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WO1994017818A1 - Procedes permettant le traitement de la sclerose laterale amyotrophique avec le cntf - Google Patents

Procedes permettant le traitement de la sclerose laterale amyotrophique avec le cntf Download PDF

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Publication number
WO1994017818A1
WO1994017818A1 PCT/US1994/001227 US9401227W WO9417818A1 WO 1994017818 A1 WO1994017818 A1 WO 1994017818A1 US 9401227 W US9401227 W US 9401227W WO 9417818 A1 WO9417818 A1 WO 9417818A1
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WO
WIPO (PCT)
Prior art keywords
cntf
day
als
patients
administered
Prior art date
Application number
PCT/US1994/001227
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English (en)
Inventor
Frank Collins
Mark Dietz
Original Assignee
The Syntex-Synergen Neuroscience Joint Venture
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Syntex-Synergen Neuroscience Joint Venture filed Critical The Syntex-Synergen Neuroscience Joint Venture
Priority to AU61698/94A priority Critical patent/AU6169894A/en
Priority to EP94908700A priority patent/EP0682525A1/fr
Publication of WO1994017818A1 publication Critical patent/WO1994017818A1/fr

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Classifications

    • 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
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3

Definitions

  • the present invention includes methods for the treatment of amyotrophic lateral sclerosis (ALS) in human patients.
  • ALS amyotrophic lateral sclerosis
  • ALS Amyotrophic lateral sclerosis
  • ALS is a common disease, with an annual incidence rate of 0.4 to 1.76 per 100,000 population
  • ALS occurs in a random pattern throughout the world; it is estimated that in about 5% of cases ALS is familial, being inherited as an autosomal dominant trait.
  • ALS affects neuromuscular functions in the hand, leg, thoracic, abdominal, or posterior neck muscles. Typical initial symptoms in the hand include
  • the principal finding is a loss of nerve cells in the anterior horns of the spinal cord and motor nuclei of the lower brainstem. There is an extensive neuronal loss and gliosis involving the premotor area,
  • inferolateral cortex of the temporal lobes Many of the surviving nerve cells are small, shrunken, and filled with lipofuscin. Lost cells are replaced by fibrous astrocytes.
  • CPK creatine phosphokinase
  • TQNE Tufts Quantitative Neuromuscular Exam
  • the present invention includes the use of the protein neurotrophic factor ciliary neurotrophic factor (CNTF) to treat ALS.
  • Neurotrophic factors are protein neurotrophic factor ciliary neurotrophic factor (CNTF) to treat ALS.
  • CNTF protein neurotrophic factor ciliary neurotrophic factor
  • Neurotrophic factors have been found in the target cells to which an innervating nerve cell connects. Such target-derived neurotrophic factors regulate the number of contacts formed between innervating nerve cells and the target cell population, and are necessary for the survival and maintenance of these nerve cells.
  • Neurotrophic factors are also found in cells that are not innervated.
  • An example of such a neurotrophic factor is CNTF.
  • Human CNTF and the gene encoding human CNTF are described in detail in United States patent numbers 4,997,929, 5,141,856 and co-pending United States patent application serial number 07/857,544 filed March 24, 1992. Each of these documents are specifically incorporated herein by this reference.
  • CNTF appears to be released upon injury to the nervous system and may limit the extent of injury or neuronal damage.
  • Highly-purified CNTF has been shown to support the survival in cell cultures of chick embryonic parasym- pathetic, sympathetic, sensory, and motor neurons.
  • CNTF is a neurotrophic factor for peripheral primary neurons in vivo and in vitro. See, U.S. patent application serial number 07/735,538 filed July 23, 1991, specifically incorporated herein by this reference.
  • CNTF ciliary neurotrophic factor
  • the present invention includes methods for the treatment of ALS by administering a human protein ciliary neurotrophic factor to a patient in need thereof.
  • the invention provides methods for administering therapeutically effective amounts of CNTF by therapeutically effective routes of
  • recombinant human CNTF is administered to human
  • patients suffering from ALS in doses of less than about 10 ⁇ g/kg/day. More specifically, daily doses of about 2-3 ⁇ g/kg/day are utilized.
  • the present invention includes a method for treating a patient suffering from ALS by administering to that patient the human neurotrophic factor CNTF.
  • CNTFs are naturally occurring proteins.
  • the naturally- occurring proteins are preferred in part because they pose a possibly lower risk of producing unforeseen and undesirable physiological side effects in patients treated therewith.
  • Human CNTFs are preferred for use in this invention.
  • non- human CNTFs are substantially equivalent to human CNTFs and possess equivalent biological activity, they are considered to be within the scope of this invention.
  • a protein is deemed to be "naturally-occurring” if it or a substantially equivalent protein can be found to exist normally in healthy humans.
  • “Naturally- occurring” proteins specifically includes forms of proteins found to exist in healthy humans that are partially truncated at the amino or carboxyl terminus of such proteins or that have amino acids that are deamidated or otherwise chemically modified.
  • “Naturally-occurring” proteins may be obtained by recombinant DNA methods as well as by isolation from cells which ordinarily produce them. “Naturally- occurring” also encompasses proteins that contain or lack an NH 2 -terminal methionyl group as a consequence of expression in E. coli.
  • Substantially equivalent as used throughout the specification and claims is defined to mean possessing a very high degree of amino acid residue homology (See generally M. Dayhoff, Atlas of Protein Seguence and
  • invention includes proteins that have a significant degree of homology with the naturally occurring
  • CNTF proteins of this invention neurotrophic activity of the CNTF proteins of this invention.
  • One measure of the biological activity of CNTF accepted by those skilled in the art is the ability to support the survival in cell cultures of chick embryonic ciliary ganglia as described in U.S. patent 5,011,914.
  • a protein is considered to have the same or comparable biological activity as the naturally occurring proteins of this invention if the protein has a specific activity within two orders of magnitude as the naturally-occurring proteins of this invention.
  • Particularly preferred CNTFs of the present invention are the naturally-occurring proteins that have previously been described in a currently pending United States patent application.
  • This application is U.S. Patent Application Serial No. 07/857,544 filed March 24, 1992 of Collins et al., which is entitled "Purified Ciliary Neurotrophic Factor.” (See also, U.S. patents 5,011,914; 5,141,856; and 4,997,929).
  • CNTF is modified by attachment of one or more polyethylene glycol (PEG) or other repeating polymeric moieties.
  • PEG polyethylene glycol
  • rhCNTF naturally-occurring recombinant human CNTF
  • One disclosed method consists of isolating CNTF from various sources, such as peripheral nerve tissues.
  • a second disclosed method involves isolating the genes responsible for coding CNTF, cloning the gene in suitable vectors and cell types, and expressing the gene in order to produce the CNTF.
  • the latter method which is exemplary of recombinant DNA methods in general, is a preferred method of the present
  • Recombinant DNA methods are preferred in part because they are capable of achieving
  • the above described CNTFs are produced by the aforementioned method in “substantially pure” form.
  • substantially pure it is meant that CNTF, in an unmodified form, has comparable biological activity to the purified CNTF described in United
  • a therapeutic composition comprising CNTF is administered in an effective amount to patients in order to effectively treat the symptoms of ALS.
  • the function of the preferred CNTFs is imparted by one or more discrete and separable portions of the CNTF protein
  • the method of the present invention could be practiced by administering a therapeutic composition whose active ingredient consists of that portion (or those portions) of CNTF which controls (or control) CNTF function.
  • parenteral administration is subcutaneous.
  • other effective administration forms such as parenteral slow-release formulations, intrathecally by continuous infusion from an implanted pump, inhalant mists, orally active formulations, or suppositories, are also present.
  • the CNTF of this invention is preferably formulated with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier is a carrier that is not harmful to the patient and does not degrade, deactivate, or in any other way hinder the effects of the CNTF.
  • One preferred carrier is physiological saline solution, but it is contemplated that other pharmaceutically acceptable carriers may also be used.
  • the carrier and the CNTF constitute a physiologically- compatible, slow-release formulation.
  • the primary solvent in such a carrier may be either aqueous or non- aqueous in nature.
  • the carrier may contain other pharmacologically-acceptable excipients for modifying or maintaining the pH, osmolarity, viscosity, clarity, color, sterility, stability, rate of dissolution, or odor of the formulation.
  • the carrier may contain still other pharmacologically- acceptable excipients for modifying or maintaining the stability, rate of dissolution, release, or absorption of the CNTF.
  • excipients are those substances usually and customarily employed to formulate dosages for parenteral administration in either unit dose or multi-dose form or for intrathecal delivery by continuous or periodic infusion from an implanted pump or intrathecally by periodic injection.
  • formulated it may be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or
  • dehydrated or lyophilized powder Such formulations may be stored either in a ready to use form or
  • formulations is at temperatures at least as low as 4°C and preferably at -70°C. It is also preferred that such formulations containing CNTF are stored and administered at or near physiological pH. It is presently believed that storage and administration in a formulation at a pH below approximately pH 5.5 and above approximately pH 8.0 is undesirable.
  • administering the formulations containing CNTF is via a subcutaneous or intramuscular route.
  • preferred administration is parenterally via a
  • CNTF neuropeptide FFFF
  • single or repeated subcutaneous or intramuscular injections may be administered. It is believed that the administration of CNTF in doses below approximately 0.005 ⁇ g/kg/day may not be effective, while the
  • the dose of CNTF is between 0.5-50 ⁇ g/kg/day.
  • the periodic administrations may
  • Example 2 patients suffering from ALS were administered daily injections of rhCNTF in dosages including 2 ⁇ g/kg/day, 5 ⁇ g/kg/day, 10 ⁇ g/kg/day and 20 ⁇ gkg/day.
  • the progression of the ALS symptoms in the patients were monitored by the TQNE evaluation.
  • patients suffering from ALS are administered rhCNTF in doses of less than about 10 ⁇ g/kg and preferable about 2-3 ⁇ g/kg. Further, in the preferred embodiment the rhCNTF is administered once daily.
  • CNTF which is administered in this fashion is encapsulated.
  • the encapsulated CNTF may be
  • the capsule is designed so that the active portion of the formulation is released at that point in the gastro-intestinal tract when bioavailability is maximized and pre-systemic degradation is minimized.
  • Additional excipients may be included to facilitate absorption of CNTF. Diluents, flavorings, low melting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders may also be employed.
  • the specific dose is calculated according to the
  • a patient in need of a treatment for ALS is administered a
  • the dosage sufficient to deliver a
  • terapéuticaally effective amount of CNTF can be determined by those of ordinary skill in the art without undue experimentation.
  • a “therapeutically effective amount” may be defined as the amount of CNTF sufficient to give rise to subjective or objective improvements in the condition of the patient suffering from ALS.
  • CNTF formulations described herein may be used for veterinary as well as human applications and that the term "patient” should not be construed in a limiting manner. In the case of veterinary applications, the dosage ranges should be the same as specified above.
  • ALS amyotrophic lateral sclerosis
  • the patient was male or female between the ages of 21-85 years.
  • the patient was an outpatient at the time of enrollment.
  • the patient was willing to be housed for 7 days in a medical unit, and was able to comply with the study visit schedule.
  • WBCs blood cells
  • Exclusion criteria Patients were excluded from the test if they met any of the following criteria:
  • the patient has uncontrolled (over the last 30 days), clinically significant
  • cardiovascular cardiovascular, pulmonary, endocrine, or gastrointestinal disease.
  • the patient has clinically significant hematologic, metabolic, hepatic, or renal disease.
  • the patient's FVC and/or FEV- is ⁇ 40% of
  • the patient has evidence for GM1 antibodies, paraproteinemia, familial ALS, or "pure” motor syndromes (Spinal muscular atrophy, etc.)
  • the patient is lactating or pregnant.
  • the patient has any other major neurologic disease in addition to ALS.
  • the patient has a history of recent ethanol or drug abuse, or noncompliance with treatment on other experimental protocols. 9. The patient has limited mental capacity such that he/she cannot provide written informed consent, information regarding adverse experiences or comply with evaluation
  • the rhCNTF was supplied in a sterile solution ready for injection.
  • This solution was comprised of a Tris (10mM) and sodium phosphate buffered solution (10mM) at pH 7.2, containing 205 mM sodium chloride, 10% v/v glycerol, 0.2% w/w polysorbate 80, and 0.1% human serum albumin.
  • the concentration of rhCNTF was either 1.0 mg/mL or 4 mg/mL.
  • the rhCNTF and placebo were packaged in 3 cc glass vials with Teflon-faced butyl rubber stoppers. Each vial contained 1.7 mL of formulated material. This study also used a placebo which was the vehicle for dilution of rhCNTF.
  • the rhCNTF and placebo were stored frozen at -20 or -70 degrees Celsius. Frozen, formulated rhCNTF and placebo were thawed at room temperature. Prior to use, the liquid formulations were gently inverted several times to afford a homogenous solution.
  • Dosing of rhCNTF was performed with a 1 or 3 cc syringe fitted with a 27 gauge needle.
  • a solution of 0.1 mg/mL was produced by adding 0.43 mL of 1 mg/mL solution to one vial of placebo (1.7 mL).
  • Serum levels of creatine phosphokinase (CPK) were measured in the test group of patients at various times for most patients, levels of serum CPK were determined prior to the initiation of administration, on the day the treatment began and weekly thereafter. The results of these measurements are shown in Table II below.
  • Drug/Placebo D represents patients who received CNTF and P represents patients who received placebo, and the number represents the dosage of CNTF in mg/kg/day.
  • ALS patients meeting the inclusion and exclusion criteria set forth in Example 1 were given a daily single subcutaneous administration of rhCNTF.
  • the condition of the patients in the study was monitored by TQNE.
  • the Neuromuscular Research Unit at the New England Medical Center has developed a standarzied test battery to measure the clinical deficit in ALS, the Tufts
  • TQNE Quantitative Neuromuscular Exam
  • MVIC maximum voluntary isometric contraction
  • the TQNE is most commonly used to measure disease progression and efficacy of investigational agents.
  • the TQNE measurements obtained at a given visit are transformed to megascores as described in Andres 1988 reference supra, by averaging the Z-transformed items (the raw score minus the mean, divided by the standard deviation of the TUFTS ALS population for that score) that compose that category.
  • Table 3 shows TQNE changes over 28 days of
  • the left column lists muscle groups and their respective megascores. Each column group to the right of this is a dose level (placebo, 2 5, 10, and 20 ⁇ g/kg/day). Individual columns group in each are patients who had evaluable TQNEs at baseline and at Day 28. A "+” sign demonstrate a 28-day score better than the baseline score. A "-" sign
  • Table 4 shows a summary table of megascore improvement per dose group. Although changes in this small number of patients are not statistically significant, there is a positive trend in the 2 ⁇ g/kg/day dose group.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Psychology (AREA)
  • Neurology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Immunology (AREA)
  • Neurosurgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de traitement de la SLA, et consistant à administrer une dose thérapeutiquement efficace de facteur nemotrophe ciliaire (CNTF).
PCT/US1994/001227 1993-02-08 1994-02-03 Procedes permettant le traitement de la sclerose laterale amyotrophique avec le cntf WO1994017818A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU61698/94A AU6169894A (en) 1993-02-08 1994-02-03 Methods for treating amyotrophic lateral sclerosis with cntf
EP94908700A EP0682525A1 (fr) 1993-02-08 1994-02-03 Procedes permettant le traitement de la sclerose laterale amyotrophique avec le cntf

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US1521893A 1993-02-08 1993-02-08
US08/015,218 1993-02-08
US11644093A 1993-09-03 1993-09-03
US08/116,440 1993-09-03

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WO1994017818A1 true WO1994017818A1 (fr) 1994-08-18

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AU (1) AU6169894A (fr)
CA (1) CA2155540A1 (fr)
WO (1) WO1994017818A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996035446A1 (fr) * 1995-05-12 1996-11-14 The Rockefeller University Traitement de la maladie d'alzheimer par modulation des synapsines
WO1997012635A1 (fr) * 1995-10-02 1997-04-10 Cytotherapeutics, Inc. Procede de traitement de la sclerose laterale amyotrophique
WO1998056403A1 (fr) * 1997-06-13 1998-12-17 Roche Diagnostics Gmbh Amelioration de la regeneration des gaines de myeline
WO2002006341A1 (fr) * 2000-07-14 2002-01-24 Children's Medical Center Corporation Facteur tropique capable de produire un effet salutaire sur le systeme nerveux chez un sujet
US10335485B2 (en) 2010-04-16 2019-07-02 Biogen Ma Inc. Anti-VLA-4 antibodies
US12037398B2 (en) 2018-06-04 2024-07-16 Biogen Ma Inc. Anti-VLA-4 antibodies having reduced effector function

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4923696A (en) * 1987-05-04 1990-05-08 Baylor College Of Medicine Method to prepare a neurotrophic composition
US4997929A (en) * 1989-01-05 1991-03-05 Synergen, Inc. Purified ciliary neurotrophic factor
WO1991004316A2 (fr) * 1989-09-15 1991-04-04 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Facteur neurotrophique ciliaire
US5011914A (en) * 1989-01-05 1991-04-30 Collins Franklin D Purified ciliary neurotrophic factor
US5093317A (en) * 1989-06-05 1992-03-03 Cephalon, Inc. Treating disorders by application of insulin-like growth factor

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4923696A (en) * 1987-05-04 1990-05-08 Baylor College Of Medicine Method to prepare a neurotrophic composition
US4997929A (en) * 1989-01-05 1991-03-05 Synergen, Inc. Purified ciliary neurotrophic factor
US5011914A (en) * 1989-01-05 1991-04-30 Collins Franklin D Purified ciliary neurotrophic factor
US5093317A (en) * 1989-06-05 1992-03-03 Cephalon, Inc. Treating disorders by application of insulin-like growth factor
WO1991004316A2 (fr) * 1989-09-15 1991-04-04 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Facteur neurotrophique ciliaire

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
L.S. GOODMAN et al., "The Pharmacological Basis of Therapeutics", published 1975 by Macmillan Publishing Company, Inc. (N.Y.), pages 1-46, see entire document. *
Neurology, Volume 43, Number 4, Supplement 2, issued April 1993, B.R. BROOKS et al., "Recombinant Human Ciliary Neurotrophic Factor (rHCNTF) in Amytrophic Lateral Sclerosis (ALS) Patients: Phase I-II Safety, Tolerability and Pharmacokinetic Studies", page A416, Abstract No. 9905, see entire Abstract. *
Science, Volume 246, issued 24 November 1989, L.H. LIN et al., "Purification, Cloning, and Expression of Ciliary Neurotrophic Factor (CNTF)", pages 1023-1025, see entire document. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996035446A1 (fr) * 1995-05-12 1996-11-14 The Rockefeller University Traitement de la maladie d'alzheimer par modulation des synapsines
WO1997012635A1 (fr) * 1995-10-02 1997-04-10 Cytotherapeutics, Inc. Procede de traitement de la sclerose laterale amyotrophique
WO1998056403A1 (fr) * 1997-06-13 1998-12-17 Roche Diagnostics Gmbh Amelioration de la regeneration des gaines de myeline
WO2002006341A1 (fr) * 2000-07-14 2002-01-24 Children's Medical Center Corporation Facteur tropique capable de produire un effet salutaire sur le systeme nerveux chez un sujet
US10335485B2 (en) 2010-04-16 2019-07-02 Biogen Ma Inc. Anti-VLA-4 antibodies
US11083791B2 (en) 2010-04-16 2021-08-10 Biogen Ma Inc. Anti-VLA-4 antibodies
US11571477B2 (en) 2010-04-16 2023-02-07 Biogen Ma Inc. Anti-VLA-4 antibodies
US12037398B2 (en) 2018-06-04 2024-07-16 Biogen Ma Inc. Anti-VLA-4 antibodies having reduced effector function

Also Published As

Publication number Publication date
AU6169894A (en) 1994-08-29
EP0682525A1 (fr) 1995-11-22
CA2155540A1 (fr) 1994-08-18

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