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WO2000059530A1 - Utilisation d'un recepteur du facteur de necrose tumorale soluble dans le traitement de l'insuffisance cardiaque - Google Patents

Utilisation d'un recepteur du facteur de necrose tumorale soluble dans le traitement de l'insuffisance cardiaque Download PDF

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Publication number
WO2000059530A1
WO2000059530A1 PCT/US2000/008161 US0008161W WO0059530A1 WO 2000059530 A1 WO2000059530 A1 WO 2000059530A1 US 0008161 W US0008161 W US 0008161W WO 0059530 A1 WO0059530 A1 WO 0059530A1
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patient
heart failure
improvement
tnfr
patients
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PCT/US2000/008161
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English (en)
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F. Ann Hayes
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Immunex Corporation
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Priority to AU39271/00A priority Critical patent/AU763575B2/en
Priority to CA002365824A priority patent/CA2365824A1/fr
Priority to EP00918469A priority patent/EP1165116A1/fr
Publication of WO2000059530A1 publication Critical patent/WO2000059530A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/191—Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta

Definitions

  • CHF Chronic heart failure
  • diseases such as high blood pressure, a heart attack, poor blood supply to the heart, a defective heart valve, atherosclerosis, rheumatic fever, heart muscle disease and so on.
  • the failing heart becomes inefficient, resulting in fluid retention and shortness of breath, fatigue and exercise intolerance.
  • CHF is defined by the symptom complex of dyspnea, fatigue and depressed left ventricular systolic function (ejection fraction ⁇ 35-40%), and is the ultimate endpoint of all forms of serious heart disease.
  • CHF CHF has been directed primarily to prolonging the patient's life, although the benefits from treatment generally is assessed through improvement in other areas. For example, a reduced degree of dyspnea or improvement in performance in a standardized walking test have a substantial positive impact on the lifestyle of patients who live with this disease.
  • An increased ejection fraction which can be measured by echocardiogram or by multigated radionuclide ventriculography (MUGA), is another indicator of a successful treatment regimen.
  • MUGA multigated radionuclide ventriculography
  • TNF ⁇ is a pleiotropic cytokine that is produced by the heart under certain forms of stress (Kapadia et al, 1. Clin Invest 96:1042-1052, 1995b; Kapadia et al., Circ Re-s 81: 187-195, 1997).
  • patients with various types of heart disease have elevated levels of circulating TNF ⁇ , and the levels of TNF ⁇ have been shown to increase with disease progression (see, e.g., Maury et al., J.
  • TNF ⁇ are sufficient to mimic many aspects of the heart failure phenotype, including left ventricular dilation, left ventricular dysfunction, as well as activation of the fetal gene program (Suffredini et al., N Engl I Med 52i:280-287, 1989; Hegewisch et al., Lancet 2:294-295, 1990), hence it has been suggested that TNF ⁇ plays a contributory role in the pathogenesis of heart failure (see, e.g., Seta et al., J. Cardiac Failure 2:243-249, 1996).
  • TNF ⁇ has been shown in isolated hamster heart to inhibit contractility (Finkel et al., Science 257:387-389, 1992). In mice, antibodies against TNF ⁇ were effective in ameliorating the severity of artificially-induced heart disease (Smith et al., Circ Res 70: 856-863, 1992).
  • TNF ⁇ -induced depression in left ventricle function in rats was partially reversed by administering the TNF ⁇ antagonist TNFR:Fc (Bozkurt et al., Circulation 97(14): 1382-1391, 1998), and in yet a different study, TNFR:Fc was shown to suppress the negative inotropic effect of TNF in cultured myocytes (Kapadia et al., Am 1 Physiol 57:H517-H525, 1995a). Others demonstrated that TNFR:Fc could reduce burn-induced myocardial dysfunction in guinea pigs (Giroir et al., Am I Physiol 267 (Heart Circ Physiol 36):H118-H125, 1994).
  • vesnarinone an agent used to treat CHF, could suppress lipoprotein-induced TNF ⁇ production human blood cells in vitro (Matsumori et al., Circulation 89:955-958, 1994a).
  • a small group of human CHF patients were given a single dose of TNFR:Fc, and fourteen days later exhibited decreased levels of circulating TNF ⁇ , increased ability to exercise, and improved symptomology (Deswal et al., Abstract #472, American Heart Association 70 th Scientific Session, Circulation 96(8Suppl.), 1997 1323).
  • TNF ⁇ suppressor pentoxifylline reportedly induces improved left ventricle function concomitant with decreased levels of serum TNF ⁇ levels in patients with idiopathic dilated cardiomyopathy (Skudicky et al., American Heart Association Meeting, Abstract No. 3415 November, 1998; Sliwa et al., Lancet 351: 1091-1093, 1998).
  • TNF ⁇ antagonists The treatment of various heart diseases with TNF ⁇ antagonists is disclosed also in a number of U.S. patents and in several published patent applications (see, e.g., U.S. 5,594,106; U.S. 5,629,285; U.S. 5,691,382; U.S. 5,700,838; U.S. 5,886,010; WO 91/15451; WO 94/10990; WO 95/19957; WO 96/21447; WO 97/30088; EP 0 453 898 Bl; EP 0 486 809
  • TNF ⁇ binds to cells through two membrane receptor molecules having molecular weights of approximately 55 kDa and 75 kDa (p55 and p75). In addition to binding
  • TNF ⁇ these same receptors mediate the binding to cells of TNF ⁇ , which is another cytokine associated with inflammation.
  • TNF ⁇ also known as lymphotoxin- ⁇ (LT ⁇ )
  • LT ⁇ lymphotoxin- ⁇
  • the invention provides methods for treating chronic heart failure by repeatedly administering a recombinant TNFR:Fc, more specifically, etanercept, for a period of time sufficient to induce a sustained improvement in the patient's condition.
  • FIGURE 1 illustrates the improved NYHA classification that was observed in the patients who received etanercept in the study described in Example 1.
  • FIGURES 2A and 2B illustrate the improved left ventricular ejection fraction by MUGA in the patients who received etanercept in the study described in Example 1.
  • FIGURE 3 illustrates the improved Quality of Life (MLWHF) that was observed in patients who received etanercept in the study described in Example 1.
  • FIGURE 4 illustrates the end-of-study clinical composite score distributions for the patients who participated in the study described in Example 1.
  • the invention provides methods of treating chronic heart failure (CHF) that involve administering to a CHF patient a TNF ⁇ antagonist that is capable of inhibiting the binding of TNF ⁇ to a TNF ⁇ receptor.
  • CHF chronic heart failure
  • the TNF ⁇ antagonist is one that mimics the 75 kDa TNFR and that binds to TNF ⁇ in the patient's body. Once bound to the antagonist, the TNF ⁇ is prevented from binding its natural receptor, and thus cannot manifest its biological activities.
  • a TNF ⁇ antgonist suitable for use in treating CHF is recombinant TNFR:Fc (hereafter referred to as "TNFR:Fc" or "etanercept").
  • Etanercept is currently sold by Immunex Corporation under the trade name ENBREL, ® and is a dimer of two molecules of the extracellular portion of the p75 TNF ⁇ receptor, each molecule consisting of a 235 amino acid polypeptide that is fused to a 232 amino acid Fc portion of human IgG r
  • ENBREL a dimer of two molecules of the extracellular portion of the p75 TNF ⁇ receptor, each molecule consisting of a 235 amino acid polypeptide that is fused to a 232 amino acid Fc portion of human IgG r
  • the use of other soluble mimics of the p75 molecule for treating CHF are within the scope of the invention.
  • TNFR:Fc or another TNF ⁇ -binding mimic of p75 is administered repeatedly to a CHF patient in an amount and for a time sufficient to induce a sustained improvement over baseline in at least one indicator that reflects the degree of the patient's heart disease.
  • an improvement is considered “sustained” if the patient exhibits the improvement on at least two occasions separated by at least four weeks.
  • a sustained degree of improvement generally is obtained by repeatedly administering TNFR:Fc over a period of at least a month, e.g., for one, two, or three months or longer.
  • Various indicators that reflect the patient's degree of heart failure may be assessed for determining whether the amount and time of the treatment is sufficient.
  • the baseline value for the chosen indicator or indicators is established by examination of the patient within about 60 days prior to administration of the first dose of the etanercept or other TNF ⁇ -binding molecule.
  • the effective amount of TNFR:Fc ranges from 1-20 mg/m 2 , and preferably is about 5-12 mg/m 2 .
  • a flat dose may be administered, whose amount may range from 5-100 mg/dose.
  • An exemplary range for a flat dose is about 20-30 mg per dose.
  • a flat dose of 25 mg/dose is repeatedly administered by subcutaneous injection. If a route of administration other than injection is used, the dose is appropriately adjusted in accord with standard medical practices.
  • the specific dose level and frequency of administration for a given patient may depend upon a variety of factors such as their age, body weight, general health, sex, diet, time of administration, other drugs being concurrently administered, side-effects the patient may experience and the severity of their heart disease.
  • chronic heart failure is treated by administering to the patient by subcutaneous injection a dose of TNFR:Fc at 5 mg/m 2 or 12 mg/m 2 per dose up to a maximum of 25 mg per dose at least two times per week for a time sufficient to induce a sustained improvement over baseline of one of the following indicators: i) left ventricular ejection fraction; ii) New York Heart Association class; and iii) clinical composite score.
  • the sufficiency of treatment is determined by evaluating the patient for an improvement in their left ventricular function.
  • a sufficient degree of improvement with respect to this indication is obtained by repeatedly administering a dose of TNFR:Fc or other TNF ⁇ -binding molecule until the patient manifests an at least 5%, or more preferably an at least 10% increase over baseline in left ventricular ejection fraction.
  • the left ventricular ejection fraction can be determined by any suitable means, such as echocardiogram or by multigated radionuclide ventriculography (MUGA).
  • the treatment is regarded as suffient when it has induced a sustained improvement in the recipient's clinical composite score.
  • a patient's clinical composite score is designated as "improved,” “unchanged,” or “worse” relative to baseline according to the following definitions. "Worse” means that the patient (1) died; (2) has had a hospitalization related to CHF; (3) has a worse NYHA functional classification (e.g., degenerates from Class I to Class II, from Class II to Class III or from Class III to Class IV); or (4) indicates that he or she feels moderately or markedly worse in a subjective patient global assessment after 24 weeks of treatment.
  • NYHA functional classification e.g., degenerates from Class I to Class II, from Class II to Class III or from Class III to Class IV
  • the patient global assessment consists of the patient's response when asked whether their heart failure is: markedly better; moderately better; slightly better; unchanged; slightly worse; moderately worse; or markedly worse.
  • An "improved" clinical composite score means that NYHA class is decreased by at least one class level (e.g., from Class III to Class II) and that the patient's global assessment of CHF is moderately or markedly improved. If the patient's clinical composite score is neither worse nor improved according to the foregoing criteria, then the clinical composite is scored as "unchanged.” If clinical composite score is used as an indicator of the patient's degree of heart failure, a designation of "improved" is considered indicative that the time and amount of the treatment with TNRF:Fc is sufficient.
  • the indicator used to assess the patient's degree of heart failure is NYHA class of heart disease, and the amount and time of treatment is considered sufficient if the treatment has induced the patient's NYHA class to improve by at least one level, e.g., from Class II to Class I, from Class III to Class II, or from Class IV to Class HI.
  • the amount and time of treatment with TNFR:Fc is determined to be sufficient when the treatment has induced an increase in the patient's quality of life as scored by the Minnesota Living with Heart Failure Quality of Life Questionnaire (MLWHF Scale).
  • the treatment will induce an improvement of at least 19%, or more preferably at least 25% over baseline in the patient's MLWHF score.
  • treatment with TNFR:Fc may be continued after the patient has shown improvement, and may be continued indefinitely if the patient's physician determines that this would be beneficial to the patient.
  • Long-term treatment may be administered at the original dose or at a reduced maintenance dose.
  • the treatment may be resumed if the patient's condition should worsen.
  • TNFR:Fc can be administered to a CHF patient, for example, via intra- articular injection, intramuscular injection, intraperitoneal infusion or bolus injection, continuous infusion into a vein or artery, intrathecal or subdural injection, sustained release from implants, aerosol inhalation, suppository, oral preparations, such as tablets, capsules, pills or syrups, transdermal patch, biodegradable icrocapsules or other suitable techniques, such as in vivo or ex vivo transfection of the patient's cells with recombinant DNA expressing a TNFR:Fc polypeptide.
  • TNFR:Fc is administered in the form of a composition
  • a composition comprising purified recombinant protein in conjunction with physiologically acceptable carriers, excipients or diluents.
  • Such carriers should be nontoxic to recipients at the dosages and concentrations employed.
  • the preparation of such compositions entails combining the TNFR:Fc with buffers, antioxidants such as ascorbic acid, low molecular weight polypeptides (such as those having fewer than 10 amino acids), proteins, amino acids, carbohydrates such as glucose, sucrose or dextrins, chelating agents such as EDTA, glutathione and other stabilizers and excipients.
  • Neutral buffered saline or saline mixed with conspecific serum albumin are exemplary appropriate diluents.
  • the TNFR:Fc is formulated as a lyophiliz'ate using appropriate excipient solutions (e.g., sucrose) as diluents.
  • Appropriate dosages can be determined in standard dosing trials, and may vary according to the route of administration that is chosen. In accordance with appropriate industry standards, preservatives may also be added, such as benzyl alcohol. The amount and frequency of administration will depend, of course, on such factors as the nature and severity of the indication being treated, the desired response, the condition of the patient, and so forth.
  • compositions described herein preferably are administered at least one time per week.
  • TNFR:Fc is administered at least two times per week, and in another preferred embodiment, it is administered at least three times a week.
  • Etanercept is a dimeric TNFR that competes for TNF ⁇ with the receptors on the cell surface, thus inhibiting TNF ⁇ from binding to the cell.
  • inhibitors comprising a TNFR are capable also of binding to the inflammatory cytokine LT ⁇ .
  • TNRF:Fc has the capacity to suppress the binding of LT ⁇ to its natural receptors, which may contribute to the potency of TNFR:Fc.
  • Example 1 Evaluation of TNFR:Fc in patients with chronic heart failure. Forty-seven patients with Class III-IV heart failure were evaluated in a Phase I II randomized, placebo controlled double-blinded study to determine whether the long-term subcutaneous biweekly administration of etanercept (recombinant TNFR:Fc) was safe in this patient population and whether efficacy could be documented. Two dose levels of TNFR:Fc were evaluated in this study. To assess improvement in the patient's degree of heart disease, parameters assessed at the end of the study included ventricular function (as indicated by left ventricular ejection fraction), NYHA class, quality of life, clinical composite score, as well as numerous other measures that reflected the patient's degree of heart disease.
  • ventricular function as indicated by left ventricular ejection fraction
  • NYHA class quality of life
  • clinical composite score as well as numerous other measures that reflected the patient's degree of heart disease.
  • the walking test is a simple objective guide to disability in patients with chronic heart failure. The tests were carried out in a level corridor and each patient was instructed prior to the test to cover as much ground as possible in 6 minutes.
  • CLASS III A Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea.
  • CLASS i ⁇ B Marked limitation of physical activity. Comfortable at rest, but minimal exertion causes fatigue, palpitation or dyspnea. CLASS IV
  • Patients were considered "worse” if events 1 and 2 above occurred within 24 weeks following randomization or if events 3 or 4 occurred at 24 weeks.
  • a patient was considered to have had a CHF hospitalization if he/she was hospitalized for or with worsening heart failure (admission of at least 1 day defined as a change in dates) and received intravenous diuretics, vasodilators or positive inotropic drugs for the treatment of heart failure.
  • Patients who were eligible for enrollment met the following criteria: male or female between 18 and 75 years of age; not pregnant if female; willing to practice contraception during the trial; NYHA Class III or IV (see below); ejection fraction ⁇ 35% (as assessed by radionuclide ventriculography within 60 days prior to randomization); receiving standard and stable (1 month) triple therapy for heart failure (angiotensin converting enzyme (ACE) inhibitor and diuretics); able to walk a minimum of 100 m during a standard 6 minute corridor walking test. Patients with severe infections were excluded. All patients provided informed consent.
  • ACE angiotensin converting enzyme
  • TNFR:Fc etanercept
  • etanercept Recombinant human TNFR:Fc (etanercept) that was used in this study was obtained from Immunex Corporation.
  • the gene fragments encoding the etanercept polypeptides were expressed in a Chinese hamster ovary (CHO) expression vector.
  • TNFR:Fc was supplied as a sterile lyophilized powder containing 10 mg or 25 mg TNFR:Fc; 40 mg mannitol, USP; 10 mg sucrose, NF; and 1.2 mg tromethamine (TRIS), USP per vial.
  • Vials of etanercept were reconstituted by aseptic injection of 1.0 mL Bacteriostatic Water for Injection, USP, (containing 0.9% benzyl alcohol). The reconstituted solution was not filtered during preparation or prior to administration. If storage was required, the reconstituted solutions were stored at 2-8°C (36-46°F) in the original vial or in a plastic syringe for a period of no longer than 28 days.
  • Study drug was dispensed in syringes to patients to be self-administered at home. Study drug was given twice weekly at approximately the same time of day, and the site for injection rotated to a different site with each subcutaneous injection. Patient Evaluations included:
  • FIGURE 1 a shift to a lower NYHA classification was observed in patients who received either dose of etanercept, the shift being more pronounced in the group who received the higher dose.
  • FIGURES 2A and 2B illustrate that, as compared with the placebo, the patients who received etanercept exhibited improved left ventricular ejection fraction by MUGA. Eight to thirteen percent of the etanercept recipients but none of the placebo group showed an at least 10% improvement in LV ejection fraction (see FIGURE 2B).
  • FIGURE 3 shows further that the patients who received etanercept exhibited an improved Quality of Life (MLWHF-physical dimension) as compared with the placebo group
  • FIGURE 4 illustrates that a greater proportion of the etanercept recipients as compared with the placebo group ended the study with an improved clinical composite score.
  • the benefits illustrated in FIGURES 2A, 2B, 3 and 4 showed a dose-dependency that is consistent with the benefits being attributable to the etanercept.
  • etanercept dosed for three months was well tolerated in patients with CHF and induced an overall improvement in their condition, as manifest by a number of indicators, including NYHA classification, clinical composite score, ventricular function and quality of life scores. These changes were more pronounced in the 12 mg/m 2 group, but were apparent also in the 5 mg/m 2 group.
  • Example 2 Multi-site randomized TNFR:Fc study in CHF patients A double-blind, placebo controlled study will be conducted in multiple sites and will involve 900 patients with heart failure, stratified based upon baseline ⁇ -blocker use and NYHA functional class. This clinical trial will evaluate the efficacy of two dosing regimens of etanercept subcutaneous (SC) injections and placebo in patients with Class II- IV chronic heart failure (CHF). Endpoints will include the clinical composite score at 24 weeks and a combined analysis of all-cause mortality and morbidity (CHF hospitalizations). Specific covariates will be examined, including left ventricular ejection fraction (LVEF), etiology of heart failure, age, and gender.
  • LVEF left ventricular ejection fraction
  • Baseline values for all study parameters will be determined by examining each patient within about 60 days prior to administration of the first dose of etanercept. Unless otherwise indicated, values for various indicators of heart disease (e.g., NYHA class, serum TNF ⁇ , walking test, left ventricle function, clinical composite score, MLWHF score, etc.) will be be determined as described above in Example 1. The etanercept employed for this study and its preparation for injection is described above in Example 1.
  • various indicators of heart disease e.g., NYHA class, serum TNF ⁇ , walking test, left ventricle function, clinical composite score, MLWHF score, etc.
  • the data obtained will be analyzed in combination with data from a second trial of etanercept whose design will be similar to this 900 patient clinical trial.
  • a time to first event analysis will be included, and study duration will depend on event rate.
  • the study will continue at least until all enrolled patients have completed 24 weeks of treatment, and may continue for up to one year longer in order to observe the targeted number of events (389 events, including either mortality or CHF hospitilizations) for the combined patients in the two studies.
  • patients must meet the following criteria: 18-85 years of age; agree to use contraception throughout the study; exhibit NYHA Functional Class II-IV CHF; have a ventricular ejection fraction ⁇ 30%; receiving stable (> 2 weeks) therapy for heart failure; 6-minute walk distance > 50 meters and ⁇ 375 meters or ⁇ 425 meters plus hospitalization for CHF within previous 6 months.
  • Patients included in the study must be receiving therapy for heart failure including a diuretic and an ACE inhibitor (unless there is a history of ACE intolerance or a contraindication to use), and may also be receiving digoxin, angiotensin II antagonist, beta blocker, amiodarone, nitrates, and hydralazine, but these medications must have been constant for 2 weeks prior to randomization.
  • Female patients may not be pregnant or lactating. Throughout the study, treatment with antiarrhythmic drugs and nonsteroidal anti-inflammatory drugs will be avoided.
  • a detailed medical history will be taken prior to study entry, which will include ischemic heart disease; myocardial infarction; history of arryghmia; hypertension; dilated cardiomyopathy; CHF history, including NYHA class; and history of recent hospitilizations.
  • Patients during the study will be evaluated for vital signs and physical examination, cardiopulmonary assessment, routine labs, antibody formation against etanercept, and adverse events.
  • Laboratory assessments will be performed at screening and at weeks 2, 4, 12 and 24.
  • serum samples will be collected from a subgroup of 200 randomly selected patients at Day 1 and at the end of Weeks 4, 12, and 24.
  • patient evaluations will include: NYHA classification; physician global assessments; changes in the Minnesota Living with Heart Failure (MLWHF) Scale and VAS; vitals signs including weight; limited physical exam; cardiopulmonary exam; review AEs and concomitant medications; routine laboratory; serum/plasma bank (for markers of heart failure); etanercept antibodies; chest x-ray; and change in left ventricular ejection fraction (MUGA) in 300 patients.
  • MWHF Minnesota Living with Heart Failure
  • MUGA left ventricular ejection fraction

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Abstract

L'invention concerne des méthodes visant à traiter l'insuffisance cardiaque chronique chez un patient et consistant à administrer de manière répétée un récepteur du facteur de nécrose tumorale (TNFR: Fc) sur une durée suffisamment longue pour produire une amélioration dans un indicateur d'insuffisance cardiaque chronique.
PCT/US2000/008161 1999-04-02 2000-03-28 Utilisation d'un recepteur du facteur de necrose tumorale soluble dans le traitement de l'insuffisance cardiaque WO2000059530A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU39271/00A AU763575B2 (en) 1999-04-02 2000-03-28 Use of soluble tumor necrosis factor receptor for treatment heart failure
CA002365824A CA2365824A1 (fr) 1999-04-02 2000-03-28 Utilisation d'un recepteur du facteur de necrose tumorale soluble dans le traitement de l'insuffisance cardiaque
EP00918469A EP1165116A1 (fr) 1999-04-02 2000-03-28 Utilisation d'un recepteur du facteur de necrose tumorale soluble dans le traitement de l'insuffisance cardiaque

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US12758899P 1999-04-02 1999-04-02
US60/127,588 1999-04-02

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7070783B1 (en) 1995-05-09 2006-07-04 The Mathilda And Terence Kennedy Institute Of Rheumatology Small molecular weight TNF receptor multimeric molecule
US7087224B2 (en) 2000-10-31 2006-08-08 Amgen Inc. Method of treating anemia by administering IL-1ra
US7186810B2 (en) 1998-10-23 2007-03-06 Amgen Inc. Modified peptides as therapeutic agents
WO2022123293A1 (fr) 2020-12-09 2022-06-16 에이치케이이노엔 주식회사 ANTICORPS ANTI-OX40L, ANTICORPS BISPÉCIFIQUE ANTI-OX40L/ANTI-TNFα ET LEURS UTILISATIONS

Citations (2)

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WO1994006476A1 (fr) * 1992-09-15 1994-03-31 Immunex Corporation Procede de traitement de l'inflammation dependante du facteur necrosant des tumeurs malignes (tnf) a l'aide d'antagonistes dudit tnf
WO1997030088A2 (fr) * 1996-02-16 1997-08-21 The Kennedy Institute Of Rheumatology Procedes de traitement d'une maladie vasculaire au moyen d'antagonistes du tnf (facteur de necrose tumorale)

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WO1994006476A1 (fr) * 1992-09-15 1994-03-31 Immunex Corporation Procede de traitement de l'inflammation dependante du facteur necrosant des tumeurs malignes (tnf) a l'aide d'antagonistes dudit tnf
WO1997030088A2 (fr) * 1996-02-16 1997-08-21 The Kennedy Institute Of Rheumatology Procedes de traitement d'une maladie vasculaire au moyen d'antagonistes du tnf (facteur de necrose tumorale)

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Title
BOZKURT, B. ET AL: "Pathophysiologically Relevant Concentrations of Tumor Necrosis Factor-alpha Promote Progressive Left Ventricular Dysfunction and Remodeling in Rats.", CIRCULATION, vol. 97, no. 14, 14 April 1998 (1998-04-14), pages 1382 - 1391, XP000929170 *
DESWAL, A. ET AL: "A Phase I Trial Of Tumor Necrosis Factor Receptor (p75) Fusion Protein (TNFR:Fc) In Patients With Advanced Heart Failure", CIRCULATION, vol. 96, no. 8, 21 October 1997 (1997-10-21), pages I-323, XP000925228 *
MORELAND L W ET AL: "Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein [see comments]", NEW ENGLAND JOURNAL OF MEDICINE, THE,US,MASSACHUSETTS MEDICAL SOCIETY, WALTHAM, MA, vol. 337, no. 3, 17 July 1997 (1997-07-17), pages 141 - 147, XP002115639, ISSN: 0028-4793 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7070783B1 (en) 1995-05-09 2006-07-04 The Mathilda And Terence Kennedy Institute Of Rheumatology Small molecular weight TNF receptor multimeric molecule
US7186810B2 (en) 1998-10-23 2007-03-06 Amgen Inc. Modified peptides as therapeutic agents
US7087224B2 (en) 2000-10-31 2006-08-08 Amgen Inc. Method of treating anemia by administering IL-1ra
US7867481B2 (en) 2000-10-31 2011-01-11 Amgen Inc. Method of treating anemia by administering IL-1ra
WO2022123293A1 (fr) 2020-12-09 2022-06-16 에이치케이이노엔 주식회사 ANTICORPS ANTI-OX40L, ANTICORPS BISPÉCIFIQUE ANTI-OX40L/ANTI-TNFα ET LEURS UTILISATIONS

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CA2365824A1 (fr) 2000-10-12
AU763575B2 (en) 2003-07-24
AU3927100A (en) 2000-10-23
EP1165116A1 (fr) 2002-01-02

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