino acid sequence following amino acid 155 without loss of activity. See, for example, U.S. Patent No. 5,690,925. Native IFN- gamma moieties include molecules variously extending from amino acid residues 24-150; 24-151, 24-152; 24- 153, 24-155; and 24-157. Any of these variants, and other variants known in the art and having IFN-γ activity, may be used in the present methods.

[00179] The sequence of the IFN-γ polypeptide may be altered in various ways known in tl e art to generate targeted changes in sequence. A variant polypeptide will usually be substantially similar to the sequences provided herein, i.e., will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. The sequence changes may be substitutions, insertions or deletions. Scanning mutations that systematically introduce alanine, or other residues, may be used to determine key amino acids. Specific amino acid substitutions of interest include conservative and non-conservative changes. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).

[00180] Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. IFN-gamma may be modified with one or more polyethylene glycol moieties (PEGylated). In one embodiment, the invention contemplates the use of IFN-gamma variants with one or more non-naturally occurring glycosylation and/or pegylation sites that are engineered to provide glycosyl- and/or PEG-derivatized polypeptides with reduced serum clearance, such as the IFN-gamma polypeptide variants described in International Patent Publication No. WO 01/36001 or WO 02/081507. Also included are modifications of glycosylation, e.g., those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g., by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e.g., phosphotyrosine, phosphoserine, or phosphothreonine.

[00181] Included in the subject invention are polypeptides that have been modified using ordinary chemical techniques so as to improve their resistance to proteolytic degradation, to optimize solubility properties, or to render them more suitable as a therapeutic agent. For examples, the backbone of the peptide may be cyclized to enhance stability (see, for example, Friedler et al. 2000, J. Biol. Chem. 275:23783-23789). Analogs may be used that include residues other than naturally occurring L-amino acids, e.g., D-amino acids or non-naturally occurring synthetic amino acids. The protein may be pegylated to enhance stability.

[00182] The polypeptides may be prepared by in vitro synthesis, using conventional methods as known in the art, by recombinant methods, or may be isolated from cells induced or naturally producing the protein. The particular sequence and the manner of preparation will be determined by convenience, economics, purity required, and the like. If desired, various groups may be introduced into the polypeptide during synthesis or during expression, which allow for linking to other molecules or to a surface. Thus cysteines can be used to make thioethers, histidines for linking to a metal ion complex, carboxyl groups for forming amides or esters, amino groups for fonning amides, and the like.

[00183] The polypeptides may also be isolated and purified in accordance with conventional methods of recombinant synthesis. A lysate may be prepared of the expression host and the lysate purified using HPLC, exclusion chromatography, gel electrophoresis, affinity chromatography, or other purification technique. For the most part, the compositions which are used will comprise at least 20% by weight of the desired product, more usually at least about 75% by weight, preferably at least about 95% by weight, and for therapeutic purposes, usually at least about 99.5% by weight, in relation to contaminants related to the method of preparation of the product and its purification. Usually, the percentages will be based upon total protein. TNF Antagonists

[00184] Suitable TNF-α antagonists for use herein include agents that decrease the level of TNF-α synthesis, agents that block or inhibit the binding of TNF-α to a TNF-α receptor (TNFR), and agents that block or inhibit TNFR-mediated signal transduction. Unless otherwise expressly stated, every reference to a "TNF-α antagonist" or "TNF antagonist" herein will be understood to mean a TNF-α antagonist other than pirfenidone or a pirfenidone analog.

[00185] As used herein, the terms "TNF receptor polypeptide" and "TNFR polypeptide" refer to polypeptides derived from TNFR (from any species) that are capable of binding TNF. Two distinct cell-surface TNFRs have described: Type II TNFR (or p75 TNFR or TNFRII) and Type I TNFR (or ρ55 TNFR or TNFRI). The mature full-length human p75 TNFR is a glycoprotein having a molecular weight of about 75-80 kilodaltons (kD). The mature full- length human p55 TNFR is a glycoprotein having a molecular weight of about 55-60 kD. Exemplary TNFR polypeptides are derived from TNFR Type I and/or TNFR type II. Soluble TNFR includes p75 TNFR polypeptide; fusions of p75 TNFR with heterologous fusion partners, e.g., the Fc portion of an immunoglobulin.

[00186] TNFR polypeptide may be an intact TNFR or a suitable fragment of TNFR. U.S. Pat. No. 5,605,690 provides examples of TNFR polypeptides, including soluble TNFR polypeptides, appropriate for use in the present invention. In many embodiments, the TNFR polypeptide comprises an extracellular domain of TNFR. In some embodiments, the TNFR polypeptide is a fusion polypeptide comprising an extracellular domain of TNFR linked to a constant domain of an immunoglobulin molecule. In other embodiments, the TNFR polypeptide is a fusion polypeptide comprising an extracellular domain of the p75 TNFR linked to a constant domain of an IgGl molecule. In some embodiments, when administration to humans is contemplated, an Ig used for fusion proteins is human, e.g., human IgGl.

[00187] Monovalent and multivalent forms of TNFR polypeptides may be used in the present invention. Multivalent forms of TNFR polypeptides possess more than one TNF binding site. In some embodiments, the TNFR is a bivalent, or dimeric, form of TNFR. For example, as described in U.S. Pat. No. 5,605,690 and in Mohler et al., 1993, J. Immunol., 151:1548-1561, a chimeric antibody polypeptide with TNFR extracellular domains substituted for the variable domains of either or both of the immunoglobulin heavy or light chains would provide a TNFR polypeptide for the present invention. Generally, when such a chimeric TNFR: antibody polypeptide is produced by cells, it forms a bivalent molecule through disulfide linkages between the immunoglobulin domains. Such a chimeric TNFR:antibody polypeptide is referred to as TNFR:Fc.

[00188] In one embodiment, a subject method involves administration of an effective amount of the soluble TNFR ENBREL® etanercept. ENBREL® is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human 75 kilodalton (p75) TNFR linked to the Fc portion of human IgGl. The Fc component of ENBREL® contains the CH2 domain, the CH3 domain and hinge region, but not the CHI domain of IgGl. ENBREL® is produced in a Chinese hamster ovary (CHO) mammalian cell expression system. It consists of 934 amino acids and has an apparent molecular weight of approximately 150 kilodaltons. Smith et al. (1990) Science 248:1019-1023; Mohler et al. (1993) J Immunol. 151:1548-1561; U.S. Pat. No. 5,395,760; and U.S. Pat. No. 5,605,690.

[00189] Also suitable for use are monoclonal antibodies that bind TNF-α. Monoclonal antibodies include "humanized" mouse monoclonal antibodies; chimeric antibodies; monoclonal antibodies that are at least about 80%, at least about 90%, at least about 95%, or 100% human in amino acid sequence; and the like. See, e.g., WO 90/10077; WO 90/04036; and WO 92/02190. Suitable monoclonal antibodies include antibody fragments, such as Fv, F(ab')₂ and Fab; synthetic antibodies; artificial antibodies; phage display antibodies; and the like.

[00190] Examples of suitable monoclonal antibodies include infliximab (REMICADE®, Centocor); and adalimumab (HUMIRA™, Abbott) REMICADE® is a chimeric monoclonal anti-TNF-α antibody that includes about 25% mouse amino acid sequence and about 75%) human amino acid sequence. REMICADE® comprises a variable region of a mouse monoclonal anti-TNF-α antibody fused to the constant region of a human IgGl. Elliott et al. (1993) Arthritis Rheum. 36:1681-1690; Elliott et al. (1994) Lancet 344:1105-1110; Baert et al. (1999) Gastroenterology 116:22-28. HUMIRA™ is a human, full-length IgGl monoclonal antibody that was identified using phage display technology. Piascik (2003) J. Am. Pharm. Assoc. 43:327-328.

[00191] Also included in the term "TNF antagonist," and therefore suitable for use in a subject method, are stress-activated protein kinase (SAPK) inhibitors. SAPK inhibitors are known in the art, and include, but are not limited to 2-alkyl imidazoles disclosed in U.S. Patent No. 6,548,520; 1,4,5-substituted imidazole compounds disclosed in U.S. Patent No. 6,489,325; 1,4,5-substituted imidazole compounds disclosed in U.S. Patent No. 6,569,871; heteroaryl aminophenyl ketone compounds disclosed in Published U.S. Patent Application No. 2003/0073832; pyridyl imidazole compounds disclosed in U.S. Patent No. 6,288,089; and heteroaryl aminobenzophenones disclosed in U.S. Patent No. 6,432,962. Also of interest are compounds disclosed in U.S. Patent Application Publication No. 2003/0149041; and U.S. Patent No. 6,214,854. A stress-activated protein kinase is a member of a family of mitogen- activated protein kinases that are activated in response to stress stimuli. SAPK include, but are not limited to, p38 (Lee et al. (1994) Nature 372:739) and c-jun N-terminal kinase (JNK).

[00192] Methods to assess TNF antagonist activity are known in the art and exemplified herein. For example, TNF antagonist activity may be assessed with a cell-based competitive binding assay. In such an assay, radiolabeled TNF is mixed with serially diluted TNF antagonist and cells expressing cell membrane bound TNFR. Portions of the suspension are centrifuged to separate free and bound TNF and the amount of radioactivity in the free and bound fractions determined. TNF antagonist activity is assessed by inhibition of TNF binding to the cells in the presence of the TNF antagonist.

[00193] As another example, TNF antagonists may be analyzed for the ability to neutralize TNF activity in vitro in a bioassay using cells susceptible to the cytotoxic activity of TNF as target cells. In such an assay, target cells, cultured with TNF, are treated with varying amounts of TNF antagonist and subsequently are examined for cytolysis. TNF antagonist activity is assessed by a decrease in TNF-induced target cell cytolysis in the presence of the TNF antagonist. Type I Interferon Receptor Agonists

[00194] Type I interferon receptor agonists suitable for use in a subject method include an IFN- α; an IFN-β; an IFN-tau; an IFN-ω; antibody agonists specific for a Type I interferon receptor; and any other agonist of Type I interferon receptor, including non-polypeptide agonists. Interferon-Alpha

[00195] Any known IFN-α can be used in the instant invention. The term "interferon-alpha" as used herein refers to a family of related polypeptides that inhibit viral replication and cellular proliferation and modulate immune response. The term "IFN-α" includes naturally occurring IFN-α; synthetic IFN-α; derivatized IFN-α (e.g., PEGylated IFN-α, glycosylated IFN-α, and the like); and analogs of naturally occurring or synthetic IFN-α; essentially any IFN-α that has antiviral properties, as described for naturally occurring IFN-α.

[00196] Suitable alpha interferons include, but are not limited to, naturally-occurring IFN-α (including, but not limited to, naturally occurring IFN-α2a, IFN-α2b); recombinant interferon alpha-2b such as Intron-A interferon available from Schering Corporation, Kenilworth, N.J.; recombinant interferon alpha-2a such as Roferon interferon available from Hoffmann-La Roche, Nutley, N. J.; recombinant interferon alpha-2C such as Berofor alpha 2 interferon available from Boehringer Ingelheim Pharmaceutical, Inc., Ridgefield, Conn.; interferon alpha- nl, a purified blend of natural alpha interferons such as Sumiferon available from Sumitomo, Japan or as Wellferon interferon alpha-nl (INS) available from the Glaxo-Wellcome Ltd., London, Great Britain; and interferon alpha-n3 a mixture of natural alpha interferons made by Interferon Sciences and available from the Purdue Frederick Co., Norwalk, Conn., under the Alferon Tradename.

[00197] The term "IFN-α" also encompasses consensus IFN-α. Consensus IFN-α (also referred to as "CIFN" and "IFN-con" and "consensus interferon") encompasses but is not limited to the amino acid sequences designated IFN-coni, IFN-con₂ and IFN-con₃ which are disclosed in U.S. Pat. Nos. 4,695,623 and 4,897,471; and consensus interferon as defined by determination of a consensus sequence of naturally occurring interferon alphas (e.g., Infergen®, InterMune, Inc., Brisbane, Calif). IFN-con_t is the consensus interferon agent in the Infergen® alfacon-1 product. The Infergen® consensus interferon product is referred to herein by its brand name (Infergen®) or by its generic name (interferon alfacon-1). DNA sequences encoding IFN-con may be synthesized as described in the aforementioned patents or other standard methods. Use of CIFN is of particular interest.

[00198] Also suitable for use in the present invention are fusion polypeptides comprising an IFN-α and a heterologous polypeptide. Suitable IFN-α fusion polypeptides include, but are not limited to, Albuferon-alpha™ (a fusion product of human albumin and IFN-α; Human Genome Sciences; see, e.g., Osborn et al. (2002) J Pharmacol. Exp. Therap. 303:540-548). Also suitable for use in the present invention are gene-shuffled forms of IFN-α. See., e.g., Masci et al. (2003) Curr. Oncol. Rep. 5:108-113. PEGylated Interferon- Alpha

[00199] The term "IFN-α" also encompasses derivatives of IFN-α that are derivatized (e.g., are chemically modified) to alter certain properties such as serum half-life. As such, the term "IFN-α" includes glycosylated IFN-α; IFN-α derivatized with polyethylene glycol ("PEGylated IFN-α"); and the like. PEGylated IFN-α, and methods for making same, is discussed in, e.g., U.S. Patent Nos. 5,382,657; 5,981,709; and 5,951,974. PEGylated IFN-α encompasses conjugates of PEG and any of the above-described IFN-α molecules, including, but not limited to, PEG conjugated to interferon alpha-2a (Roferon, Hoffman La-Roche, Nutley, N. J.), interferon alpha 2b (Intron, Schering-Plough, Madison, N. J.), interferon alpha-2c (Berofor Alpha, Boehringer Ingelheim, Ingelheim, Germany); and consensus interferon as defined by determination of a consensus sequence of naturally occurring interferon alphas (Infergen®, InterMune, Inc., Brisbane, Calif). [00200] Any of the above-mentioned IFN-α polypeptides can be modified with one or more polyethylene glycol moieties, i.e., PEGylated. The PEG molecule of a PEGylated IFN-α polypeptide is conjugated to one or more amino acid side chains of the IFN-α polypeptide. In some embodiments, the PEGylated IFN-α contains a PEG moiety on only one amino acid. In other embodiments, the PEGylated IFN-α contains a PEG moiety on two or more amino acids, e.g., the IFN-α contains a PEG moiety attached to two, three, four, five, six, seven, eight, nine, or ten different amino acid residues.

[00201] IFN-α may be coupled directly to PEG (i.e., without a linking group) through an amino group, a sulfhydryl group, a hydroxyl group, or a carboxyl group.

[00202] In some embodiments, the PEGylated IFN-α is PEGylated at or near the amino terminus (N-terminus) of the IFN-α polypeptide, e.g., the PEG moiety is conjugated to the IFN-α polypeptide at one or more amino acid residues from amino acid 1 through amino acid 4, or from amino acid 5 through about 10.

[00203] In other embodiments, the PEGylated IFN-α is PEGylated at one or more amino acid residues from about 10 to about 28.

[00204] In other embodiments, the PEGylated IFN-α is PEGylated at or near the carboxyl terminus (C-terminus) of the IFN-α polypeptide, e.g., at one or more residues from amino acids 156-166, or from amino acids 150 to 155.

[00205] In other embodiments, the PEGylated IFN-α is PEGylated at one or more amino acid residues at one or more residues from amino acids 100-114.

[00206] The polyethylene glycol derivatization of amino acid residues at or near the receptor- binding and/or active site domains of the IFN-α protein can disrupt the functioning of these domains. In certain embodiments of the invention, amino acids at which PEGylation is to be avoided include amino acid residues from amino acid 30 to amino acid 40; and amino acid residues from amino acid 113 to amino acid 149.

[00207] In some embodiments, PEG is attached to IFN-α via a linking group. The linking group is any biocompatible linking group, where "biocompatible" indicates that the compound or group is non-toxic and may be utilized in vitro or in vivo without causing injury, sickness, disease, or death. PEG can be bonded to the linking group, for example, via an ether bond, an ester bond, a thiol bond or an amide bond. Suitable biocompatible linking groups include, but are not limited to, an ester group, an amide group, an imide group, a carbamate group, a carboxyl group, a hydroxyl group, a carbohydrate, a succinimide group (including, for example, succinimidyl succinate (SS), succinimidyl propionate (SPA), succinimidyl butanoate (SB A), succinimidyl carboxymethylate (SCM), succinimidyl succinamide (SSA) or N-hydroxy succinimide (NHS)), an epoxide group, an oxycarbonylimidazole group (including, for example, carbonyldimidazole (CDI)), a nitro phenyl group (including, for example, nitrophenyl carbonate (NPC) or trichlorophenyl carbonate (TPC)), a trysylate group, an aldehyde group, an isocyanate group, a vinylsulfone group, a tyrosine group, a cysteine group, a histidine group or a primary amine.

[00208] Methods for making succinimidyl propionate (SPA) and succinimidyl butanoate (SBA) ester-activated PEGs are described in U.S. Pat. No. 5,672,662 (Harris, et al.) and WO 97/03106.

[00209] Methods for attaching a PEG to an IFN-α polypeptide are known in the art, and any known method can be used. See, for example, by Park et al, Anticancer Res., 1 :373-376 (1981); Zaplipsky and Lee, Polyethylene Glycol Chemistry: Biotechnical and Biomedical Applications, J. M. Harris, ed., Plenum Press, NY, Chapter 21 (1992); U.S. Patent No. 5,985,265; U.S. Pat. No. 5,672,662 (Harris, et al.) and WO 97/03106.

[00210] Pegylated IFN-α, and methods for making same, is discussed in, e.g., U.S. Patent Nos. 5,382,657; 5,981,709; 5,985,265; and 5,951,974. Pegylated IFN-α encompasses conjugates of PEG and any of the above-described IFN-α molecules, including, but not limited to, PEG conjugated to interferon alpha-2a (Roferon, Hoffman LaRoche, Nutley, N.J.), where PEGylated Roferon is known as Pegasys (Hoffman LaRoche); interferon alpha 2b (Intron, Schering-Plough, Madison, N. J.), where PEGylated Intron is known as PEG-Intron (Schering- Plough); interferon alpha-2c (Berofor Alpha, Boehringer Ingelheim, Ingelheim, Germany); and consensus interferon (CIFN) as defined by determination of a consensus sequence of naturally occurring interferon alphas (Infergen®, InterMune, Inc., Brisbane, Calif), where PEGylated Infergen is referred to as PEG-Infergen.

[00211] In many embodiments, the PEG is a monomethoxyPEG molecule that reacts with primary amine groups on the IFN-α polypeptide. Methods of modifying polypeptides with monomethoxy PEG via reductive alkylation are known in the art. See, e.g., Chamow et al. (1994) Bioconj. Chem. 5:133-140.

[00212] In one non-limiting example, PEG is linked to IFN-α via an SPA linking group. SPA esters of PEG, and methods for making same, are described in U.S. Patent No. 5,672,662. SPA linkages provide for linkage to free amine groups on the IFN-α polypeptide.

[00213] For example, a PEG molecule is covalently attached via a linkage that comprises an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of a surface-exposed lysine residue in the IFN-α polypeptide. Such a bond can be formed, e.g., by condensation of an α-methoxy, omega propanoic acid activated ester of PEG (mPEGspa). [00214] As one non-limiting example, one monopegylated CIFN conjugate preferred for use herein has a linear PEG moiety of about 30 kD attached via a covalent linkage to the CIFN polypeptide, where the covalent linkage is an amide bond between a propionyl group of the PEG moiety and the epsilon amino group of a surface-exposed lysine residue in the CIFN polypeptide, where the surface-exposed lysine residue is chosen from lys³¹, lys⁵⁰, lys⁷¹, lys⁸⁴, lys , lys , lys , lys , and lys , and the amide bond is formed by condensation of an α- methoxy, omega propanoic acid activated ester of PEG. Polyethylene glycol

[00215] Polyethylene glycol suitable for conjugation to an IFN-α polypeptide is soluble in water at room temperature, and has the general formula R(O-CH₂-CH )_nO-R, where R is hydrogen or a protective group such as an alkyl or an alkanol group, and where n is an integer from 1 to 1000. Where R is a protective group, it generally has from 1 to 8 carbons.

[00216] In many embodiments, PEG has at least one hydroxyl group, e.g., a terminal hydroxyl group, which hydroxyl group is modified to generate a functional group that is reactive with an amino group, e.g., an epsilon amino group of a lysine residue, a free amino group at the N- terminus of a polypeptide, or any other amino group such as an amino group of asparagine, glutamine, arginine, or histidine.

[00217] In other embodiments, PEG is derivatized so that it is reactive with free carboxyl groups in the IFN-α polypeptide, e.g., the free carboxyl group at the carboxyl terminus of the IFN-α polypeptide. Suitable derivatives of PEG that are reactive with the free carboxyl group at the carboxyl-terminus of IFN-α include, but are not limited to PEG-amine, and hydrazine derivatives of PEG (e.g., PEG-NH-NH₂).

[00218] In other embodiments, PEG is derivatized such that it comprises a terminal thiocarboxylic acid group, -COSH, which selectively reacts with amino groups to generate amide derivatives. Because of the reactive nature of the thio acid, selectivity of certain amino groups over others is achieved. For example, -SH exhibits sufficient leaving group ability in reaction with N-terminal amino group at appropriate pH conditions such that the ε-amino groups in lysine residues are protonated and remain non-nucleophilic. On the other hand, reactions under suitable pH conditions may make some of the accessible lysine residues to react with selectivity.

[00219] In other embodiments, the PEG comprises a reactive ester such as an N-hydroxy succinimidate at the end of the PEG chain. Such an N-hydroxysuccinimidate-containing PEG molecule reacts with select amino groups at particular pH conditions such as neutral 6.5-7.5. For example, the N-terminal amino groups may be selectively modified under neutral pH conditions. However, if the reactivity of the reagent were extreme, accessible-NH₂ groups of lysine may also react.

[00220] The PEG can be conjugated directly to the IFN-α polypeptide, or through a linker. In some embodiments, a linker is added to the IFN-α polypeptide, forming a linker-modified IFN- α polypeptide. Such linkers provide various functionalities, e.g., reactive groups such sulfhydryl, amino, or carboxyl groups to couple a PEG reagent to the linker-modified IFN-α polypeptide.

[00221] In some embodiments, the PEG conjugated to the IFN-α polypeptide is linear. In other embodiments, the PEG conjugated to the IFN-α polypeptide is branched. Branched PEG derivatives such as those described in U.S. Pat. No. 5,643,575, "star-PEG's" and multi-armed PEG's such as those described in Shearwater Polymers, Inc. catalog "Polyethylene Glycol Derivatives 1997-1998." Star PEGs are described in the art including, e.g., in U.S. Patent No. 6,046,305.

[00222] PEG having a molecular weight in a range of from about 2 kDa to about 100 kDa, is generally used, where the term "about," in the context of PEG, indicates that in preparations of polyethylene glycol, some molecules will weigh more, some less, than the stated molecular weight. For example, PEG suitable for conjugation to IFN-α has a molecular weight of from about 2 kDa to about 5 kDa, from about 5 kDa to about 10 kDa, from about 10 kDa to about 15 kDa, from about 15 kDa to about 20 kDa, from about 20 kDa to about 25 kDa, from about 25 kDa to about 30 kDa, from about 30 kDa to about 40 kDa, from about 40 kDa to about 50 kDa, from about 50 kDa to about 60 kDa, from about 60 kDa to about 70 kDa, from about 70 kDa to about 80 kDa, from about 80 kDa to about 90 kDa, or from about 90 kDa to about 100 kDa. Preparing PEG-IFN-α conjugates

[00223] As discussed above, the PEG moiety can be attached, directly or via a linker, to an amino acid residue at or near the N-terminus, internally, or at or near the C-terminus of the IFN-α polypeptide. Conjugation can be carried out in solution or in the solid phase. N-terminal linkage

[00224] Methods for attaching a PEG moiety to an amino acid residue at or near the N-terminus of an IFN-α polypeptide are known in the art. See, e.g., U.S. Patent No. 5,985,265.

[00225] In some embodiments, known methods for selectively obtaining an N-terminally chemically modified IFN-α are used. For example, a method of protein modification by reductive alkylation which exploits differential reactivity of different types of primary amino groups (lysine versus the N-terminus) available for derivatization in a particular protein can be used. Under the appropriate reaction conditions, substantially selective derivatization of the protein at the N-terminus with a carbonyl group containing polymer is achieved. The reaction is performed at pH which allows one to take advantage of the pK_a differences between the ε- amino groups of the lysine residues and that of the α-amino group of the N-terminal residue of the protein. By such selective derivatization attachment of a PEG moiety to the IFN-α is controlled: the conjugation with the polymer takes place predominantly at the N-terminus of the IFN-α and no significant modification of other reactive groups, such as the lysine side chain amino groups, occurs. C-terminal linkage

[00226] N-terminal-specific coupling procedures such as described in U.S. Patent No. 5,985,265 provide predominantly monoPEGylated products. However, the purification procedures aimed at removing the excess reagents and minor multiply PEGylated products remove the N-terminal blocked polypeptides. In terms of therapy, such processes lead to significant increases in manufacturing costs. For example, examination of the structure of the well-characterized Infergen® Alfacon-1 CIFN polypeptide amino acid sequence reveals that the clipping is approximate 5% at the carboxyl terminus and thus there is only one major C- terminal sequence. Thus, in some embodiments, N-terminally PEGylated IFN-α is not used; instead, the IFN-α polypeptide is C-terminally PEGylated.

[00227] An effective synthetic as well as therapeutic approach to obtain mono PEGylated Infergen product is therefore envisioned as follows:

[00228] A PEG reagent that is selective for the C-terminal can be prepared with or without spacers. For example, polyethylene glycol modified as methyl ether at one end and having an amino function at the other end may be used as the starting material.

[00229] Preparing or obtaining a water-soluble carbodiimide as the condensing agent can be carried out. Coupling IFN-α (e.g., Infergen® Alfacon-1 CIFN or consensus interferon) with a water-soluble carbodiimide as the condensing reagent is generally carried out in aqueous medium with a suitable buffer system at an optimal pH to effect the amide linkage. A high molecular weight PEG can be added to the protein covalently to increase the molecular weight.

[00230] The reagents selected will depend on process optimization studies. A non-limiting example of a suitable reagent is ED AC or l-ethyl-3- (3-dimethylaminopropyl) carbodiimide. The water solubility of ED AC allows for direct addition to a reaction without the need for prior organic solvent dissolution. Excess reagent and the isourea formed as the by-product of the cross-linking reaction are both water-soluble and may easily be removed by dialysis or gel filtration. A concentrated solution of ED AC in water is prepared to facilitate the addition of a small molar amount to the reaction. The stock solution is prepared and used immediately in view of the water labile nature of the reagent. Most of the synthetic protocols in literature suggest the optimal reaction medium to be in pH range between 4.7 and 6.0. However the condensation reactions do proceed without significant losses in yields up to pH 7.5. Water may be used as solvent. In view of the contemplated use of Infergen, preferably the medium will be 2-(N-morpholino)ethane sulfonic acid buffer pre-titrated to pH between 4.7 and 6.0. However, 0.1M phosphate in the pH 7-7.5 may also be used in view of the fact that the product is in the same buffer. The ratios of PEG amine to the IFN-α molecule is optimized such that the C- terminal carboxyl residue(s) are selectively PEGylated to yield monoPEGylated derivative(s).

[00231] Even though the use of PEG amine has been mentioned above by name or structure, such derivatives are meant to be exemplary only, and other groups such as hydrazine derivatives as in PEG-NH-NH which will also condense with the carboxyl group of the IFN-α protein, can also be used. In addition to aqueous phase, the reactions can also be conducted on solid phase. Polyethylene glycol can be selected from list of compounds of molecular weight ranging from 300-40000. The choice of the various polyethylene glycols will also be dictated by the coupling efficiency and the biological performance of the purified derivative in vitro and in vivo i.e., circulation times, anti viral activities etc.

[00232] Additionally, suitable spacers can be added to the C-terminal of the protein. The spacers may have reactive groups such as SH, NH₂ or COOH to couple with appropriate PEG reagent to provide the high molecular weight IFN-α derivatives. A combined solid/solution phase methodology can be devised for the preparation of C-terminal pegylated interferons. For example, the C-terminus of IFN-α is extended on a solid phase using a Gly-Gly-Cys-NH₂ spacer and then monopegylated in solution using activated dithiopyridyl-PEG reagent of appropriate molecular weights. Since the coupling at the C-terminus is independent of the blocking at the N-terminus, the envisioned processes and products will be beneficial with respect to cost (a third of the protein is not wasted as in N-terminal PEGylation methods) and contribute to tlie economy of the therapy to treat chronic hepatitis C infections, liver fibrosis etc.

[00233] There may be a more reactive carboxyl group of amino acid residues elsewhere in the molecule to react with the PEG reagent and lead to monoPEGylation at that site or lead to multiple PEGylations in addition to the -COOH group at the C-terminus of the IFN-α. It is envisioned that these reactions will be minimal at best owing to the steric freedom at the C- terminal end of the molecule and the steric hindrance imposed by the carbodiimides and the PEG reagents such as in branched chain molecules. It is therefore the preferred mode of PEG modification for Infergen and similar such proteins, native or expressed in a host system, which may have blocked N-termini to varying degrees to improve efficiencies and maintain higher in vivo biological activity.

[00234] Another method of achieving C-terminal PEGylation is as follows. Selectivity of C- terminal PEGylation is achieved with a sterically hindered reagent which excludes reactions at carboxyl residues either buried in the helices or internally in IFN-α. For example, one such reagent could be a branched chain PEG ~40kd in molecular weight and this agent could be synthesized as follows:

[00235] OH₃C-(CH₂CH₂O)n-CH₂CH₂NH₂ + Glutamic Acid i.e., HOCO-CH₂CH₂CH(NH2)- COOH is condensed with a suitable agent e.g., dicyclohexyl carbodiimide or water-soluble EDC to provide the branched chain PEG agent OH₃C-(CH₂CH₂O)„- CH₂CH₂NHCOCH(NH₂)CH₂OCH₃-(CH₂CH₂O)„-CH₂CH₂NHCOCH₂. o H₃C-0-(CH₂CH₂0)_n-CH₂CH₂NH₂+ HO C-CH₂CH₂CH-COOH

CHNH₂ EDAC

H₃C-0-(CH₂CH₂0)_n-CH₂CH₂NH-CO

CHNH₂

(CH₂)₂ H₃C-0-(CH₂CH₂0)_n-CH₂CH₂NH-CO

[00236] This reagent can be used in excess to couple the amino group with the free and flexible carboxyl group of IFN-α to form the peptide bond.

[00237] If desired, PEGylated IFN-α is separated from unPEGylated IFN-α using any known method, including, but not limited to, ion exchange chromatography, size exclusion cliromatography, and combinations thereof. For example, where the PEG-IFN-α conjugate is a monoPEGylated IFN-α, the products are first separated by ion exchange chromatography to obtain material having a charge characteristic of monoPEGylated material (other multi- PEGylated material having the same apparent charge may be present), and then the monoPEGylated materials are separated using size exclusion chromatography. MonoPEG (30 kD, linear)-ylated IFN-α

[00238] PEGylated IFN-α that is suitable for use in the present invention includes a monopegylated consensus interferon (CIFN) molecule comprised of a single CIFN polypeptide and a single polyethylene glycol (PEG) moiety, where the PEG moiety is linear and about 30 kD in molecular weight and is directly or indirectly linked through a stable covalent linkage to either the N-terminal residue in the CIFN polypeptide or a lysine residue in the CIFN polypeptide. In some embodiments, the monoPEG (30 kD, linear)-ylated IFN-α is monoPEG (30 kD, linear)-ylated INFERGEN® interferon alfacon-1.

[00239] In some embodiments, the PEG moiety is linked to either the alpha-amino group of the N-terminal residue in the CIFN polypeptide or the epsilon-amino group of a lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon- amino group of the lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of tl e PEG moiety and either the alpha-amino group of the N-terminal residue or the epsilon-amino group of the lysine residue in the CIFN polypeptide, thereby forming a hydrolytically stable linkage between the PEG moiety and the CIFN polypeptide.

[00240] In some embodiments, the PEG moiety is linked to the N-terminal residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the alpha-amino group of the N-terminal residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the alpha-amino group of the N-terminal residue of the CIFN polypeptide.

[00241] In some embodiments, the PEG moiety is linked to a lysine residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the lysine group in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the lysine group in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon- amino group of the lysine residue in the CIFN polypeptide.

[00242] In some embodiments, the PEG moiety is linked to a surface-exposed lysine residue in the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a surface-exposed lysine residue in the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the surface-exposed lysine residue in the CIFN polypeptide.

[00243] In some embodiments, the PEG moiety is linked to a lysine chosen from lys³¹, lys⁵⁰, lys⁷¹, lys⁸⁴, lys¹²¹, lys¹²², lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ of the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a lysine chosen from lys³¹, lys⁵⁰, lys⁷¹, lys⁸⁴, lys¹²¹, lys¹²², lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ of the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide.

[00244] In some embodiments, the PEG moiety is linked to a lysine chosen from lys¹²¹, lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ of the CIFN polypeptide. In other embodiments, the PEG moiety is linked to the epsilon-amino group of a lysine chosen from lys¹²¹, lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ of the CIFN polypeptide. In further embodiments, the linkage comprises an amide bond between the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In still further embodiments, the linkage comprises an amide bond between a propionyl group of the PEG moiety and the epsilon-amino group of the chosen lysine residue in the CIFN polypeptide. In additional embodiments, the amide bond is formed by condensation of an alpha-methoxy, omega-propanoic acid activated ester of the PEG moiety and the epsilon- amino group of the chosen lysine residue in the CIFN polypeptide.

[00245] In connection with the above-described monopegylated CIFN molecules, the invention contemplates embodiments of each such molecule where the CIFN polypeptide is chosen from interferon alpha-con_! , interferon alpha-con₂, and interferon alpha-con₃, the amino acid sequences of which CIFN polypeptides are disclosed in U.S. Pat. No. 4,695,623. Populations of IFN-α

[00246] In addition, any of the methods of tlie invention can employ a PEGylated IFN-α composition that comprises a population of monopegylated IFNα molecules, where the population consists of one or more species of monopegylated IFNα molecules as described above. The subject composition comprises a population of modified IFN-α polypeptides, each with a single PEG molecule linked to a single amino acid residue of the polypeptide.

[00247] In some of these embodiments, the population comprises a mixture of a first IFN-α polypeptide linked to a PEG molecule at a first amino acid residue; and at least a second IFN-α polypeptide linked to a PEG molecule at a second amino acid residue, wherein the first and second IFN-α polypeptides are the same or different, and wherein the location of the first amino acid residue in the amino acid sequence of the first IFN-α polypeptide is not the same as the location of the second amino acid residue in the second IFN-α polypeptide. As one non- limiting example, a subject composition comprises a population of PEG-modified IFN-α polypeptides, the population comprising an IFN-α polypeptide linked at its amino terminus to a linear PEG molecule; and an IFN-α polypeptide linked to a linear PEG molecule at a lysine residue.

[00248] Generally, a given modified IFN-α species represents from about 0.5% to about 99.5% of the total population of monopegylated IFNα polypeptide molecules in a population, e.g, a given modified IFN-α species represents about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 99.5% of the total population of monopegylated IFN-α polypeptide molecules in a population. In some embodiments, a composition suitable for use in a subject method comprises a population of monopegylated IFN-α polypeptides, which population comprises at least about 70%, at least about 80%, at least about 90%, at least about 95%o, or at least about 99%, IFN-α polypeptides linked to PEG at the same site, e.g., at the N-terminal amino acid. [00249] In particular embodiments of interest, a composition suitable for use in a subject method comprises a population of monopegylated CIFN molecules, the population consisting of one or more species of molecules, where each species of molecules is characterized by a single CIFN polypeptide linked, directly or indirectly in a covalent linkage, to a single linear PEG moiety of about 30 kD in molecular weight, and where the linkage is to either a lysine residue in the CIFN polypeptide, or the N-terminal amino acid residue of the CIFN polypeptide.

[00250] The amino acid residue to which the PEG is attached is in many embodiments the N- terminal amino acid residue. In other embodiments, the PEG moiety is attached (directly or via a linker) to a surface-exposed lysine residue. In additional embodiments, the PEG moiety is attached (directly or via a linker) to a lysine residue chosen from lys³¹, lys⁵⁰, lys⁷¹, lys⁸⁴, lys¹²¹, lys¹²², lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ of the CIFN polypeptide. In further embodiments, the PEG moiety is attached (directly or via a linker) to a lysine residue chosen from lys¹²¹, lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ of the CIFN polypeptide.

[00251] As an example, a composition suitable for use in a subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue of a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A composition suitable for use in a subject method can further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00252] As another example, a composition suitable for use in a subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first surface- exposed lysine residue of a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A composition suitable for use in a subject method can further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a surface-exposed lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00253] As another example, a composition suitable for use in a subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue selected from one of lys³¹, lys⁵⁰, lys⁷¹, lys⁸⁴, lys¹²¹, lys¹²², lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A composition suitable for use in a subject method can further comprise a third monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a second lysine residue selected from one of lys³¹, lys⁵⁰, lys⁷¹, lys⁸⁴, lys¹²¹, lys¹²², lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ in a third CIFN polypeptide, where the third CIFN polypeptide is the same or different from either of the first and second CIFN polypeptides, where the second lysine residue is located in a position in the amino acid sequence of the third CIFN polypeptide that is not the same as the position of the first lysine residue in the amino acid sequence of the second CIFN polypeptide. A composition suitable for use in a subject method may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys³¹, lys⁵⁰, lys⁷¹, lys⁸⁴, lys¹²¹, lys¹²², lys¹³⁴, lys¹³⁵, and lys¹⁶⁵, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00254] As another example, a composition suitable for use in a subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at the N-terminal amino acid residue of a first CIFN polypeptide, and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue selected from one of lys¹²¹, lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different. A composition suitable for use in a subject method can further comprise a third monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a second lysine residue selected from one of lys¹²¹, lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ in a third CIFN polypeptide, where the third CIFN polypeptide is the same or different from either of the first and second CIFN polypeptides, where the second lysine residue is located in a position in the amino acid sequence of the third CIFN polypeptide that is not the same as the position of the first lysine residue in the amino acid sequence of the second CIFN polypeptide. A composition suitable for use in a subject method may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys¹²¹, lys¹³⁴, lys¹³⁵, and lys¹⁶⁵, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00255] As another non-limiting example, a composition suitable for use in a subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first lysine residue in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the first lysine is located in a position in the amino acid sequence of the first CIFN polypeptide that is not the same as the position of the second lysine residue in the amino acid sequence of the second CIFN polypeptide. A composition suitable for use in a subject method may further comprise at least one additional monopegylated CIFN species of molecules characterized by a PEG moiety linked to a lysine residue in the CIFN polypeptide, where tlie location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00256] As another non-limiting example, a composition suitable for use in a subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a first lysine residue chosen from lys³¹, lys⁵⁰, lys⁷¹, lys⁸⁴, lys¹²¹, lys¹²², lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue chosen from lys³¹, lys⁵⁰, lys⁷¹, lys⁸⁴, lys¹²¹, lys¹²², lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the second lysine residue is located in a position in the amino acid sequence of the second CIFN polypeptide that is not the same as the position of the first lysine residue in the first CIFN polypeptide. The composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys³¹, lys⁵⁰, lys⁷¹, lys⁸⁴, lys¹²¹, lys¹²², lys¹³⁴, lys¹³⁵, and lys¹⁶⁵, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD. [00257] As another non-limiting example, a composition suitable for use in a subject method comprises a population of monopegylated CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a first lysine residue chosen from lys , lys , lys , and lys in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second lysine residue chosen from lys¹²¹, lys¹³⁴, lys¹³⁵, and lys¹⁶⁵ in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the second lysine residue is located in a position in the amino acid sequence of the second CIFN polypeptide that is not the same as the position of the first lysine residue in the first CIFN polypeptide. The composition may further comprise at least one additional monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to one of lys¹²¹, lys¹³⁴, lys¹³⁵, and lys¹⁶⁵, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD. [00258] As another non-limiting example, a composition suitable for use in a subject method comprises a monopegylated population of CIFN molecules, consisting of a first monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked to a first surface-exposed lysine residue in a first CIFN polypeptide; and a second monopegylated CIFN polypeptide species of molecules characterized by a PEG moiety linked at a second surface- exposed lysine residue in a second CIFN polypeptide, where the first and second CIFN polypeptides are the same or different, and where the first surface-exposed lysine is located in a position in the amino acid sequence of the first CIFN polypeptide that is not the same as the position of the second surface-exposed lysine residue in the amino acid sequence of the second CIFN polypeptide. A composition suitable for use in a subject method may further comprise at least one additional monopegylated CIFN species of molecules characterized by a PEG moiety linked to a surface-exposed lysine residue in the CIFN polypeptide, where the location of the linkage site in each additional monopegylated CIFN polypeptide species is not the same as the location of the linkage site in any other species. In all species in this example, the PEG moiety is a linear PEG moiety having an average molecular weight of about 30 kD.

[00259] In connection with each of the above-described populations of monopegylated CIFN molecules, the invention contemplates embodiments where the molecules in each such population comprise a CIFN polypeptide chosen from interferon alpha-con_l5 interferon alpha- con₂, and interferon alpha-con₃.

[00260] The invention further features use in a subject method of a product that is produced by the process of reacting CIFN polypeptide with a succinimidyl ester of alpha-methoxy, omega- propionylpoly(ethylene glycol) (mPEGspa) that is linear and about 30 kD in molecular weight, where the reactants are initially present at a molar ratio of about 1 : 1 to about 1 :5 CIFN:mPEGspa, and where the reaction is conducted at a pH of about 7 to about 9, followed by recovery of the monopegylated CIFN product of the reaction. In one embodiment, the reactants are initially present at a molar ratio of about 1 :3 CIFN:mPEGspa and the reaction is conducted at a pH of about 8. In another embodiment where the product of the invention is generated by a scaled-up procedure needed for toxicological and clinical investigations, the reactants are initially present in a molar ratio of 1 :2 CIFN:mPEGspa and the reaction is conducted at a pH of about 8.0.

[00261] In connection with the above-described product-by-process, the invention contemplates embodiments where the CIFN reactant is chosen from interferon alpha-con_l3 interferon alpha- con , and interferon alpha-con₃. IFN-β

[00262] The term interferon-beta ("LFN-β") includes IFN-β polypeptides that are naturally occurring; non-naturally-occurring IFN-β polypeptides; and analogs of naturally occurring or non-naturally occurring IFN-β that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN-β.

[00263] Any of a variety of beta interferons can be delivered by the continuous delivery method of the present invention. Suitable beta interferons include, but are not limited to, naturally- occurring IFN-β; IFN-βla, e.g., Avonex® (Biogen, Inc.), and Rebif® (Serono, SA); IFN-βlb (Betaseron®; Berlex); and the like.

[00264] The IFN-β formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN-β. [00265] IFN-β polypeptides can be produced by any known method. DNA sequences encoding IFN-β may be synthesized using standard methods. In many embodiments, IFN-β polypeptides are the products of expression of manufactured DNA sequences transformed or transfected into bacterial hosts, e.g., E. coli, or in eukaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and the like). In these embodiments, the IFN-β is "recombinant IFN- β." Where the host cell is a bacterial host cell, the IFN-β is modified to comprise an N- terminal methionine.

[00266] It is to be understood that IFN-β as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like. IFN-tau

[00267] The term interferon-tau includes IFN-tau polypeptides that are naturally occurring; non- naturally-occurring IFN-tau polypeptides; and analogs of naturally occurring or non-naturally occurring IFN-tau that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN-tau.

[00268] Suitable tau interferons include, but are not limited to, naturally-occurring IFN-tau; Tauferon® (Pepgen Corp.); and the like.

[00269] IFN-tau may comprise an amino acid sequence as set forth in any one of GenBank Accession Nos. PI 5696; P56828; P56832; P56829; P56831; Q29429; Q28595; Q28594; S08072; Q08071; Q08070; Q08053; P56830; P28169; P28172; and P28171. The sequence of any known IFN-tau polypeptide may be altered in various ways known in the art to generate targeted changes in sequence. A variant polypeptide will usually be substantially similar to the sequences provided herein, i.e. will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. The sequence changes may be substitutions, insertions or deletions. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).

[00270] Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and tl e like. Also included are modifications of glycosylation, e.g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g. by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e.g. phosphotyrosine, phosphoserine, or phosphothreonine.

[00271] The IFN-tau formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN-tau.

[00272] IFN-tau polypeptides can be produced by any known method. DNA sequences encoding IFN-tau may be synthesized using standard methods. In many embodiments, IFN-tau polypeptides are the products of expression of manufactured DNA sequences transformed or transfected into bacterial hosts, e.g., E. coli, or in eukaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and the like). In these embodiments, the IFN-tau is "recombinant IFN-tau." Where the host cell is a bacterial host cell, the IFN-tau is modified to comprise an N-terminal methionine.

[00273] It is to be understood that IFN-tau as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like. IFN-ω

[00274] The term interferon-omega ('TFN-ω") includes IFN-ω polypeptides that are naturally occurring; non-naturally-occurring IFN-ω polypeptides; and analogs of naturally occurring or non-naturally occurring IFN-ω that retain antiviral activity of a parent naturally-occurring or non-naturally occurring IFN-ω.

[00275] Any known omega interferon can be used in a combination therapy method of the present invention. Suitable IFN-ω include, but are not limited to, naturally-occurring IFN-ω; recombinant IFN-ω, e.g., Biomed 510 (BioMedicines); and the like.

[00276] IFN-ω may comprise an amino acid sequence as set forth in GenBank Accession No. NP_002168; or AAA70091. The sequence of any known IFN-ω polypeptide may be altered in various ways known in the art to generate targeted changes in sequence. A variant polypeptide will usually be substantially similar to the sequences provided herein, i.e. will differ by at least one amino acid, and may differ by at least two but not more than about ten amino acids. The sequence changes may be substitutions, insertions or deletions. Conservative amino acid substitutions typically include substitutions within the following groups: (glycine, alanine); (valine, isoleucine, leucine); (aspartic acid, glutamic acid); (asparagine, glutamine); (serine, threonine); (lysine, arginine); or (phenylalanine, tyrosine).

[00277] Modifications of interest that may or may not alter the primary amino acid sequence include chemical derivatization of polypeptides, e.g., acetylation, or carboxylation; changes in amino acid sequence that introduce or remove a glycosylation site; changes in amino acid sequence that make the protein susceptible to PEGylation; and the like. Also included are modifications of glycosylation, e.g. those made by modifying the glycosylation patterns of a polypeptide during its synthesis and processing or in further processing steps; e.g. by exposing the polypeptide to enzymes that affect glycosylation, such as mammalian glycosylating or deglycosylating enzymes. Also embraced are sequences that have phosphorylated amino acid residues, e.g. phosphotyrosine, phosphoserine, or phosphothreonine.

[00278] The IFN-ω formulation may comprise an N-blocked species, wherein the N-terminal amino acid is acylated with an acyl group, such as a formyl group, an acetyl group, a malonyl group, and the like. Also suitable for use is a consensus IFN-ω.

[00279] IFN-ω polypeptides can be produced by any known method. DNA sequences encoding IFN-ω may be synthesized using standard methods. In many embodiments, IFN-ω polypeptides are the products of expression of manufactured DNA sequences transformed or transfected into bacterial hosts, e.g., E. coli, or in eukaryotic host cells (e.g., yeast; mammalian cells, such as CHO cells; and the like). In these embodiments, the IFN-ω is "recombinant IFN- ω." Where the host cell is a bacterial host cell, the IFN-ω is modified to comprise an N- terminal methionine.

[00280] It is to be understood that IFN-ω as described herein may comprise one or more modified amino acid residues, e.g., glycosylations, chemical modifications, and the like. Side effect management agents

[00281] In some embodiments, a subject therapy comprises administering a palliative agent (e.g., an agent that reduces patient discomfort caused by a therapeutic agent), or other agent for the avoidance, treatment, or reduction of a side effect of a therapeutic agent. Such agents are also referred to as "side effect management agents."

[00282] Suitable side effect management agents include agents that are effective in pain management; agents that ameliorate gastrointestinal discomfort; analgesics, anti- inflammatories, antipsychotics, antineurotics, anxiolytics, and hematopoietic agents. In addition, the invention contemplates the use of any compound for palliative care of patients suffering from pain or any other side effect in the course of treatment with a subject therapy. Exemplary palliative agents include acetaminophen, ibuprofen, and other NSAIDs, H2 blockers, and antacids.

[00283] Analgesics that can be used to alleviate pain in the methods of the invention include non-narcotic analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) acetaminophen, salicylate, acetyl-salicylic acid (aspirin, diflunisal), ibuprofen, Motrin, Naprosyn, Nalfon, and Trilisate, indomethacin, glucametacine, acemetacin, sulindac, naproxen, piroxicam, diclofenac, benoxaprofen, ketoprofen, oxaprozin, etodolac, ketorolac tromethamine, ketorolac, nabumetone, and the like, and mixtures of two or more of the foregoing.

[00284] Other suitable analgesics include fentanyl, buprenorphine, codeine sulfate, morphine hydrochloride, codeine, hydromorphone (Dilaudid), levorphanol (Levo-Dromoran), methadone (Dolophine), morphine, oxycodone (in Percodan), and oxymorphone (Numorphan). Also suitable for use are benzodiazepines including, but not limited to, flurazepam (Dalmane), diazepam (Valium), and Versed, and the like. Anti-inflammatory agents

[00285] Suitable anti-inflammatory agents include, but are not limited to, steroidal anti- inflammatory agents, and non-steroidal anti-inflammatory agents.

[00286] Suitable steroidal anti-inflammatory agents include, but are not limited to, hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone- phosphate, beclomethasone dipropionate, clobetasol valerate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, conisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortamate, meprednisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, and mixtures of two or more of the foregoing.

[00287] Suitable non-steroidal anti-inflammatory agents, include, but are not limited to, 1) the oxicams, such as piroxicam, isoxicam, tenoxicam, and sudoxicam; 2) the salicylates, such as aspirin, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal; 3) the acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepiract, clidanac, oxepinac, and felbinac; 4) the fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids; 5) the propionic acid derivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic; and 6) the pyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone, and trimethazone, mixtures of these non-steroidal anti-inflammatory agents may also be employed, as well as the pharmaceutically-acceptable salts and esters of these agents.

[00288] Suitable anti-inflammatory agents include, but are not limited to, Alclofenac; Alclometasone Dipropionate; Algestone Acetonide; Alpha Amylase; Amcinafal; Amcinafide; Amfenac Sodium; Amiprilose Hydrochloride; Anakinra; Anirolac; Anitrazafen; Apazone; Balsalazide Disodium; Bendazac; Benoxaprofen; Benzydamine Hydrochloride; Bromelains; Broperamole; Budesonide; Carprofen; Cicloprofen; Cintazone; Cliprofen; Clobetasol Propionate; Clobetasone Butyrate; Clopirac; Cloticasone Propionate; Cormethasone Acetate; Cortodoxone; Deflazacort; Desonide; Desoximetasone; -Dexamethasone Dipropionate; Diclofenac Potassium; Diclofenac Sodium; Diflorasone Diacetate; -Diflumidone Sodium; Diflunisal; Difluprednate; Diftalone; Dimethyl Sulfoxide; Drocinonide; Endrysone; Enlimomab Enolicam Sodium; Epirizole; Etodolac; Etofenamate; Felbinac; Fenamole; Fenbufen; Fenclofenac; Fenclorac; Fendosal; Fenpipalone; Fentiazac; Flazalone; Fluazacort; Flufenamic Acid; Flumizole; Flunisolide Acetate; Flunixin; Flunixin Meglumine; Fluocortin Butyl; Fluorometholone Acetate; Fluquazone; Flurbiprofen; Fluretofen; Fluticasone Propionate; Furaprofen; Furobufen; Halcinonide; Halobetasol Propionate; Halopredone Acetate; Ibufenac; Ibuprofen; Ibuprofen Aluminum; Ibuprofen Piconol; Ilonidap; Indomethacin; Indomethacin Sodium; Indoprofen; Indoxole; Intrazole; Isoflupredone Acetate; Isoxepac; Isoxicam; Ketoprofen; Lofemizole Hydrochloride; Lornoxicam; Loteprednol Etabonate; Meclofenamate Sodium; Meclofenamic Acid; Meclorisone Dibutyrate; Mefenamic Acid; Mesalamine; Meseclazone; Methylprednisolone Suleptanate; Momiflumate; Nabumetone; Naproxen; Naproxen Sodium; Naproxol; Nimazone; Olsalazine Sodium; Orgotein; Orpanoxin; Oxaprozin; Oxyphenbutazone; Paranyline Hydrochloride; Pentosan Polysulfate Sodium; Phenbutazone Sodium Glycerate; Pirfenidone; Piroxicam; Piroxicam Cinnamate; Piroxicam Olamine; Pirprofen; Prednazate; Prifelone; Prodolic Acid; Proquazone; Proxazole; Proxazole Citrate; Rimexolone; Romazarit; Salcolex; Salnacedin; Salsalate; Sanguinarium Chloride; Seclazone; Sermetacin; Sudoxicam; Sulindac; Suprofen; Talmetacin; Talniflumate; Talosalate; Tebufelone; Tenidap; Tenidap Sodium; Tenoxicam; Tesicam; Tesimide; Tetrydamine; Tiopinac; Tixocortol Pivalate; Tolmetin; Tolmetin Sodium; Triclonide; Triflumidate; Zidometacin; Zomepirac Sodium.

[00289] Antipsychotic and antineurotic drugs that can be used to alleviate psychiatric side effects in the methods of the invention include any and all selective serotonin receptor inhibitors (SSRIs) and other anti-depressants, anxiolytics (e.g. alprazolam), etc. Anti- depressants include, but are not limited to, serotonin reuptake inhibitors such as Celexa®, Desyrel®, Effexor®, Luvox®, Paxil®, Prozac®, Zoloft®, and Serzone®; tricyclics such as Adapin®, Anafrinil®, Elavil®, Janimmine®, Ludiomil®, Pamelor®, Tofranil®, Vivactil®, Sinequan®, and Surmontil®; monoamine oxidase inhibitors such as Eldepryl®, Marplan®, Nardil®, and Parnate®. Anti-anxiety agents include, but are not limited to, azaspirones such as BuSpar®, benzodiazepines such as Ativan®, Librium®, Tranxene®, Centrax®, Klonopin®, Paxipam®, Serax®, Valium®, and Xanax®; and beta-blockers such as Inderal® and Tenormin®.

[00290] Agents that reduce gastrointestinal discomfort such as nausea, diarrhea, gastrointestinal cramping, and the like are suitable palliative agents for use in a subject combination therapy. Suitable agents include, but are not limited to, antiemetics, anti-diarrheal agents, H2 blockers, antacids, and the like.

[00291] Suitable H2 blockers (histamine type 2 receptor antagonists) that are suitable for use as a palliative agent in a subject therapy include, but are not limited to, Cimetidine (e.g., Tagamet, Peptol, Nu-cimet, apo-cimetidine, non-cimetidine); Ranitidine (e.g., Zantac, Nu-ranit, Novo- randine, and apo-ranitidine); and Famotidine (Pepcid, Apo-Famotidine, and Novo-Famotidine).

[00292] Suitable antacids include, but are not limited to, aluminum and magnesium hydroxide (Maalox®, Mylanta®); aluminum carbonate gel (Basajel®); aluminum hydroxide (Amphojel®, AltemaGEL®); calcium carbonate (Turns®, Titralac®); magnesium hydroxide; and sodium bicarbonate.

[00293] Antiemetics include, but are not limited to, 5-hydroxytryptophan-3 (5HT3) inhibitors; corticosteroids such as dexamethasone and methylprednisolone; Marinol® (dronabinol); prochlorperazine; benzodiazepines; promethazine; and metoclopramide cisapride; Alosetron Hydrochloride; Batanopride Hydrochloride; Bemesetron; Benzquinamide; Chlorpromazine; Chlorpromazine Hydrochloride; Clebopride; Cyclizine Hydrochloride; Dimenhydrinate; Diphenidol; Diphenidol Hydrochloride; Diphenidol Pamoate; Dolasetron Mesylate; Domperidone; Dronabinol; Fludorex; Flumeridone; Galdansetron Hydrochloride; Granisetron; Granisetron Hydrochloride; Lurosetron Mesylate; Meclizine Hydrochloride; Metoclopramide Hydrochloride; Metopimazine; Ondansetron Hydrochloride; Pancopride; Prochlorperazine; Prochlo erazine Edisylate; Prochlorperazine Maleate; Promethazine Hydrochloride; Thiethylperazine; Thiethylperazine Malate; Thiethylperazine Maleate; Trimethobenzamide Hydrochloride; Zacopride Hydrochloride.. [00294] Anti-diarrheal agents include, but are not limited to, Rolgamidine, Diphenoxylate hydrochloride (Lomotil), Metronidazole (Flagyl), Methylprednisolone (Medrol), Sulfasalazine (Azulfidine), and the like.

[00295] Suitable hematopoietic agents that can be used to prevent or restore depressed blood cell populations in the methods of the invention include erythropoietins, such as EPOGEN™ epoetin-alfa, granulocyte colony stimulating factors (G-CSFs), such as NEUPOGEN™ filgrastim, granulocyte-macrophage colony stimulating factors (GM-CSFs), thrombopoietins, etc. DOSAGES, FORMULATIONS, AND ROUTES OF ADMINISTRATION

[00296] A therapeutic agent (e.g., pirfenidone, a TGF-β antagonist, a Type II interferon receptor agonist, an endothelin receptor antagonist, etc.) is administered to individuals in a formulation (e.g., in separate formulations) with a pharmaceutically acceptable excipient(s). A wide variety of pharmaceutically acceptable excipients are known in the art and need not be discussed in detail herein. Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 20th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., eds., 7^th ed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) A.H. Kibbe et al., eds., 3^r ed. Amer. Pharmaceutical Assoc.

[00297] The pharmaceutically acceptable excipients, such as vehicles, adjuvants, carriers or diluents, are readily available to the public. Moreover, pharmaceutically acceptable auxiliary substances, such as pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like, are readily available to the public.

[00298] In the subject methods, the active agents (e.g., pirfenidone, a TGF-β antagonist, a Type II interferon receptor agonist, an endothelin receptor antagonist, etc.) may be administered to the host using any convenient means capable of resulting in the desired therapeutic effect. Thus, the agents can be incorporated into a variety of formulations for therapeutic administration. More particularly, the agents (e.g., pirfenidone, a TGF-β antagonist, a Type II interferon receptor agonist, an endothelin receptor antagonist, etc.) can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers or diluents, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants and aerosols. [00299] As such, administration of the agents can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, subcutaneous, intramuscular, transdermal, intratracheal, etc., administration. In some embodiments, two different routes of administration are used. For example, in some embodiments, a first therapeutic agent is administered subcutaneously, and a second therapeutic agent is administered orally.

[00300] Subcutaneous administration of a therapeutic agent, e.g., pirfenidone, a Type II interferon receptor agonist, a TGF-β antagonist or an endothelin receptor antagonist, etc., can be accomplished using standard methods and devices, e.g., needle and syringe, a subcutaneous injection port delivery system, and the like. See, e.g., U.S. Patent Nos. 3,547,119; 4,755,173; 4,531,937; 4,311,137; and 6,017,328. A combination of a subcutaneous injection port and a device for administration of a therapeutic agent to a patient through the port is referred to herein as "a subcutaneous injection port delivery system." In some embodiments, subcutaneous administration is achieved by a combination of devices, e.g., bolus delivery by needle and syringe, followed by delivery using a continuous delivery system.

[00301] In some embodiments, a therapeutic agent, e.g., pirfenidone, a Type II interferon receptor agonist, a TGF-β antagonist or endothelin receptor antagonist, etc., is delivered by a continuous delivery system. The term "continuous delivery system" is used interchangeably herein with "controlled delivery system" and encompasses continuous (e.g., controlled) delivery devices (e.g., pumps) in combination with catheters, injection devices, and the like, a wide variety of which are known in the art.

[00302] Mechanical or electromechanical infusion pumps can also be suitable for use with the present invention. Examples of such devices include those described in, for example, U.S. Pat. Nos. 4,692,147; 4,360,019; 4,487,603; 4,360,019; 4,725,852; 5,820,589; 5,643,207; 6,198,966; and the like. In general, the present treatment methods can be accomplished using any of a variety of refillable, pump systems. Pumps provide consistent, controlled release over time. Typically, the agent (e.g., pirfenidone, a Type II interferon receptor agonist, a TGF-β antagonist, an endothelin receptor antagonist, etc.) is in a liquid formulation in a drug- impermeable reservoir, and is delivered in a continuous fashion to the individual.

[00303] In one embodiment, the drug delivery system is an at least partially implantable device. The implantable device can be implanted at any suitable implantation site using methods and devices well known in the art. An implantation site is a site within the body of a subject at which a drug delivery device is introduced and positioned. Implantation sites include, but are not necessarily limited to a subdermal, subcutaneous, intramuscular, or other suitable site within a subject's body. Subcutaneous implantation sites are generally preferred because of convenience in implantation and removal of the drug delivery device.

[00304] Drug release devices suitable for use in the invention may be based on any of a variety of modes of operation. For example, the drug release device can be based upon a diffusive system, a convective system, or an erodible system (e.g., an erosion-based system). For example, the drug release device can be an electrochemical pump, osmotic pump, an electroosmotic pump, a vapor pressure pump, or osmotic bursting matrix, e.g., where the drug is incoφorated into a polymer and the polymer provides for release of drug formulation concomitant with degradation of a drug-impregnated polymeric material (e.g., a biodegradable, drug-impregnated polymeric material). In other embodiments, the drug release device is based upon an electrodiffusion system, an electrolytic pump, an effervescent pump, a piezoelectric pump, a hydrolytic system, etc.

[00305] Drug release devices based upon a mechanical or electromechanical infusion pump can also be suitable for use with the present invention. Examples of such devices include those described in, for example, U.S. Pat. Nos. 4,692,147; 4,360,019; 4,487,603; 4,360,019; 4,725,852, and the like. In general, the present treatment methods can be accomplished using any of a variety of refillable, non-exchangeable pump systems. Pumps and other convective systems are generally preferred due to their generally more consistent, controlled release over time. Osmotic pumps are particularly preferred due to their combined advantages of more consistent controlled release and relatively small size (see, e.g., PCT published application no. WO 97/27840 and U.S. Pat. Nos. 5,985,305 and 5,728,396)). Exemplary osmotically-driven devices suitable for use in the invention include, but are not necessarily limited to, those described in U.S. Pat. Nos. 3,760,984; 3,845,770; 3,916,899; 3,923,426; 3,987,790; 3,995,631; 3,916,899; 4,016,880; 4,036,228; 4,111,202; 4,111,203; 4,203,440; 4,203,442; 4,210,139; 4,327,725; 4,627,850; 4,865,845; 5,057,318; 5,059,423; 5,112,614; 5,137,727; 5,234,692; 5,234,693; 5,728,396; and the like.

[00306] In some embodiments, the drug delivery device is an implantable device. The drug delivery device can be implanted at any suitable implantation site using methods and devices well known in tlie art. As noted infra, an implantation site is a site within the body of a subject at which a drug delivery device is introduced and positioned. Implantation sites include, but are not necessarily limited to a subdermal, subcutaneous, intramuscular, or other suitable site within a subject's body.

[00307] In some embodiments, a therapeutic agent, e.g., pirfenidone, a Type II interferon receptor agonist, a TGF-β antagonist, an endothelin receptor antagonist, etc., is delivered using an implantable drug delivery system, e.g., a system that is programmable to provide for administration of a therapeutic agent or endothelin receptor antagonist. Exemplary programmable, implantable systems include implantable infusion pumps. Exemplary implantable infusion pumps, or devices useful in connection with such pumps, are described in, for example, U.S. Pat. Nos. 4,350,155; 5,443,450; 5,814,019; 5,976,109; 6,017,328; 6,171,276; 6,241,704; 6,464,687; 6,475,180; and 6,512,954. A further exemplary device that can be adapted for the present invention is the Synchromed infusion pump (Medtronic).

[00308] In pharmaceutical dosage forms, the agents may be administered in the form of their pharmaceutically acceptable salts, or they may also be used alone or in appropriate association, as well as in combination, with other pharmaceutically active compounds. The following methods and excipients are merely exemplary and are in no way limiting.

[00309] For oral preparations, the agents can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, for example, with conventional additives, such as lactose, mannitol, corn starch or potato starch; with binders, such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators, such as corn starch, potato starch or sodium carboxymethylcellulose; with lubricants, such as talc or magnesium stearate; and if desired, with diluents, buffering agents, moistening agents, preservatives and flavoring agents.

[00310] The agents can be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives.

[00311] Furthermore, the agents can be made into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. The compounds of the present invention can be administered rectally via a suppository. The suppository can include vehicles such as cocoa butter, carbowaxes and polyethylene glycols, which melt at body temperature, yet are solidified at room temperature.

[00312] Unit dosage forms for oral or rectal administration such as syrups, elixirs, and suspensions may be provided wherein each dosage unit, for example, teaspoonful, tablespoonful, tablet or suppository, contains a predetermined amount of the composition containing one or more active agents (e.g., pirfenidone, a TGF-β antagonist, a Type II interferon receptor agonist, an endothelin receptor antagonist, etc.). Similarly, unit dosage forms for injection or intravenous administration may comprise the active agent(s) (e.g., pirfenidone, a TGF-β antagonist, a Type II interferon receptor agonist, an endothelin receptor antagonist, etc.) in a composition as a solution in sterile water, normal saline or another pharmaceutically acceptable carrier.

[00313] The term "unit dosage form," as used herein, refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of an active agent (e.g., pirfenidone, a TGF-β antagonist, a Type II interferon receptor agonist, an endothelin receptor antagonist, etc.) calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle. The specifications for each active agent depend on the particular agent employed and the effect to be achieved, and the pharmacodynamics associated with each agent in the host.

[00314] In connection with each of the methods described herein, the invention provides embodiments in which the therapeutic agent, e.g., pirfenidone, a Type II interferon receptor agonist, a TGF-β antagonist, an endothelin receptor antagonist, etc., is administered to the patient by a controlled drug delivery device. In some embodiments, the therapeutic agent is delivered to the patient substantially continuously or continuously by the controlled drug delivery device. Optionally, an implantable infusion pump is used to deliver the therapeutic agent to the patient substantially continuously or continuously by subcutaneous infusion.

[00315] In other embodiments, the therapeutic agent, e.g., pirfenidone, Type II interferon receptor agonist, TGF-β antagonist, endothelin receptor antagonist, etc., is administered to the patient so as to achieve and maintain a desired average daily serum concentration of the therapeutic agent at a substantially steady state for the duration of the therapy. Optionally, an implantable infusion pump is used to deliver the therapeutic agent to the patient by subcutaneous infusion so as to achieve and maintain a desired average daily serum concentration of the therapeutic agent at a substantially steady state for the duration of the therapy.

[00316] Effective dosages of pirfenidone or a specific pirfenidone analog include a weight- based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally. Other doses and formulations of pirfenidone and specific pirfenidone analogs suitable for use in the treatment of fibrotic diseases are described in U.S. Pat. Nos., 5,310,562; 5,518,729; 5,716,632; and 6,090,822.

[00317] Pirfenidone or a pirfenidone analog is administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00318] Multiple doses of pirfenidone or pirfenidone analog can be administered, e.g., the pirfenidone or pirfenidone analog can be administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. Pirfenidone or a pirfenidone analog and a TGF-β antagonist

[00319] In some embodiments, pirfenidone or a pirfenidone analog is administered throughout the entire course of TGF-β antagonist treatment. In other embodiments, pirfenidone or a pirfenidone analog is administered less than the entire course of TGF-β antagonist treatment, e.g., only during the first phase of TGF-β antagonist treatment, only during the second phase of TGF-β antagonist treatment, or some other portion of the TGF-β antagonist treatment regimen.

[00320] In some embodiments, the pirfenidone or pirfenidone analog and TGF-β antagonist are administered in the same formulation, and are administered simultaneously. In other embodiments, the pirfenidone or pirfenidone analog and the TGF-β antagonist are administered separately, e.g., in separate formulations. In some of these embodiments, the pirfenidone or pirfenidone analog and the TGF-β antagonist are administered separately, and are administered simultaneously. In other embodiments, the pirfenidone or pirfenidone analog and the TGF-β antagonist are administered separately and are administered within about 5 seconds to about 15 seconds, within about 15 seconds to about 30 seconds, within about 30 seconds to about 60 seconds, within about 1 minute to about 5 minutes, within about 5 minutes to about 15 minutes, within about 15 minutes to about 30 minutes, within about 30 minutes to about 60 minutes, within about 1 hour to about 2 hours, within about 2 hours to about 6 hours, within about 6 hours to about 12 hours, witnm about 12 hours to about 24 hours, or witnin aoout t hours to about 48 hours of one another.

[00321] Multiple doses of pirfenidone or pirfenidone analog can be administered, e.g., the pirfenidone or pirfenidone analog can be administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00322] Effective dosages of a TGF-β antagonist include a weight-based dosage in the range from about 0.25 mg/kg/day to about 25 mg/kg/day, or a fixed dosage of about from about 25 μg to about 1000 mg per day (e.g., from about 25 μg to about 50 μg, from about 50 μg to about 75 μg, from about 75 μg to about 100 μg, from about 100 μg to about 200 μg, from about 200 μg to about 500 μg, from about 500 μg to about 1 mg, from about 1 mg to about 10 mg, from about 10 mg to about 25 mg, from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 200 mg, from about 200 mg to about 300 mg, from about 300 mg to about 400 mg, from about 400 mg to about 500 mg, from about 500 mg to about 750 mg, or from about 750 mg to about 1000 mg, per day), admimstered orally, subcutaneously, intravenously, or intramuscularly. The dosage will depend, in part, on the specific TGF-β antagonist administered.

[00323] In some embodiments, the TGF-β antagonist is GLEEVEC™. Suitable dosages of GLEEVEC™ include, e.g., from about 25 mg to about 1000 mg daily, e.g., 25 mg to 50 mg, 50 mg to 100 mg, 100 mg to 200 mg, 200 mg to 300 mg, 300 mg to 400 mg, 400 mg to 500 mg, 500 mg to 600 mg, 600 mg to 700 mg, 700 mg to 800 mg, 800 mg to 900 mg, or 900 mg to 1000 mg of Gleevec™ daily. In certain embodiments, the total daily dose is administered to a subject as two daily doses of 25 mg to 50 mg, 50 mg to 100 mg, 100 mg to 200 mg, 200 mg to 300 mg, 300 mg to 400 mg, or 400 mg to 500 mg. hi a particular embodiment, GLEEVEC™ is administered in an amount of 400 mg GLEEVEC™ orally daily. In another particular embodiment, GLEEVEC™ is administered in an amount of 600 mg GLEEVEC™ orally daily.

[00324] A TGF-β antagonist is administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00325] Multiple doses of a TGF-β antagonist can be administered, e.g., the TGF-β antagonist can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or daily, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00326] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of pirfenidone or a pirfenidone analog, in a weight- based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; and b) a dosage a TGF-β antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[00327] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of pirfenidone containing an amount of about 400 mg orally per day, for the desired treatment duration; and b) a dosage Gleevec™ containing an amount of 400 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder. [00328] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of pirfenidone containing an amount of about 800 mg orally per day, for the desired treatment duration; and b) a dosage Gleevec™ containing an amount of 400 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00329] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of pirfenidone containing an amount of about 1000 mg orally per day, for the desired treatment duration; and b) a dosage Gleevec™ containing an amount of 400 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00330] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of pirfenidone containing an amount of about 1200 mg orally per day, for the desired treatment duration; and b) a dosage Gleevec™ containing an amount of 400 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00331] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of pirfenidone containing an amount of about 1600 mg orally per day, for the desired treatment duration; and b) a dosage Gleevec™ containing an amount of 400 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00332] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of pirfenidone containing an amount of about 1800 mg orally per day, for the desired treatment duration; and b) a dosage Gleevec™ containing an amount of 400 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00333] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of pirfenidone containing an amount of about 2400 mg orally per day, for the desired treatment duration; and b) a dosage Gleevec™ containing an amount of 400 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00334] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of pirfenidone containing an amount of about 2800 mg orally per day, for the desired treatment duration; and b) a dosage Gleevec™ containing an amount of 400 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00335] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of pirfenidone containing an amount of about 3200 mg orally per day, for the desired treatment duration; and b) a dosage Gleevec™ containing an amount of 400 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00336] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of pirfenidone containing an amount of about 3600 mg orally per day, for the desired treatment duration; and b) a dosage Gleevec™ containing an amount of 400 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00337] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of pirfenidone containing an amount of about 400 mg orally per day, for the desired treatment duration; and b) a dosage Gleevec™ containing an amount of 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00338] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of pirfenidone containing an amount of about 800 mg orally per day, for the desired treatment duration; and b) a dosage Gleevec™ containing an amount of 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00339] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of pirfenidone containing an amount of about 1000 mg orally per day, for the desired treatment duration; and b) a dosage Gleevec™ containing an amount of 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00340] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of pirfenidone containing an amount of about 1200 mg orally per day, for the desired treatment duration; and b) a dosage Gleevec™ containing an amount of 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00341] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of pirfenidone containing an amount of about 1600 mg orally per day, for the desired treatment duration; and b) a dosage Gleevec™ containing an amount of 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00342] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of pirfenidone containing an amount of about 1800 mg orally per day, for the desired treatment duration; and b) a dosage Gleevec™ containing an amount of 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00343] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of pirfenidone containing an amount of about 2400 mg orally per day, for the desired treatment duration; and b) a dosage Gleevec™ containing an amount of 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00344] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of pirfenidone containing an amount of about 2800 mg orally per day, for the desired treatment duration; and b) a dosage Gleevec™ containing an amount of 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00345] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of pirfenidone containing an amount of about 3200 mg orally per day, for the desired treatment duration; and b) a dosage Gleevec™ containing an amount of 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00346] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to tlie patient a) a dosage of pirfenidone containing an amount of about 3600 mg orally per day, for the desired treatment duration; and b) a dosage Gleevec™ containing an amount of 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder. Pirfenidone or a pirfenidone analog and an endothelin receptor antagonist

[00347] In some embodiments, pirfenidone or a pirfenidone analog is administered throughout the entire course of endothelin receptor antagonist treatment. In other embodiments, pirfenidone or a pirfenidone analog is administered less than the entire course of endothelin receptor antagonist treatment, e.g., only during the first phase of endothelin receptor antagonist treatment, only during the second phase of endothelin receptor antagonist treatment, or some other portion of the endothelin receptor antagonist treatment regimen.

[00348] In some embodiments, the pirfenidone or pirfenidone analog and endothelin receptor antagonist are administered in the same formulation, and are administered simultaneously. In other embodiments, the pirfenidone or pirfenidone analog and the endothelin receptor antagonist are administered separately, e.g., in separate formulations. In some of these embodiments, the pirfenidone or pirfenidone analog and the endothelin receptor antagonist are administered separately, and are administered simultaneously. In other embodiments, the pirfenidone or pirfenidone analog and the endothelin receptor antagonist are administered separately and are administered within about 5 seconds to about 15 seconds, within about 15 seconds to about 30 seconds, within about 30 seconds to about 60 seconds, within about 1 minute to about 5 minutes, within about 5 minutes to about 15 minutes, within about 15 minutes to about 30 minutes, within about 30 minutes to about 60 minutes, within about 1 hour to about 2 hours, within about 2 hours to about 6 hours, within about 6 hours to about 12 hours, within about 12 hours to about 24 hours, or within about 24 hours to about 48 hours of one another.

[00349] Multiple doses of pirfenidone or pirfenidone analog can be administered, e.g., the pirfenidone or pirfenidone analog can be administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00350] Effective dosages of an endothelin receptor antagonist include a weight-based dosage in the range from about 0.25 mg/kg/day to about 25 mg/kg/day, or a fixed dosage of about from about 25 μg to about 1000 mg per day (e.g., from about 25 μg to about 50 μg, from about 50 μg to about 75 μg, from about 75 μg to about 100 μg, from about 100 μg to about 200 μg, from about 200 μg to about 500 μg, from about 500 μg to about 1 mg, from about 1 mg to about 10 mg, from about 10 mg to about 25 mg, from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 200 mg, from about 200 mg to about 300 mg, from about 300 mg to about 400 mg, from about 400 mg to about 500 mg, from about 500 mg to about 750 mg, or from about 750 mg to about 1000 mg, per day). The dosage will depend, in part, on the specific endothelin receptor antagonist administered. An endothelin receptor antagonist is generally administered orally, subcutaneously, intravenously, or intramuscularly, although other routes of administration are also possible.

[00351] In some embodiments, the endothelin receptor antagonist is TRACLEER™. Suitable dosages of TRACLEER™ include, e.g., from about 25 mg to about 150 mg twice daily, e.g., from about 25 mg to about 30 mg, from about 30 mg to about 40 mg, from about 40 mg to about 50 mg, from about 50 mg to about 60 mg, from about 60 mg to about 70 mg, from about 70 mg to about 80 mg, from about 80 mg to about 90 mg, from about 90 mg to about 100 mg, from about 100 mg to about 125 mg, or from about 125 mg to about 150 mg of TRACLEER™ twice daily. In some embodiments, TRACLEER™ is administered in an amount of 62.5 mg TRACLEER ™ orally bid for 4 weeks, followed by administering TRACLEER™ in an amount of 125 mg bid orally for the desired treatment duration.

[00352] An endothelin receptor antagonist is administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00353] Multiple doses of an endothelin receptor antagonist can be administered, e.g., the pirfenidone or pirfenidone analog can be administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00354] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone or a pirfenidone analog, in a weight- based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; and b) a dosage of an endothelin receptor antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[00355] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 400 mg orally per day, for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 62.5 mg, administered orally bid for tlie desired treatment duration, to treat the fibrotic disorder.

[00356] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 800 mg orally per day, for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 62.5 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00357] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 1200 mg orally per day, for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 62.5 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00358] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 1600 mg orally per day, for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 62.5 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00359] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 1800 mg orally per day, for the desired treatment duration; and b) a dosage of TRACLEER™ containing ah amount of 62.5 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00360] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 2400 mg orally per day, for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 62.5 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00361] In some embodiments, the invention provides a combination therapy method using combined effective amoxmts of i) pirfenidone or a pirfenidone analog, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 2800 mg orally per day, for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 62.5 mg, admimstered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00362] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 3200 mg orally per day, for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 62.5 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00363] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 3600 mg orally per day, for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 62.5 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00364] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 400 mg orally per day, for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 125 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00365] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 800 mg orally per day, for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 125 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00366] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) an endothelin receptor antagonist in tlie treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 1200 mg orally per day, for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 125 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00367] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 1600 mg orally per day, for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 125 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00368] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to tlie patient a) a dosage of pirfenidone containing an amount of about 1800 mg orally per day, for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 125 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00369] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 2400 mg orally per day, for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 125 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00370] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 2800 mg orally per day, for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 125 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00371] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 3200 mg orally per day, for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 125 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00372] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, and ii) an endothelin receptor antagonist in the treatment of^" a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone containing an amount of about 3600 mg orally per day, for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 125 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder. Combination therapy with a Type II interferon receptor agonist

[00373] Effective dosages of IFN-γ can range from about 0.5 μg/m² to about 500 μg/m², usually from about 1.5 μg/m² to 200 μg/m², depending on the size of the patient. This activity is based on 10⁶ international units (U) per 50 μg of protein. IFN-γ can be administered daily, every other day, three times a week (tiw), or substantially continuously or continuously. In specific embodiments of interest, IFN-γ is administered to an individual in a unit dosage form of from about 25 μg to about 500 μg, from about 50 μg to about 400 μg, or from about 100 μg to about 300 μg. In particular embodiments of interest, the dose is about 200 μg IFN-γ. In many embodiments of interest, IFN-γ lb is administered. In some embodiments, the IFN-γ is Actimmune® human IFN-γ lb.

[00374] Where the dosage is 200 μg IFN-γ per dose, the amount of IFN-γ per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4.4 μg IFN-γ per kg body weight to about 1.48 μg IFN-γ per kg body weight.

[00375] The body surface area of individuals to be treated generally ranges from about 1.33 m to about 2.50 m². Thus, in many embodiments, an IFN-γ dosage ranges from about 150 μg/m² to about 20 μg/m². For example, an IFN-γ dosage ranges from about 20 μg/m² to about 30 μg/m², from about 30 μg/m² to about 40 μg/m², from about 40 μg/m² to about 50 μg/m², from about 50 μg/m² to about 60 μg/m², from about 60 μg/m² to about 70 μg/m², from about 70 0 0 0 0 0 μg/m to about 80 μg/m , from about 80 μg/m to about 90 μg/m , from about 90 μg/m to about 100 μg/m², from about 100 μg/m² to about 110 μg/m², from about 110 μg/m² to about 120 μg/m², from about 120 μg/m² to about 130 μg/m², from about 130 μg/m² to about 140 μg/m², or from about 140 μg/m² to about 150 μg/m². In some embodiments, the dosage groups 0 0 range from about 25 μg/m to about 100 μg/m . In other embodiments, the dosage groups range from about 25 μg/m² to about 50 μg/m². [00376] In many embodiments, multiple doses of an IFN-γ are administered. For example, an IFN-γ is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00377] In some embodiments, the IFN-γ is Actimmune® human IFN-γlb, and is administered subcutaneously tiw in a dosage containing an amount of about 25 μg, 50 μg, 100 μg, 150 μg, or 200 μg.

[00378] In some embodiments, effective dosages of IFN-γ range from about 0.5 μg/m² to about 500 μg/m², e.g., from about 1.5 μg/m² to 200 μg/m², depending on the size of the patient. This activity is based on 10⁶ international units (IU) per 50 μg of protein.

[00379] Where the agent is a polypeptide, polynucleotide (e.g., a polynucleotide encoding IFN- γ), it may be introduced into tissues or host cells by any number of routes, including viral infection, microinjection, or fusion of vesicles. Jet injection may also be used for intramuscular administration, as described by Furth et al. (1992), Anal Biochem 205:365-368. The DNA may be coated onto gold microparticles, and delivered intradermally by a particle bombardment device, or "gene gun" as described in the literature (see, for example, Tang et al. (1992), Nature 356:152-154), where gold microprojectiles are coated with the therapeutic DNA, then bombarded into skin cells. Of particular interest in these embodiments is use of a liver-specific promoter to drive transcription of an operably linked IFN-γ coding sequence preferentially in liver cells.

[00380] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means.

[00381] In particular embodiments of interest, IFN-γ is administered as a solution suitable for subcutaneous injection. For example, IFN-γ is in a formulation containing 40 mg mannitol/mL, 0.72 mg sodium succinate/mL, 0.10 mg polysorbate 20/mL. In particular embodiments of interest, IFN-γ is administered in single-dose forms of 200 μg/dose subcutaneously.

[00382] Multiple doses of IFN-γ can be administered, e.g., IFN-γ can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or daily, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. In particular embodiments of interest, IFN-γ is administered three times per week over a period of about 48 weeks.

[00383] In some embodiments, a Type II interferon receptor agonist (e.g., IFN-γ) is administered throughout the entire course of TGF-β antagonist treatment. In other embodiments, a Type II interferon receptor agonist is administered less than the entire course of TGF-β antagonist treatment, e.g., only during the first phase of TGF-β antagonist treatment, only during the second phase of TGF-β antagonist treatment, or some other portion of the TGF-β antagonist treatment regimen.

[00384] In some embodiments, the Type II interferon receptor agonist and TGF-β antagonist are administered in the same formulation, and are administered simultaneously. In other embodiments, the Type II interferon receptor agonist and the TGF-β antagonist are administered separately, e.g., in separate formulations. In some of these embodiments, the Type II interferon receptor agonist and the TGF-β antagonist are administered separately, and are administered simultaneously. In other embodiments, the Type II interferon receptor agonist and the TGF-β antagonist are administered separately and are administered within about 5 seconds to about 15 seconds, within about 15 seconds to about 30 seconds, within about 30 seconds to about 60 seconds, within about 1 minute to about 5 minutes, within about 5 minutes to about 15 minutes, within about 15 minutes to about 30 minutes, within about 30 minutes to about 60 minutes, within about 1 hour to about 2 hours, within about 2 hours to about 6 hours, within about 6 hours to about 12 hours, within about 12 hours to about 24 hours, or within about 24 hours to about 48 hours of one another.

[00385] Effective dosages of a TGF-β antagonist include a weight-based dosage in the range from about 0.25 mg/kg/day to about 25 mg/kg/day, or a fixed dosage of about from about 25 μg to about 1000 mg per day (e.g., from about 25 μg to about 50 μg, from about 50 μg to about 75 μg, from about 75 μg to about 100 μg, from about 100 μg to about 200 μg, from about 200 μg to about 500 μg, from about 500 μg to about 1 mg, from about 1 mg to about 10 mg, from about 10 mg to about 25 mg, from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 200 mg, from about 200 mg to about 300 mg, from about 300 mg to about 400 mg, from about 400 mg to about 500 mg, from about 500 mg to about 750 mg, or from about 750 mg to about 1000 mg, per day), administered orally, subcutaneously, intravenously, or intramuscularly. The dosage will depend, in part, on the specific TGF-β antagonist administered. [00386] In some embodiments, the TGF-β antagonist is GLEEVEC™. Suitable dosages of GLEEVEC™ include, e.g., from about 25 mg to about 1000 mg daily, e.g., 25 mg to 50 mg, 50 mg to 100 mg, 100 mg to 200 mg, 200 mg to 300 mg, 300 mg to 400 mg, 400 mg to 500 mg, 500 mg to 600 mg, 600 mg to 700 mg, 700 mg to 800 mg, 800 mg to 900 mg, or 900 mg to 1000 mg of Gleevec™ daily. In certain embodiments, the total daily dose is administered to a subject as two daily doses of 25 mg to 50 mg, 50 mg to 100 mg, 100 mg to 200 mg, 200 mg to 300 mg, 300 mg to 400 mg, or 400 mg to 500 mg. In a particular embodiment, GLEEVEC™ is administered in an amount of 400 mg GLEEVEC™ orally daily. In another particular embodiment, GLEEVEC™ is administered in an amount of 600 mg GLEEVEC™ orally daily.

[00387] A TGF-β antagonist is administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00388] Multiple doses of a TGF-β antagonist can be administered, e.g., the TGF-β antagonist can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or daily, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00389] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a dosage of IFN-γ, in a size-based dosage in the range from about 25 μg/m² to about 100 μg/m², or a fixed dosage of from about 50μg to about 200 μg, administered subcutaneously tiw for the desired treatment duration; and b) a dosage a TGF-β antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to treat the fibrotic disorder. [00390] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co- administering to the patient a) a size-based dosage of IFN-γ containing an amount of from 0 0 about 25 μg/m to about 100 μg/m , or a fixed dosage of IFN-γ containing an amount of from about 50μg to about 200 μg, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of Gleevec™ containing an amount of 400 mg or 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00391] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of from about 25 μg/m² to about 100 μg/m² IFN-γ, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of Gleevec™ containing an amount of 400 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00392] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of from about 25 μg/m² to about 50 μg/m² IFN-γ, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of Gleevec™ containing an amount of 400 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00393] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of from about 50μg to about 200 μg IFN-γ, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of Gleevec™ containing an amount of 400 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00394] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of from about 50μg to about 100 μg IFN-γ, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of Gleevec™ containing an amount of 400 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00395] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of about 200 μg IFN-γ, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of Gleevec™ containing an amount of 400 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00396] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount 0 0 of from about 25 μg/m to about 100 μg/m IFN-γ, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of Gleevec™ containing an amount of 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00397] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of from about 25 μg/m² to about 50 μg/m² IFN-γ, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of Gleevec™ containing an amount of 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00398] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of from about 50μg to about 200 μg IFN-γ, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of Gleevec™ containing an amount of 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00399] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of from about 50μg to about 100 μg IFN-γ, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of Gleevec™ containing an amount of 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00400] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of about 200 μg IFN-γ, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of Gleevec™ containing an amount of 600 mg, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00401] In some embodiments, a Type II interferon receptor agonist (e.g., IFN-γ) is administered throughout the entire course of endothelin receptor antagonist treatment. In other embodiments, a Type II interferon receptor agonist is administered less than the entire course of endothelin receptor antagonist treatment, e.g., only during the first phase of endothelin receptor antagonist treatment, only during the second phase of endothelin receptor antagonist treatment, or some other portion of the endothelin receptor antagonist treatment regimen.

[00402] In some embodiments, the Type II interferon receptor agonist and the endothelin receptor antagonist are administered in the same formulation, and are administered simultaneously. In other embodiments, the Type II interferon receptor agonist and the endothelin receptor antagonist are administered separately, e.g., in separate formulations. In some of these embodiments, the Type II interferon receptor agonist and the endothelin receptor antagonist are administered separately, and are administered simultaneously. In other embodiments, the Type II interferon receptor agonist and the endothelin receptor antagonist are administered separately and are administered within about 5 seconds to about 15 seconds, within about 15 seconds to about 30 seconds, within about 30 seconds to about 60 seconds, within about 1 minute to about 5 minutes, witliin about 5 minutes to about 15 minutes, within about 15 minutes to about 30 minutes, within about 30 minutes to about 60 minutes, within about 1 hour to about 2 hours, within about 2 hours to about 6 hours, within about 6 hours to about 12 hours, within about 12 hours to about 24 hours, or within about 24 hours to about 48 hours of one another.

[00403] Effective dosages of an endothelin receptor antagonist include a weight-based dosage in the range from about 0.25 mg/kg/day to about 25 mg/kg/day, or a fixed dosage of about from about 25 μg to about 1000 mg per day (e.g., from about 25 μg to about 50 μg, from about 50 μg to about 75 μg, from about 75 μg to about 100 μg, from about 100 μg to about 200 μg, from about 200 μg to about 500 μg, from about 500 μg to about 1 mg, from about 1 mg to about 10 mg, from about 10 mg to about 25 mg, from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 200 mg, from about 200 mg to about 300 mg, from about 300 mg to about 400 mg, from about 400 mg to about 500 mg, from about 500 mg to about 750 mg, or from about 750 mg to about 1000 mg, per day). The dosage will depend, in part, on the specific endothelin receptor antagonist administered. An endothelin receptor antagonist is generally administered orally, subcutaneously, intravenously, or intramuscularly, although other routes of administration are also possible.

[00404] In some embodiments, the endothelin receptor antagonist is TRACLEER™. Suitable dosages of TRACLEER™ include, e.g., from about 25 mg to about 250 mg once or twice daily, e.g., from about 25 mg to about 30 mg, from about 30 mg to about 40 mg, from about 40 mg to about 50 mg, from about 50 mg to about 60 mg, from about 60 mg to about 70 mg, from about 70 mg to about 80 mg, from about 80 mg to about 90 mg, from about 90 mg to about 100 mg, from about 100 mg to about 125 mg, or from about 125 mg to about 150 mg of TRACLEER™ once or twice daily. In some embodiments, TRACLEER™ is administered in an amount of 62.5 mg TRACLEER ™ orally bid for 4 weeks, followed by administering TRACLEER™ in an amount of 125 mg bid orally for the desired treatment duration.

[00405] An endothelin receptor antagonist is administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00406] Multiple doses of an endothelin receptor antagonist can be administered, e.g., the endothelin receptor antagonist can be administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. [00407] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ, in a size-based dosage in the range from 0 about 25 μg/m to about 100 μg/m , or a fixed dosage of from about 50μg to about 200 μg, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of an endothelin receptor antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[00408] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-γ containing an amount of from about 25 μg/m² to about 100 μg/m², or a fixed dosage of IFN-γ containing an amount of from about 50μg to about 200 μg, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 62.5 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00409] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of from about 25 μg/m² to about 100 μg/m² IFN-γ, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 62.5 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00410] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of from about 25 μg/m² to about 50 μg/m² IFN-γ, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 62.5 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00411] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of from about 50μg to about 200 μg IFN-γ, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of TRACLEER™ contaimng an amount of 62.5 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00412] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of from about 50μg to about 100 μg IFN-γ, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 62.5 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00413] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) an endothelin antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of about 200 μg IFN-γ, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 62.5 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00414] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-γ containing an amount of from about 25 μg/m² to about 100 μg/m², or a fixed dosage of IFN-γ containing an amount of from about 50μg to about 200 μg, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 125 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00415] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) an endothelin receptor antagonist in tlie treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing 0 0 an amount of from about 25 μg/m to about 100 μg/m IFN-γ, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 125 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder. [00416] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing 0 0 an amount of from about 25 μg/m to about 50 μg/m IFN-γ, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 125 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00417] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of from about 50μg to about 200 μg IFN-γ, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 125 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00418] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of from about 50μg to about 100 μg IFN-γ, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 125 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00419] In one embodiment, the present invention provides for treatment of a fibrotic disorder, comprising administering combined effective amounts of i) a Type II interferon receptor agonist, and ii) an endothelin antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of about 200 μg IFN-γ, administered subcutaneously tiw for the desired treatment duration; and b) a dosage of TRACLEER™ containing an amount of 125 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder. Combination therapy comprising administering pirfenidone, a pirfenidone analog or a Type II interferon receptor agonist, a TGF-β antagonist or an endothelin receptor antagonist, and at least one additional therapeutic agent

[00420] Any of the above-described treatment regimens can be modified by administration of one or more additional therapeutic agents. Suitable additional therapeutic agents include, but are not limited to, pirfenidone or a pirfenidone analog, a TGF-β receptor antagonist, an endothelin receptor antagonist, a Type II interferon receptor agonist, a tumor necrosis factor (TNF) antagonist, a Type I interferon receptor agonist, and the like. Pirfenidone or a pirfenidone analog

[00421] Effective dosages of pirfenidone or a specific pirfenidone analog include a weight- based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally. Other doses and formulations of pirfenidone and specific pirfenidone analogs suitable for use in the treatment of fibrotic diseases are described in U.S. Pat. Nos., 5,310,562; 5,518,729; 5,716,632; and 6,090,822.

[00422] Pirfenidone or a pirfenidone analog is administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00423] Multiple doses of pirfenidone or pirfenidone analog can be administered, e.g., the pirfenidone or pirfenidone analog can be administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. [00424] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) an endothelin receptor antagonist, and iii) pirfenidone or a pirfenidone analog in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN- γ containing an amount of from about 25 μg to about 500 μg subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration; b) a dosage of an endothelin receptor antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration; and c) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration, to treat the fibrotic disorder.

[00425] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) an endothelin receptor antagonist, and iii) pirfenidone or a pirfenidone analog in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN- γ containing an amount of from about 25 μg to about 500 μg subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration; b) a dosage of TRACLEER™ containing an amount of 62.5 mg or 125 mg, administered orally bid for the desired treatment duration; and c) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration, to treat the fibrotic disorder.

[00426] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) an endothelin receptor antagonist, and iii) pirfenidone or a pirfenidone analog in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based 0 0 dosage of IFN-γ containing an amount of from about 25 μg/m to about 100 μg/m , or a fixed dosage of IFN-γ containing an amount of from about 50 μg to about 200 μg, administered subcutaneously tiw for the desired treatment duration; b) a dosage of an endothelin receptor antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration; and c) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration, to treat the fibrotic disorder. [00427] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) an endothelin receptor antagonist, and iii) pirfenidone or a pirfenidone analog in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based 0 0 dosage of IFN-γ containing an amount of from about 25 μg/m to about 100 μg/m , or a fixed dosage of IFN-γ containing an amount of from about 50 μg to about 200 μg, administered subcutaneously tiw for the desired treatment duration; b) a dosage of TRACLEER™ containing an amount of 62.5 mg or 125 mg, administered orally bid for the desired treatment duration; and c) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration, to treat the fibrotic disorder. [00428] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-β antagonist, and iii) pirfenidone or a pirfenidone analog in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of from about 25 μg to about 500 μg subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once montlily, for the desired treatment duration; b) a dosage of a TGF-β antagonist contaimng an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and c) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration, to treat the fibrotic disorder. [00429] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-β antagonist, and iii) pirfenidone or a pirfenidone analog in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-γ containing an amount of from about 25 μg/m² to about 100 μg/m², or a fixed dosage of IFN-γ containing an amount of from about 50 μg to about 200 μg, administered subcutaneously tiw for the desired treatment duration; b) a dosage of a TGF-β antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and c) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration, to treat the fibrotic disorder.

[00430] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-β antagonist, and iii) pirfenidone or a pirfenidone analog in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-γ containing an amount of from about 25 μg/m² to about 100 μg/m², or a fixed dosage of IFN-γ containing an amount of from about 50 μg to about 200 μg, administered subcutaneously tiw for the desired treatment duration; b) a dosage of Gleevec™ containing an amount of 400 mg or 600 mg, administered orally once daily for the desired treatment duration; and c) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration, to treat the fibrotic disorder. TGF-β antagonists

[00431] In some embodiments, a subject therapeutic regimen further involves administering a TGF-β antagonist. Effective amounts of a TGF-β antagonist include a weight-based dosage in the range from about 0.25 mg/kg/day to about 25 mg/kg/day, or a fixed dosage of about from about 25 μg to about 1000 mg per day (e.g., from about 25 μg to about 50 μg, from about 50 μg to about 75 μg, from about 75 μg to about 100 μg, from about 100 μg to about 200 μg, from about 200 μg to about 500 μg, from about 500 μg to about 1 mg, from about 1 mg to about 10 mg, from about 10 mg to about 25 mg, from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 200 mg, from about 200 mg to about 300 mg, from about 300 mg to about 400 mg, from about 400 mg to about 500 mg, from about 500 mg to about 750 mg, or from about 750 mg to about 1000 mg, per day), administered orally, subcutaneously, intravenously, or intramuscularly. The dosage will depend, in part, on the specific TGF-β antagonist administered.

[00432] In some embodiments, the TGF-β antagonist is GLEEVEC™. Suitable dosages of GLEEVEC™ include, e.g., from about 25 mg to about 1000 mg daily, e.g., 25 mg to 50 mg, 50 mg to 100 mg, 100 mg to 200 mg, 200 mg to 300 mg, 300 mg to 400 mg, 400 mg to 500 mg, 500 mg to 600 mg, 600 mg to 700 mg, 700 mg to 800 mg, 800 mg to 900 mg, or 900 mg to 1000 mg of Gleevec™ daily. In certain embodiments, the total daily dose is administered to a subject as two daily doses of 25 mg to 50 mg, 50 mg to 100 mg, 100 mg to 200 mg, 200 mg to 300 mg, 300 mg to 400 mg, or 400 mg to 500 mg. In a particular embodiment, GLEEVEC™ is administered in an amount of 400 mg GLEEVEC™ orally daily. In another particular embodiment, GLEEVEC™ is administered in an amount of 600 mg GLEEVEC™ orally daily.

[00433] A TGF-β antagonist is administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00434] Multiple doses of a TGF-β antagonist can be administered, e.g., the TGF-β antagonist can be administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or daily, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00435] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) an endothelin receptor antagonist, and iii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of from about 25 μg to about 500 μg subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; b) a dosage of an endothelin receptor antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or inframuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration; and c) a dosage of a TGF-β antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, infravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired freatment duration, to treat the fibrotic disorder.

[00436] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) an endothelin receptor antagonist, and iii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of from about 25 μg to about 500 μg subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; b) a dosage of TRACLEER™ containing an amount of 62.5 mg or 125 mg, administered orally bid for the desired freatment duration; and c) a dosage of GLEEVEC™ containing an amount of 400 mg or 600 mg per day, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder.

[00437] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) an endothelin receptor antagonist, and iii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-γ containing an amount of from about 25 μg/m² to about 100 μg/m², or a fixed dosage of IFN-γ containing an amount of from about 50 μg to about 200 μg, administered subcutaneously tiw for the desired treatment duration; b) a dosage of an endothelin receptor antagonist containing an amoxmt of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and c) a dosage of GLEEVEC™ containing an amount of 400 mg or 600 mg per day, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder. [00438] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) an endothelin receptor antagonist, and iii) a TGF-β antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-γ containing an amount of from about 25 μg/m² to about 100 μg/m², or a fixed dosage of IFN-γ containing an amount of from about 50 μg to about 200 μg, administered subcutaneously tiw for the desired treatment duration; b) a dosage of TRACLEER™ containing an amount of 62.5 mg or 125 mg, administered orally bid for the desired treatment duration; and c) a dosage of GLEEVEC™ containing an amount of 400 mg or 600 mg per day, administered orally once daily for the desired treatment duration, to treat the fibrotic disorder. Endothelin receptor antagonists

[00439] In some embodiments, a subject therapeutic regimen further involves administering an endothelin receptor antagonist. Effective dosages of an endothelin receptor antagonist include a weight-based dosage in the range from about 0.25 mg/kg/day to about 25 mg/kg/day, or a fixed dosage of about from about 25 μg to about 1000 mg per day (e.g., from about 25 μg to about 50 μg, from about 50 μg to about 75 μg, from about 75 μg to about 100 μg, from about 100 μg to about 200 μg, from about 200 μg to about 500 μg, from about 500 μg to about 1 mg, from about 1 mg to about 10 mg, from about 10 mg to about 25 mg, from about 25 mg to about 50 mg, from about 50 mg to about 100 mg, from about 100 mg to about 200 mg, from about 200 mg to about 300 mg, from about 300 mg to about 400 mg, from about 400 mg to about 500 mg, from about 500 mg to about 750 mg, or from about 750 mg to about 1000 mg, per day). The dosage will depend, in part, on the specific endothelin receptor antagonist administered. An endothelin receptor antagonist is generally administered orally, subcutaneously, intravenously, or intramuscularly, although other routes of administration are also possible.

[00440] In some embodiments, the endothelin receptor antagonist is TRACLEER™. Suitable dosages of TRACLEER™ include, e.g., from about 25 mg to about 150 mg once or twice daily, e.g., from about 25 mg to about 30 mg, from about 30 mg to about 40 mg, from about 40 mg to about 50 mg, from about 50 mg to about 60 mg, from about 60 mg to about 70 mg, from about 70 mg to about 80 mg, from about 80 mg to about 90 mg, from about 90 mg to about 100 mg, from about 100 mg to about 125 mg, or from about 125 mg to about 150 mg of TRACLEER™ once or twice daily. In some embodiments, TRACLEER™ is administered in an amount of 62.5 mg TRACLEER ™ orally bid for 4 weeks, followed by administering TRACLEER™ in an amount of 125 mg bid orally for the desired treatment duration. [00441] An endothelin receptor antagonist is administered once per month, twice per month, three times per month, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, daily, or in divided daily doses ranging from once daily to 5 times daily over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00442] Multiple doses of an endothelin receptor antagonist can be administered, e.g., the endothelin receptor antagonist can be administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00443] In some embodiments, the invention provides a combination therapy method using combined effective amoxints of i) pirfenidone or a pirfenidone analog, ii) a TGF-β antagonist, and iii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired freatment duration; b) a dosage of a TGF-β antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and c) a dosage of an endothelin receptor antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration, to treat the fibrotic disorder. [00444] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, ii) a TGF-β antagonist, and iii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; b) a dosage of GLEEVEC™ containing an amount of 400 mg or 600 mg per day, administered orally once daily for the desired treatment duration; and c) a dosage of TRACLEER™ containing an amount of 62.5 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00445] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, ii) a TGF-β antagonist, and iii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; b) a dosage of GLEEVEC™ containing an amount of 400 mg or 600 mg per day, administered orally once daily for the desired treatment duration; and c) a dosage of TRACLEER™ containing an amount of 125 mg, administered orally bid for the desired treatment duration, to treat the fibrotic disorder.

[00446] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-β antagonist, and iii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of from about 25 μg to about 500 μg subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; b) a dosage of a TGF-β antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and c) a dosage of an endothelin receptor antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to treat the fibrotic disorder. [00447] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-β antagonist, and iii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-γ containing 0 0 an amount of from about 25 μg/m to about 100 μg/m , or a fixed dosage of IFN-γ containing an amount of from about 50 μg to about 200 μg, administered subcutaneously tiw for the desired treatment duration; b) a dosage of a TGF-β antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and c) a dosage of an endothelin receptor antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to treat the fibrotic disorder. [00448] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-β antagonist, and iii) an endothelin receptor antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-γ containing 0 0 an amount of from about 25 μg/m to about 100 μg/m , or a fixed dosage of IFN-γ containing an amount of from about 50μg to about 200 μg, administered subcutaneously tiw for the desired freatment duration; b) a dosage of Gleevec™ containing an amount of 400 mg or 600 mg, administered orally once daily for the desired treatment duration; and c) a dosage of TRACLEER™ containing an amount of 62.5 mg or 125 mg, administered orally bid for the desired freatment duration, to treat the fibrotic disorder. Type II interferon receptor agonists [00449] In some embodiments, a subject combination therapy involves modifying any of the above-described regimens by administering a Type II interferon receptor agonist, e.g., IFN-γ. Effective dosages of IFN-γ can range from about 0.5 μg/m² to about 500 μg/m², usually from about 1.5 μg/m² to 200 μg/m², depending on the size of the patient. This activity is based on 10⁶ international units (U) per 50 μg of protein. IFN-γ can be administered daily, every other day, three times a week (tiw), or substantially continuously or continuously. In specific embodiments of interest, IFN-γ is administered to an individual in a unit dosage form of from about 25 μg to about 500 μg, from about 50 μg to about 400 μg, or from about 100 μg to about 300 μg. In particular embodiments of interest, the dose is about 200 μg IFN-γ. In many embodiments of interest, IFN-γ lb is administered. In some embodiments, the IFN-γ is Actimmune® human IFN-γ lb.

[00450] Where the dosage is 200 μg IFN-γ per dose, the amount of IFN-γ per body weight (assuming a range of body weights of from about 45 kg to about 135 kg) is in the range of from about 4.4 μg IFN-γ per kg body weight to about 1.48 μg IFN-γ per kg body weight.

[00451] The body surface area of individuals to be treated generally ranges from about 1.33 m² 0 to about 2.50 m . Thus, in many embodiments, an IFN-γ dosage ranges from about 150 μg/m 0 0 to about 20 μg/m . For example, an IFN-γ dosage ranges from about 20 μg/m to about 30 0 0 0 μg/m , from about 30 μg/m to about 40 μg/m , from about 40 μg/m to about 50 μg/m , from 0 0 0 0 about 50 μg/m to about 60 μg/m , from about 60 μg/m to about 70 μg/m , from about 70 0 0 0 0 0 μg/m to about 80 μg/m , from about 80 μg/m to about 90 μg/m , from about 90 μg/m to about 100 μg/m², from about 100 μg/m² to about 110 μg/m², from about 110 μg/m² to about 120 μg/m², from about 120 μg/m² to about 130 μg/m², from about 130 μg/m² to about 140 μg/m², or from about 140 μg/m² to about 150 μg/m². In some embodiments, the dosage groups range from about 25 μg/m² to about 100 μg/m². In other embodiments, the dosage groups range from about 25 μg/m² to about 50 μg/m².

[00452] In many embodiments, multiple doses of an IFN-γ are administered. For example, an IFN-γ is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00453] In some embodiments, the IFN-γ is Actimmune® human IFN-γ lb, and is administered subcutaneously tiw in a dosage containing an amount of about 25 μg, 50 μg, 100 μg, 150 μg, or 200 μg.

[00454] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, ii) a TGF-β antagonist, and iii) a Type II interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; b) a dosage of a TGF-β antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or inframuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration; and c) a dosage of IFN-γ containing an amount of from about 25 μg to about 500 μg subcutaneously qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[00455] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, ii) a TGF-β antagonist, and iii) a Type II interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; b) a dosage of GLEEVEC™ containing an amount of 400 mg or 600 mg per day, administered orally once daily for the desired treatment duration; and c) a dosage of IFN-γ containing an amount of from about 25 μg to about 500 μg subcutaneously qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[00456] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, ii) a TGF-β antagonist, and iii) a Type II interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to tlie patient a) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; b) a dosage of GLEEVEC™ containing an amount of 400 mg or 600 mg per day, administered orally once daily for the desired treatment duration; and c) a dosage of Actimmune® human IFN-γ lb containing an amount of about 25 μg, 50 μg, 100 μg, 150 μg, or 200 μg, administered subcutaneously tiw, to treat the fibrotic disorder. [00457] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, ii) an endothelin receptor antagonist, and iii) a Type II interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; b) a dosage of an endothelin receptor antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and c) a dosage of IFN-γ containing an amount of from about 25 μg to about 500 μg subcutaneously qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[00458] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, ii) an endothelin receptor antagonist, and iii) a Type II interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; b) a dosage of TRACLEER™ containing an amount of 62.5 mg or 125 mg, administered orally bid for the desired treatment duration; and c) a dosage of IFN-γ containing an amount of from about 25 μg to about 500 μg subcutaneously qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[00459] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, ii) a TGF-β antagonist, and iii) a Type II interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; b) a dosage of TRACLEER™ containing an amount of 62.5 mg or 125 mg, administered orally bid for the desired treatment duration; and c) a dosage of Actimmune® human IFN-γ lb containing an amount of about 25 μg, 50 μg, 100 μg, 150 μg, or 200 μg, administered subcutaneously tiw for the desired treatment duration, to treat the fibrotic disorder TNF antagonists

[00460] In some embodiments, a subject therapeutic regimen further involves administering a TNF antagonist. Effective dosages of a TNF-α antagonist range from 0.1 μg to 40 mg per dose, e.g., from about 0.1 μg to about 0.5 μg per dose, from about 0.5 μg to about 1.0 μg per dose, from about 1.0 μg per dose to about 5.0 μg per dose, from about 5.0 μg to about 10 μg per dose, from about 10 μg to about 20 μg per dose, from about 20 μg per dose to about 30 μg per dose, from about 30 μg per dose to about 40 μg per dose, from about 40 μg per dose to about 50 μg per dose, from about 50 μg per dose to about 60 μg per dose, from about 60 μg per dose to about 70 μg per dose, from about 70 μg to about 80 μg per dose, from about 80 μg per dose to about 100 μg per dose, from about 100 μg to about 150 μg per dose, from about 150 μg to about 200 μg per dose, from about 200 μg per dose to about 250 μg per dose, from about 250 μg to about 300 μg per dose, from about 300 μg to about 400 μg per dose, from about 400 μg to about 500 μg per dose, from about 500 μg to about 600 μg per dose, from about 600 μg to about 700 μg per dose, from about 700 μg to about 800 μg per dose, from about 800 μg to about 900 μg per dose, from about 900 μg to about 1000 μg per dose, from about 1 mg to about 10 mg per dose, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[00461] In some embodiments, the TNF-α antagonist is ENBREL® etanercept. Effective dosages of etanercept range from about 0.1 μg to about 40 mg per dose, from about 0.1 μg to about 1 μg per dose, from about 1 μg to about 10 μg per dose, from about 10 μg to about 100 μg per dose, from about 100 μg to about 1 mg per dose, from about 1 mg to about 5 mg per dose, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg per dose, from about 15 mg to about 20 mg per dose, from about 20 mg to about 25 mg per dose, from about 25 mg to about 30 mg per dose, from about 30 mg to about 35 mg per dose, or from about 35 mg to about 40 mg per dose.

[00462] In some embodiments, effective dosages of a TNF-α antagonist are expressed as mg/kg body weight. In these embodiments, effective dosages of a TNF-α antagonist are from about 0.1 mg/kg body weight to about 10 mg/kg body weight, e.g., from about 0.1 mg/kg body weight to about 0.5 mg/kg body weight, from about 0.5 mg/kg body weight to about 1.0 mg/kg body weight, from about 1.0 mg/kg body weight to about 2.5 mg/kg body weight, from about 2.5 mg/kg body weight to about 5.0 mg/kg body weight, from about 5.0 mg/kg body weight to about 7.5 mg/kg body weight, or from about 7.5 mg/kg body weight to about 10 mg/kg body weight.

[00463] In some embodiments, the TNF-α antagonist is REMICADE® infliximab. Effective dosages of REMICADE® range from about 0.1 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 0.5 mg/kg, from about 0.5 mg/kg to about 1.0 mg/kg, from about 1.0 mg/kg to about 1.5 mg/kg, from about 1.5 mg/kg to about 2.0 mg/kg, from about 2.0 mg/kg to about 2.5 mg/kg, from about 2.5 mg/kg to about 3.0 mg/kg, from about 3.0 mg/kg to about 3.5 mg/kg, from about 3.5 mg/kg to about 4.0 mg/kg, from about 4.0 mg/kg to about 4.5 mg/kg, from about 4.5 mg/kg to about 5.0 mg/kg, from about 5.0 mg/kg to about 7.5 mg/kg, or from about 7.5 mg/kg to about 10 mg/kg per dose.

[00464] In some embodiments the TNF-α antagonist is HUMIRA™ adalimumab. Effective dosages of HUMIRA™ range from about 0.1 μg to about 35 mg, from about 0.1 μg to about 1 μg, from about 1 μg to about 10 μg, from about 10 μg to about 100 μg, from about 100 μg to about 1 mg, from about 1 mg to about 5 mg, from about 5 mg to about 10 mg, from about 10 mg to about 15 mg, from about 15 mg to about 20 mg, from about 20 mg to about 25 mg, from about 25 mg to about 30 mg, from about 30 mg to about 35 mg, or from about 35 mg to about 40 mg per dose.

[00465] In many embodiments, a TNF-α antagonist is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be administered over longer periods of time. The TNF-α antagonist can be administered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously.

[00466] In many embodiments, multiple doses of a TNF-α antagonist are administered. For example, a TNF-α antagonist is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00467] Those of skill in the art will readily appreciate that dose levels can vary as a function of the specific compounds, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

[00468] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, ii) a TGF-β antagonist or an endothelin receptor antagonist, and iii) a TNF antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; b) a dosage of a TGF-β antagonist or an endothelin receptor antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, infravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and c) a dosage of a TNF antagonist containing an amount of from about 0.1 μg to 40 mg administered subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[00469] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, ii) a TGF-β antagonist, and iii) a TNF antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; b) a dosage of GLEEVEC™ containing an amount of 400 mg or 600 mg per day, admimstered orally once daily for the desired freatment duration; and c) a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired freatment duration, to treat the fibrotic disorder.

[00470] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, ii) a TGF-β antagonist, iii) a TNF antagonist, and iv) a Type II interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; b) a dosage of GLEEVEC™ containing an amount of 400 mg or 600 mg per day, administered orally once daily for the desired treatment duration; c) a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and d) a dosage of Actimmune® human IFN-γlb containing an amount of about 25 μg, 50 μg, 100 μg, 150 μg, or 200 μg, administered subcutaneously tiw, to treat the fibrotic disorder.

[00471] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, ii) an endothelin receptor antagonist, and iii) a TNF antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; b) a dosage of an endothelin receptor antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or inframuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and c) a dosage of a TNF antagonist containing an amount of from about 0.1 μg to 40 mg administered subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, tliree times per month, or once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[00472] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, ii) an endothelin receptor antagonist, and iii) a TNF antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration; b) a dosage of TRACLEER™ containing an amount of 62.5 mg or 125 mg, administered orally bid for the desired freatment duration; and c) a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug infravenously qw, qow, tliree times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration, to treat the fibrotic disorder.

[00473] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) pirfenidone or a pirfenidone analog, ii) an endothelin receptor antagonist, iii) a TNF antagonist, and iv) a Type II interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired freatment duration; b) a dosage of TRACLEER™ containing an amount of 62.5 mg or 125 mg, administered orally bid for the desired treatment duration; c) a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug infravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and d) a dosage of Actimmune® human IFN-γlb containing an amount of about 25 μg, 50 μg, 100 μg, 150 μg, or 200 μg, administered subcutaneously tiw for the desired treatment duration, to treat the fibrotic disorder.

[00474] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-β antagonist, and iii) a TNF antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of from about 25 μg to about 500 μg subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, tliree times per month, or once monthly, for the desired treatment duration; b) a dosage of a TGF-β antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, tliree times per month, or once monthly, for the desired treatment duration; and c) a dosage of a TNF antagonist containing an amount of from about 0.1 μg to 40 mg administered subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired freatment duration, to treat the fibrotic disorder.

[00475] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-β antagonist, and iii) a TNF antagonist in the freatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-γ containing an amount of from about 25 μg/m² to about 100 μg/m², or a fixed dosage of IFN-γ containing an amount of from about 50 μg to about 200 μg, administered subcutaneously tiw for the desired treatment duration; b) a dosage of a TGF-β antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, tliree times per month, or once monthly, for the desired treatment duration; and c) a dosage of a TNF antagonist containing an amount of from about 0.1 μg to 40 mg administered subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired freatment duration, to treat the fibrotic disorder.

[00476] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-β antagonist, and iii) a TNF antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-γ containing an amount of from about 25 μg/m² to about 100 μg/m², or a fixed dosage of IFN-γ containing an amount of from about 50μg to about 200 μg, administered subcutaneously tiw for tlie desired treatment duration; b) a dosage of Gleevec™ containing an amount of 400 mg or 600 mg, administered orally once daily for the desired treatment duration; and c) a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration, to treat the fibrotic disorder.

[00477] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-β antagonist, iii) a TNF antagonist, and iv) pirfenidone or a pirfenidone analog in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN- γ containing an amount of from about 25 μg to about 500 μg subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; b) a dosage of a TGF-β antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired freatment duration; c) a dosage of a TNF antagonist containing an amount of from about 0.1 μg to 40 mg administered subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly; and d) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired freatment duration, for the desired treatment duration, to treat the fibrotic disorder.

[00478] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-β antagonist, iii) a TNF antagonist, and iv) pirfenidone or a pirfenidone analog in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based 0 0 dosage of IFN-γ containing an amount of from about 25 μg/m to about 100 μg/m , or a fixed dosage of IFN-γ containing an amount of from about 50 μg to about 200 μg, administered subcutaneously tiw for the desired treatment duration; b) a dosage of a TGF-β antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; c) a dosage of a TNF antagonist containing an amount of from about 0.1 μg to 40 mg administered subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and d) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, administered orally for the desired treatment duration, to treat the fibrotic disorder. [00479] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-β antagonist, iii) a TNF antagonist, and iv) pirfenidone or a pirfenidone analog in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based 0 0 dosage of IFN-γ containing an amount of from about 25 μg/m to about 100 μg/m , or a fixed dosage of IFN-γ containing an amount of from about 50μg to about 200 μg, administered subcutaneously tiw for the desired freatment duration; b) a dosage of Gleevec™ containing an amount of 400 mg or 600 mg, administered orally once daily for the desired treatment duration; and c) a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration; and d) a dosage of pirfenidone or a pirfenidone analog, in a weight-based dosage in the range from about 5 mg/kg/day to about 125 mg/kg/day, or a fixed dosage of about 400 mg to about 3600 mg per day, or about 800 mg to about 2400 mg per day, or about 1000 mg to about 1800 mg per day, or about 1200 mg to about 1600 mg per day, admimstered orally for the desired freatment duration, to treat the fibrotic disorder. [00480] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) an endothelin receptor antagonist, and iii) a TNF antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of from about 25 μg to about 500 μg subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration; b) a dosage of an endothelin receptor antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or inframuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration; and c) a dosage of a TNF antagonist containing an amount of from about 0.1 μg to 40 mg administered subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, tliree times per month, once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[00481] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) an endothelin receptor antagonist, and iii) a TNF antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-γ containing an amount of from about 25 μg/m² to about 100 μg/m², or a fixed dosage of IFN-γ containing an amount of from about 50 μg to about 200 μg, administered subcutaneously tiw for the desired treatment duration; b) a dosage of an endothelin receptor antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration; and c) a dosage of a TNF antagonist containing an amount of from about 0.1 μg to 40 mg administered subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration, to treat the fibrotic disorder.

[00482] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) an endothelin receptor antagonist, and iii) a TNF antagonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-γ containing an amount of from about 25 μg/m² to about 100 μg/m², or a fixed dosage of IFN-γ containing an amount of from about 50μg to about 200 μg, administered subcutaneously tiw for the desired treatment duration; b) a dosage of TRACLEER™ containing an amount of 62.5 mg or 125 mg, administered orally bid for the desired treatment duration; and c) a dosage of a TNF-α antagonist selected from the group consisting of (i) ENBREL® in an amount of about 25 mg of drug subcutaneously biw (ii) REMICADE® in an amount of about 3 mg/kg to about 10 mg/kg of drug intravenously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks or (iii) HUMIRA™ in an amount of about 40 mg of drug subcutaneously qw, qow, three times per month, once monthly, once every 6 weeks, or once every 8 weeks, for the desired treatment duration, to treat the fibrotic disorder. Type I interferon receptor agonists

[00483] In some embodiments, a subject therapeutic regimen further involves administering a Type I interferon receptor agonist. In many embodiments, the Type I interferon receptor agonist is an IFN-α. Effective dosages of an IFN-α can range from about 1 μg to about 30 μg, from about 3 μg to about 27 μg, from about 1 MU to about 20 MU, from about 3 MU to about 10 MU, from about 90 μg to about 180 μg, or from about 18 μg to about 90 μg.

[00484] Effective dosages of Infergen® consensus IFN-α include about 3 μg, about 9 μg, about 15 μg, about 18 μg, or about 27 μg of drug per dose. Effective dosages of IFN-α2a and IFN- α2b can range from 3 million Units (MU) to 10 MU per dose. Effective dosages of PEGylated IFN-α2a can contain an amount of about 90 μg to 360 μg, or about 180 μg, of drug per dose. Effective dosages of PEGylated IFN-α2b can contain an amount of about 0.5 μg to 3.0 μg, or about 1.0 μg to 1.5 μg, of drug per kg of body weight per dose. Effective dosages of PEGylated consensus interferon (PEG-CIFN) can contain an amount of about 10 μg to about 100 μg, or about 40 μg to about 80 μg, or about 50 μg to about 70 μg, or about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN. IFN-α can be administered daily, every other day, once a week, three times a week, every other week, three times per month, once monthly, substantially continuously or continuously.

[00485] In some embodiments, monoPEG (30 kD, linear)-ylated consensus IFN-α is administered. In some embodiments, monoPEG (30 kD, linear)-ylated consensus IFN-α is administered at a dosing interval of every 7 days. In some embodiments, monoPEG (30 kD, linear)-ylated consensus IFN-α is administered at a dosing interval of every 8 days to every 14 days, e.g., once every 8 days, once every 9 days, once every 10 days, once every 11 days, once every 12 days, once every 13 days, or once every 14 days, or at a dosing interval greater than 14 days. Effective amounts of monoPEG (30 kD, linear)-ylated INFERGEN® consensus IFN- α generally range from about 45 μg to about 270 μg per dose, e.g., 60 μg per dose, 100 μg per dose, 150 μg per dose, 200 μg per dose, etc.

[00486] In many embodiments, an IFN-α is administered for a period of about 1 day to about 7 days, or about 1 week to about 2 weeks, or about 2 weeks to about 3 weeks, or about 3 weeks to about 4 weeks, or about 1 month to about 2 months, or about 3 months to about 4 months, or about 4 months to about 6 months, or about 6 months to about 8 months, or about 8 months to about 12 months, or at least one year, and may be admimstered over longer periods of time. The IFN-α can be admimstered tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, substantially continuously, or continuously. [00487] In many embodiments, multiple doses of an IFN-α are administered. For example, an IFN-α is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (bid), or three times a day (tid), substantially continuously, or continuously, over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.

[00488] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) an endothelin receptor antagonist, and iii) a Type I interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN- γ containing an amount of from about 25 μg to about 500 μg subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration; b) a dosage of an endothelin receptor antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration; and c) a dosage of an IFN-α selected from (i) INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 40 μg to about 80 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-α 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS® subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg to about 1.5 μg, of drug per kilogram of body weight per dose of PEG-INTRON® subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly for the desired treatment duration, to treat the fibrotic disorder.

[00489] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) an endothelin receptor antagonist, and iii) a Type I interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN- γ containing an amount of from about 25 μg to about 500 μg subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, once monthly, for the desired treatment duration; b) a dosage of TRACLEER™ containing an amount of 62.5 mg or 125 mg, administered orally bid for the desired freatment duration; and c) a dosage of an IFN-α selected from (i) INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 40 μg to about 80 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-α 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS® subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg to about 1.5 μg, of drug per kilogram of body weight per dose of PEG-INTRON® subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly for the desired treatment duration, to treat the fibrotic disorder.

[00490] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) an endothelin receptor antagonist, and iii) a Type I interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-γ containing an amount of from about 25 μg/m² to about 100 μg/m², or a fixed dosage of IFN-γ containing an amount of from about 50 μg to about 200 μg, administered subcutaneously tiw for the desired treatment duration; b) a dosage of an endothelin receptor antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or inframuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and c) a dosage of an IFN-α selected from (i) INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 40 μg to about 80 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-α 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS® subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg to about 1.5 μg, of drug per kilogram of body weight per dose of PEG-INTRON® subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly for the desired treatment duration, to treat the fibrotic disorder. In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) an endothelin receptor antagonist, and iii) a Type I interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-γ containing an amount of from about 25 μg/m² to about 100 μg/m², or a fixed dosage of IFN-γ containing an amount of from about 50 μg to about 200 μg, administered subcutaneously tiw for the desired treatment duration; b) a dosage of TRACLEER™ containing an amount of 62.5 mg or 125 mg, administered orally bid for tlie desired treatment duration; and c) a dosage of an IFN-α selected from (i) INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 40 μg to about 80 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-α 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS® subcutaneously qw, qow, three times per month, or monthly (v) PEG- INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg to about 1.5 μg, of drug per kilogram of body weight per dose of PEG-INTRON® subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly for the desired freatment duration, to treat the fibrotic disorder. In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-β antagonist, and iii) a Type I interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a dosage of IFN-γ containing an amount of from about 25 μg to about 500 μg subcutaneously tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; b) a dosage of a TGF-β antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or intramuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and c) a dosage of an IFN-α selected from (i) INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-α 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS® subcutaneously qw, qow, three times per month, or monthly (v) PEG- INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg to about 1.5 μg, of drug per kilogram of body weight per dose of PEG-INTRON® subcutaneously biw, qw, qow, tliree times per month, or montlily or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly for the desired treatment duration, to treat the fibrotic disorder.

[00493] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-β antagonist, and iii) a Type I interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-γ containing an amount of from about 25 μg/m² to about 100 μg/m², or a fixed dosage of IFN-γ containing an amount of from about 50 μg to about 200 μg, administered subcutaneously tiw for the desired treatment duration; b) a dosage of a TGF-β antagonist containing an amount of from about 25 μg to about 1000 mg per day, administered orally, subcutaneously, intravenously, or inframuscularly tid, bid, qd, qod, biw, tiw, qw, qow, three times per month, or once monthly, for the desired treatment duration; and c) a dosage of an IFN-α selected from (i) INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-α 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS® subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg to about 1.5 μg, of drug per kilogram of body weight per dose of PEG-INTRON® subcutaneously biw, qw, qow, three times per month, or montlily or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration, to treat the fibrotic disorder.

[00494] In some embodiments, the invention provides a combination therapy method using combined effective amounts of i) a Type II interferon receptor agonist, ii) a TGF-β antagonist, and iii) a Type I interferon receptor agonist in the treatment of a fibrotic disorder in a patient, the method comprising co-administering to the patient a) a size-based dosage of IFN-γ containing an amount of from about 25 μg/m² to about 100 μg/m², or a fixed dosage of IFN-γ containing an amount of from about 50μg to about 200 μg, administered subcutaneously tiw for the desired treatment duration; b) a dosage of Gleevec™ containing an amount of 400 mg or 600 mg, administered orally once daily for the desired freatment duration; and c) a dosage of an IFN-α selected from (i) INFERGEN® containing an amount of about 1 μg to about 30 μg of drug per dose of INFERGEN® subcutaneously qd, qod, tiw, biw, qw, qow, three times per month, once monthly, or per day continuously or substantially continuously (ii) PEGylated consensus IFN-α (PEG-CIFN) containing an amount of about 10 μg to about 100 μg, or about 45 μg to about 60 μg, of CIFN amino acid weight per dose of PEG-CIFN subcutaneously qw, qow, three times per month, or monthly (iii) IFN-α 2a, 2b or 2c containing an amount of about 3 MU to about 10 MU of drug per dose of IFN-α 2a, 2b or 2c subcutaneously qd, qod, tiw, biw, or per day continuously or substantially continuously (iv) PEGASYS® containing an amount of about 90 μg to about 360 μg, or about 180 μg, of drug per dose of PEGASYS® subcutaneously qw, qow, three times per month, or monthly (v) PEG-INTRON® containing an amount of about 0.75 μg to about 3.0 μg, or about 1.0 μg to about 1.5 μg, of drug per kilogram of body weight per dose of PEG-INTRON® subcutaneously biw, qw, qow, three times per month, or monthly or (vi) mono PEG(30 kD, linear)-ylated consensus IFN-α containing an amount of from about 100 μg to about 200 μg, or about 150 μg, of drug per dose of mono PEG(30 kD, linear)-ylated consensus IFN-α subcutaneously qw, qow, once every 8 days to once every 14 days, three times per month, or monthly, for the desired treatment duration, to treat the fibrotic disorder.

[00495] As non-limiting examples, any of the above-described treatment methods featuring a TGF-β antagonist regimen can be modified to replace the subject TGF-β antagonist regimen with a regimen of Gleevec™ comprising administering a dosage of Gleevec™ containing an amount of 400 mg to 800 mg, or 600 mg, of drug orally per day, optionally in two or more divided doses per day, for the desired treatment duration.

[00496] As non-limiting examples, any of the above-described freatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II interferon receptor agonist regimen with a regimen of IFN-γ comprising administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously tliree times per week for the desired treatment duration.

[00497] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II interferon receptor agonist regimen with a regimen of IFN-γ comprising administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week for the desired treatment duration.

[00498] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II interferon receptor agonist regimen with a regimen of IFN-γ comprising administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week for the desired treatment duration.

[00499] As non-limiting examples, any of the above-described freatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II interferon receptor agonist regimen with a regimen of IFN-γ comprising administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week for the desired treatment duration.

[00500] As non-limiting examples, any of the above-described treatment methods featuring a TGF-β antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-β antagonist and Type II interferon receptor agonist combination regimen with a TGF-β antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired freatment duration.

[00501] As non-limiting examples, any of the above-described freatment methods featuring a TGF-β antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-β antagonist and Type II interferon receptor agonist combination regimen with a TGF-β antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00502] As non-limiting examples, any of the above-described treatment methods featuring a TGF-β antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-β antagonist and Type II interferon receptor agonist combination regimen with a TGF-β antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00503] As non-limiting examples, any of the above-described treatment methods featuring a TGF-β antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-β antagonist and Type II interferon receptor agonist combination regimen with a TGF-β antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00504] As non-limiting examples, any of the above-described treatment methods featuring a TGF-β antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-β antagonist and Type II interferon receptor agonist combination regimen with a TGF-β antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired freatment duration.

[00505] As non-limiting examples, any of the above-described freatment methods featuring a TGF-β antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-β antagonist and Type II interferon receptor agonist combination regimen with a TGF-β antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; and (b) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; for the desired freatment duration.

[00506] As non-limiting examples, any of the above-described treatment methods featuring a TGF-β antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-β antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen with a TGF-β antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; (b) administering a dosage of a TNF antagonist selected from the group of: (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (c) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00507] As non-limiting examples, any of the above-described treatment methods featuring a TGF-β antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-β antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen with a TGF-β antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) admimstering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; (b) administering a dosage of a TNF antagonist selected from the group of: (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose infravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (c) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00508] As non-limiting examples, any of tlie above-described treatment methods featuring a TGF-β antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-β antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen with a TGF-β antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; (b) administering a dosage of a TNF antagonist selected from the group of: (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (c) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; for the desired freatment duration. [00509] As non-limiting examples, any of the above-described freatment methods featuring a TGF-β antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-β antagonist, TNF antagonist and Type II interferon receptor agomst combination regimen with a TGF-β antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; (b) administering a dosage of a TNF antagonist selected from the group of: (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (c) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00510] As non-limiting examples, any of the above-described treatment methods featuring a TGF-β antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-β antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen with a TGF-β antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; (b) administering a dosage of a TNF antagonist selected from the group of: (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (c) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00511] As non-limiting examples, any of the above-described treatment methods featuring a TGF-β antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-β antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen with a TGF-β antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; (b) administering a dosage of a TNF antagonist selected from the group of: (i) etanercept in an amoxmt of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (c) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; for the desired freatment duration.

[00512] As non-limiting examples, any of the above-described freatment methods featuring a TGF-β antagonist, an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-β antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with a TGF-β antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; (b) administering a dosage of Tracleer™ containing an amount of 62.5 mg of drug orally twice per day for the first 4 weeks of therapy, followed by a dosage of Tracleer™ containing an amount of 125 mg of drug orally twice per day for the remainder of therapy; and (c) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously tliree times per week; for the desired treatment duration.

[00513] As non-limiting examples, any of the above-described treatment methods featuring a TGF-β antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-β antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with a TGF-β antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; (b) administering a dosage of Tracleer™ containing an amount of 62.5 mg of drug orally twice per day for the first 4 weeks of therapy, followed by a dosage of Tracleer™ containing an amount of 125 mg of drug orally twice per day for the remainder of therapy; and (c) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00514] As non-limiting examples, any of the above-described freatment methods featuring a TGF-β antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-β antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with a TGF-β antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; (b) administering a dosage of Tracleer™ containing an amount of 62.5 mg of drag orally twice per day for the first 4 weeks of therapy, followed by a dosage of Tracleer™ containing an amount of 125 mg of drug orally twice per day for the remainder of therapy; and (c) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00515] As non-limiting examples, any of the above-described treatment methods featuring a TGF-β antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-β antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with a TGF-β antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; (b) administering a dosage of Tracleer™ containing an amount of 62.5 mg of drug orally twice per day for the first 4 weeks of therapy, followed by a dosage of Tracleer™ containing an amount of 125 mg of drug orally twice per day for the remainder of therapy; and (c) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; for the desired treatment duration.

[00516] As non-limiting examples, any of the above-described treatment methods featuring a TGF-β antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-β antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with a TGF-β antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; (b) administering a dosage of Tracleer™ containing an amount of 62.5 mg of drug orally twice per day for the first 4 weeks of therapy, followed by a dosage of Tracleer™ containing an amount of 125 mg of drug orally twice per day for the remainder of therapy; and (c) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00517] As non-limiting examples, any of the above-described treatment methods featuring a TGF-β antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject TGF-β antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with a TGF-β antagonist, endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; (b) administering a dosage of Tracleer™ containing an amount of 62.5 mg of drug orally twice per day for the first 4 weeks of therapy, followed by a dosage of Tracleer™ containing an amount of 125 mg of drag orally twice per day for the remainder of therapy; and (c) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously tliree times per week; for the desired treatment duration.

[00518] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drag per dose, orally once daily; for the desired treatment duration.

[00519] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drag per dose, orally once daily; for the desired freatment duration.

[00520] As non-limiting examples, any of the above-described metliods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously tliree times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drag per dose, orally once daily; for the desired treatment duration. [00521] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously tliree times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drag per dose, orally once daily; for the desired treatment duration.

[00522] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drag per dose, orally once daily; for the desired treatment duration.

[00523] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[00524] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 200 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drag per dose, orally once daily; for the desired treatment duration.

[00525] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 200 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[00526] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 200 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[00527] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drag per dose, orally once daily; for the desired treatment duration.

[00528] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; for the desired freatment duration.

[00529] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drag per dose, orally once daily; for the desired treatment duration.

[00530] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; for the desired freatment duration.

[00531] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drag per dose, orally once daily; for the desired treatment duration.

[00532] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[00533] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[00534] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[00535] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drag per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drag per dose, orally once daily; for the desired treatment duration.

[00536] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously tliree times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[00537] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drag per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[00538] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; for the desired treatment duration.

[00539] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[00540] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drag per dose, orally once daily; for the desired treatment duration.

[00541] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drag per dose, orally once daily; for the desired treatment duration.

[00542] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[00543] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[00544] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drag per dose, orally once daily; for the desired treatment duration.

[00545] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 200 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drag per dose, orally once daily; for the desired treatment duration.

[00546] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 200 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) admimstering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drag per dose, orally once daily; for the desired treatment duration.

[00547] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 200 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drag per dose, orally once daily; for the desired treatment duration.

[00548] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drag per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[00549] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drag per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[00550] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drag per dose, orally once daily; for the desired freatment duration.

[00551] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drag per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; for the desired freatment duration.

[00552] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagomst combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drag per dose, orally once daily; for the desired treatment duration.

[00553] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[00554] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drag per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ contaimng an amount of 200 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[00555] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drag per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; for the desired freatment duration.

[00556] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drag per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[00557] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drag per dose, orally once daily; for the desired treatment duration.

[00558] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drag per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; for the desired treatment duration.

[00559] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and TGF-β antagonist combination regimen can be modified to replace the subject IFN- α, IFN-γ and TGF-β antagonist combination regimen with an IFN-α, IFN-γ and TGF-β antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drag per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Gleevec™ containing an amount of 600 mg of drag per dose, orally once daily; for the desired treatment duration.

[00560] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α with a regimen of peginterferon alfa-2a comprising administering a dosage of peginterferon alfa-2a containing an amount of 90 μg to 360 μg, or 180 μg, of drug per dose, subcutaneously once weekly for the desired treatment duration.

[00561] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α with a regimen of peginterferon alfa-2b comprising administering a dosage of peginterferon alfa-2b containing an amount of 0.5 μg to 2.0 μg, or 1.0 μg to 1.5 μg, of drug per kilogram of body weight per dose, subcutaneously once or twice weekly for the desired treatment duration.

[00562] The subject invention provides any of the above-described treatment methods, modified to include administering an effective amount of a side effect management agent for the desired freatment duration. In many embodiments, side effect management agents are selected from one or more of acetaminophen, ibuprofen, and other NSAIDs, H2 blockers, and antacids.

[00563] As non-limiting examples, in any of the above-described treatment methods the endothelin receptor antagonist regimen can be replaced with a regimen of TRACLEER™ comprising administering a dosage of TRACLEER™ containing an amount of 25 mg to 500 mg, or an amount of 125 mg to 250 mg, of drag orally per day, optionally in two or more divided doses per day, for the desired treatment duration.

[00564] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II interferon receptor agonist regimen with a regimen of IFN-γ comprising administering a dosage of IFN-γ containing an amount of 25 μg of drug per dose, subcutaneously tliree times per week for the desired freatment duration.

[00565] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II interferon receptor agonist regimen with a regimen of IFN-γ comprising administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week for the desired treatment duration.

[00566] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II interferon receptor agonist regimen with a regimen of IFN-γ comprising administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week for the desired treatment duration. [00567] As non-limiting examples, any of the above-described treatment methods featuring a Type II interferon receptor agonist regimen can be modified to replace the subject Type II interferon receptor agonist regimen with a regimen of IFN-γ comprising administering a dosage of IFN-γ containing an amount of 200 μg of drag per dose, subcutaneously three times per week for the desired treatment duration.

[00568] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drag per dose, orally twice daily; and (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; for the desired treatment duration.

[00569] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drag per dose, orally twice daily; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00570] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drag per dose, orally twice daily; and (b) administering a dosage of IFN-γ containing an amount of 200 μg of drag per dose, subcutaneously three times per week; for the desired treatment duration.

[00571] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist and Type II interferon receptor agomst combination regimen comprising: (a) administering a dosage of TRACLEER™ containing an amount of 125 mg of drug per dose, orally twice daily; and (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; for the desired treatment duration.

[00572] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEER™ containing an amount of 125 mg of drug per dose, orally twice daily; and (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00573] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEER™ containing an amount of 125 mg of drug per dose, orally twice daily; and (b) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously tliree times per week; for the desired treatment duration.

[00574] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drug per dose, orally twice daily; (b) administering a dosage of a TNF antagonist selected from the group of: (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drag per kilogram of body weight per dose intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (c) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired freatment duration.

[00575] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drug per dose, orally twice daily; (b) administering a dosage of a TNF antagonist selected from the group of: (i) etanercept in an amount of 25 mg of drag per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drag per kilogram of body weight per dose intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drag per dose subcutaneously once weekly or once every 2 weeks; and (c) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00576] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drug per dose, orally twice daily; (b) administering a dosage of a TNF antagonist selected from the group of: (i) etanercept in an amount of 25 mg of drag per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (c) administering a dosage of IFN-γ containing an amount of 200 μg of drag per dose, subcutaneously three times per week; for the desired treatment duration.

[00577] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEER™ containing an amount of 125 mg of drag per dose, orally twice daily; (b) administering a dosage of a TNF antagonist selected from the group of: (i) etanercept in an amount of 25 mg of drug per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drag per dose subcutaneously once weekly or once every 2 weeks; and (c) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00578] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEER™ containing an amount of 125 mg of drag per dose, orally twice daily; (b) administering a dosage of a TNF antagonist selected from the group of: (i) etanercept in an amount of 25 mg of drag per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drug per dose subcutaneously once weekly or once every 2 weeks; and (c) admimstering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously three times per week; for the desired treatment duration.

[00579] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist, TNF antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of TRACLEER™ containing an amount of 125 mg of drug per dose, orally twice daily; (b) administering a dosage of a TNF antagonist selected from the group of: (i) etanercept in an amount of 25 mg of drag per dose subcutaneously twice per week, (ii) infliximab in an amount of 3 mg of drug per kilogram of body weight per dose intravenously at weeks 0, 2 and 6, and every 8 weeks thereafter, or (iii) adalimumab in an amount of 40 mg of drag per dose subcutaneously once weekly or once every 2 weeks; and (c) administering a dosage of IFN-γ containing an amount of 200 μg of drag per dose, subcutaneously three times per week; for the desired treatment duration.

[00580] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist, a TGF-β antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Tracleer™ containing an amount of 62.5 mg of drug orally twice per day; (b) administering a dosage of Gleevec™ containing an amount of 400 mg of drag per dose, orally once daily; and (c) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00581] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist, a TGF-β antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Tracleer™ containing an amount of 125 mg of drug orally twice per day; (b) administering a dosage of Gleevec™ containing an amount of 400 mg of drag per dose, orally once daily; and (c) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; for the desired treatment duration.

[00582] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Tracleer™ containing an amount of 62.5 mg of drug orally twice per day; (b) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; and (c) administering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously three times per week; for the desired treatment duration.

[00583] As non-limiting examples, any of tl e above-described treatment methods featuring an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Tracleer™ containing an amount of 125 mg of drag orally twice per day; (b) administering a dosage of Gleevec™ containing an amount of 400 mg of drag per dose, orally once daily; and (c) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00584] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Tracleer™ containing an amount of 62.5 mg of drug orally twice per day; (b) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; and (c) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00585] As non-limiting examples, any of the above-described freatment methods featuring an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Tracleer™ containing an amount of 125 mg of drug orally twice per day; (b) administering a dosage of Gleevec™ containing an amount of 400 mg of drug per dose, orally once daily; and (c) administering a dosage of IFN-γ containing an amount of 200 μg of drag per dose, subcutaneously three times per week; for the desired treatment duration.

[00586] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Tracleer™ containing an amount of 62.5 mg of drug orally twice per day; (b) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; and (c) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration. [00587] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Tracleer™ containing an amount of 125 mg of drug orally twice per day; (b) administering a dosage of Gleevec™ containing an amount of 600 mg of drag per dose, orally once daily; and (c) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00588] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Tracleer™ containing an amount of 62.5 mg of drug orally twice per day; (b) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; and (c) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00589] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Tracleer™ containing an amount of 125 mg of drag orally twice per day; (b) administering a dosage of Gleevec™ containing an amount of 600 mg of drug per dose, orally once daily; and (c) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00590] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Tracleer™ containing an amount of 62.5 mg of drug orally twice per day; (b) administering a dosage of Gleevec™ containing an amount of 600 mg of drag per dose, orally once daily; and (c) administering a dosage of IFN-γ containing an amount of 200 μg of drag per dose, subcutaneously three times per week; for the desired treatment duration.

[00591] As non-limiting examples, any of the above-described treatment methods featuring an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen can be modified to replace the subject endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen with an endothelin receptor antagonist, TGF-β antagonist and Type II interferon receptor agonist combination regimen comprising: (a) administering a dosage of Tracleer™ containing an amount of 125 mg of drug orally twice per day; (b) administering a dosage of Gleevec™ containing an amount of 600 mg of drag per dose, orally once daily; and (c) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; for the desired treatment duration.

[00592] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drag per dose, orally twice daily; for the desired treatment duration.

[00593] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drag per dose, orally twice daily; for the desired treatment duration.

[00594] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00595] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00596] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously tliree times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drag per dose, orally twice daily; for the desired treatment duration.

[00597] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drag per dose, orally twice daily; for the desired treatment duration.

[00598] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 200 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00599] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 200 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drag per dose, orally twice daily; for the desired treatment duration.

[00600] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 200 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drag per dose, orally twice daily; for the desired treatment duration.

[00601] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drag per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00602] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drag per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of Tracleer™ containing an amount of 62.5 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00603] As non-limiting examples, any of tlie above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drag per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drag per dose, orally twice daily; for the desired treatment duration.

[00604] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drag per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drug per dose, orally twice daily; for the desired treatment duration. [00605] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drag per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00606] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drag per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drag per dose, orally twice daily; for the desired treatment duration.

[00607] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drag per dose, subcutaneously tliree times per week; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drag per dose, orally twice daily; for the desired treatment duration.

[00608] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drag per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drag per dose, orally twice daily; for the desired treatment duration.

[00609] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drag per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drag per dose, orally twice daily; for the desired treatment duration.

[00610] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drag per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drag per dose, subcutaneously tliree times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drag per dose, orally twice daily; for the desired treatment duration.

[00611] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drag per dose, orally twice daily; for the desired treatment duration.

[00612] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drag per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 62.5 mg of drag per dose, orally twice daily; for the desired treatment duration.

[00613] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drug per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 125 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00614] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously tliree times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 125 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00615] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 100 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 125 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00616] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 125 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00617] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 150 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 125 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00618] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, lmear)-ylated consensus IFN-α containing an amount of 150 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 125 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00619] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 200 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 125 mg of drug per dose, orally twice daily; for the desired treatment duration. [00620] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 200 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 125 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00621] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of monoPEG (30 kD, linear)-ylated consensus IFN-α containing an amount of 200 μg of drag per dose, subcutaneously once weekly or once every 8 days; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 125 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00622] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously tliree times per week; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 125 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00623] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 125 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00624] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 125 mg of drag per dose, orally twice daily; for the desired treatment duration.

[00625] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drag per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 125 mg of drag per dose, orally twice daily; for the desired treatment duration.

[00626] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 125 mg of drag per dose, orally twice daily; for the desired treatment duration.

[00627] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 9 μg of drug per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ contaimng an amount of 125 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00628] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drag per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 125 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00629] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drag per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 125 mg of drag per dose, orally twice daily; for the desired treatment duration.

[00630] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drag per dose, subcutaneously three times per week; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 125 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00631] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drag per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 200 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 125 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00632] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drag per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 50 μg of drag per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 125 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00633] As non-limiting examples, any of the above-described methods featuring an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen can be modified to replace the subject IFN-α, IFN-γ and endothelin receptor antagonist combination regimen with an IFN-α, IFN-γ and endothelin receptor antagonist combination regimen comprising: (a) administering a dosage of INFERGEN® interferon alfacon-1 containing an amount of 15 μg of drag per dose, subcutaneously once daily; (b) administering a dosage of IFN-γ containing an amount of 100 μg of drug per dose, subcutaneously three times per week; and (c) administering a dosage of TRACLEER™ containing an amount of 125 mg of drug per dose, orally twice daily; for the desired treatment duration.

[00634] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α with a regimen of peginterferon alfa-2a comprising administering a dosage of peginterferon alfa-2a containing an amount of 90 μg to 360 μg, or 180 μg, of drag per dose, subcutaneously once weekly for the desired freatment duration.

[00635] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α can be modified to replace the regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α with a regimen of peginterferon alfa-2b comprising administering a dosage of peginterferon alfa-2b containing an amount of 0.5 μg to 2.0 μg, or 1.0 μg to 1.5 μg, of drug per kilogram of body weight per dose, subcutaneously once or twice weekly for the desired treatment duration.

[00636] As non-limiting examples, any of the above-described methods can be modified to replace the subject endothelin receptor antagonist regimen with an endothelin receptor antagonist regimen of comprising administering a dosage of Tracleer™ containing an amount of 62.5 mg of drug orally twice per day for the first 4 weeks of therapy, followed by a dosage of Tracleer™ containing an amount of 125 mg of drag orally twice per day for the remainder of the desired treatment duration.

[00637] As non-limiting examples, any of the above-described methods that includes a regimen of monoPEG (30 kD, linear)-ylated consensus IFN-α comprising administering an amount of monoPEG (30 kD, linear)-ylated consensus IFN-α once weekly or once every 8 days can be modified to administer the amount of monoPEG (30 kD, linear)-ylated consensus IFN-α once every 10 days for the desired treatment duration.

[00638] The subject invention provides any of the above-described freatment methods, modified to include administering an effective amount of a side effect management agent for the desired treatment duration. In many embodiments, side effect management agents are selected from one or more of acetaminophen, ibuprofen, and other NSAIDs, H2 blockers, and antacids. SUBJECTS SUITABLE FOR TREATMENT

[00639] The subject methods are suitable for treatment of individuals diagnosed as having a fibrotic disorder. Fibrotic disorders include, but are not limited to, pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis from a known etiology, liver fibrosis, and renal fibrosis. Other exemplary fibrotic conditions include musculoskeletal fibrosis, cardiac fibrosis, post-surgical adhesions, scleroderma, glaucoma, and skin lesions such as keloids.

[00640] The subject methods are suitable for the treatment of individuals diagnosed as having IPF. The methods are also suitable for treatment of individuals having IPF who were treated with corticosteroids within the previous 24 months, and who failed to respond to such corticosteroid therapy. IPF patients who are particularly amenable to treatment with the subject methods are characterized by an initial FVC that is at least about 55% of the predicted nonnal FVC. Also suitable for freatment are IPF patients characterized by an initial FVC that is at least about 60%, or from about 55% to about 70%, of the predicted normal FVC. The percent of predicted normal FVC are based on normal FVC values that are known in the art. See, e.g., Crapo et al, (1981) Am. Rev. Respir. Dis., 123:659-664. FVC is measured using standards methods of spirometry. [00641] Other IPF patients suitable for treatment with the subject methods are characterized by an initial carbon monoxide diffusing capacity (DLco) ≥ 25%, or > 30%, or > 35%, of predicted normal DLco- [00642] Also suitable for treatment with the subject methods are IPF patients characterized by (1) an initial DLco ≥ 35% of predicted normal DLco and (2) an initial FVC that is at least about 55% of the predicted normal FVC. [00643] Also suitable for treatment with the subject methods are IPF patients characterized by (1) an initial DLco ≥ 30% of predicted normal DLco and (2) an initial FVC that is at least about 55% of the predicted normal FVC.

EXAMPLES

[00644] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or tlie only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. Standard abbreviations may be used, e.g., bp, base pair(s); kb, kilobase(s); pi, picoliter(s); s or sec, second(s); min, minute(s); h or hr, hour(s); aa, amino acid(s); kb, kilobase(s); bp, base pair(s); nt, nucleotide(s); i.m., inframuscular(ly); i.p., intraperitoneal(ly); s.c, subcutaneous(ly); and the like. Example 1 : IFN-γlb inhibition of IL-4-induced collagen synthesis

[00645] IL-4, endothelin- 1, and TGF-β induce transcriptional up-regulation of the type I collagen gene by different mechanisms. The effect of IL-4, endothelin- 1, TGF-β, and IFN-γ, alone or in combination, on collagen synthesis by fibroblasts was assessed. Collagen was assayed by measuring the incorporation of [³H] proline into collagen. Briefly, human lung fibroblast cells (HFL1) were seeded at a density of 10⁵ cells per well into 12-well plates and were grown to confluency in F12K medium containing % 10 fetal calf serum, 2 mM glutamine, and antibiotics. Confluent cells were then serum-starved overnight and freated with 5 ng/ml concentration of IFN-γ lb for 1 h before addition of 5 ng/ml of IL-4, TGF-beta, and Endothelinl, 10 μM of ascorbic acid, and 1 μCi of [³H] -proline; and incubated for 48 h. Total protein synthesis was determined by precipitating all the proteins in 400 μl of cell supernatant onto glass fiber filters and counting in a scintiUant. NoncoUagenous proteins were assayed in a second 400 μl of the same supernatant after digestion with 40 μg of purified bacterial collagenase for 4 h at 37°C. The precipitated collagenase-resistant proteins were defined as noncollagenous. The difference between total and noncollagenous proteins counts equals the amount of collagen synthesized. The results are shown in Figure 1. While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims

CLAIMSWhat is claimed is:

1. A method of treating or preventing a fibrotic disease in an individual comprising administering to the individual a combination of pirfenidone or a pirfenidone analog and a TGF-β antagonist in an amount that is effective in treating or preventing the fibrotic disease in the individual.

2. The method of claim 1, further comprising administering a Type II interferon receptor agonist.

3. The method of claim 1 or claim 2, further comprising administering an effective amount of a TNF-α antagonist.

4. The method of claim 1 or claim 2, further comprising administering an effective amount of an endothelin receptor antagonist.

5. The method of claim 3, further comprising administering an effective amount of an endothelin receptor antagonist.

6. A method of treating or preventing a fibrotic disease in an individual comprising administering to the individual a combination of pirfenidone or a pirfenidone analog and an endothelin receptor antagonist in an amount that is effective in treating or preventing tlie fibrotic disease in the individual.

7. The method of claim 6, further comprising administering a Type II interferon receptor agonist.

8. The method of claim 6 or claim 7, further comprising administering an effective amount of a TNF-α antagonist.

9. A method of treating or preventing a fibrotic disease in an individual comprising administering to an individual a combination of IFN-γ and an endothelin receptor antagonist in an amount that is effective in treating or preventing the fibrotic disease in the individual.

10. The method of claim 9, further comprising administering an effective amount of a TNF-α antagonist.

11. The method of claim 9 or claim 10, further comprising administering an effective amount of a TGF-β antagonist.

12. The method of claim 1, wherein the TGF-β antagonist is imatinib mesylate.

13. The method of and of claims 4, 5 or 9, wherein the endothelin receptor antagonist is bosentan.

14. The method of any of claims 2, 7 or 9, wherein the Type II interferon receptor agonist is Actimmune® human interferon gamma- lb.

15. The method of claim 10 wherein the TNF-α antagonist is selected from the group consisting of etanercept, infliximab and adalimumab.

16. The method of any of claims 1, 6 or 9, wherein the fibrotic disease is pulmonary fibrosis.

17. The method of claim 16, wherein the pulmonary fibrosis is idiopathic pulmonary fibrosis.

18. The method of claim 16, wherein the pulmonary fibrosis is from a known etiology.

19. The method of any of claims 1, 6 or 9, wherein the fibrotic disease is liver fibrosis.

20. The method of any of claims 1, 6 or 9, wherein the fibrotic disease is renal fibrosis.

21. The method of any of claims 1, 6 or 9, wherein the fibrotic disease is cardiac fibrosis.

22. The method of any of claims 1 , 6 or 9, wherein the fibrotic disease is scleroderma.

23. The method of any of claims 1-22, wherein the individual is a human.