EP0682525A1 - 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

Info

Publication number
EP0682525A1
EP0682525A1 EP94908700A EP94908700A EP0682525A1 EP 0682525 A1 EP0682525 A1 EP 0682525A1 EP 94908700 A EP94908700 A EP 94908700A EP 94908700 A EP94908700 A EP 94908700A EP 0682525 A1 EP0682525 A1 EP 0682525A1
Authority
EP
European Patent Office
Prior art keywords
cntf
day
als
patients
administered
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP94908700A
Other languages
German (de)
English (en)
Inventor
Frank Collins
Mark Dietz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Syntex USA LLC
Syntex Synergen Neuroscience Joint Venture
Original Assignee
Syntex USA LLC
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 Syntex USA LLC, Syntex Synergen Neuroscience Joint Venture filed Critical Syntex USA LLC
Publication of EP0682525A1 publication Critical patent/EP0682525A1/fr
Withdrawn legal-status Critical Current

Links

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 progressive degenerative disorder of motor neurons in the spinal cord, brainstem, and motor cortex, manifested clinically by muscular weakness, atrophy, and corticospinal tract signs in varying combinations.
  • 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 uselessness of hand, awkwardness in tasks requiring fine finger movements, stiffness of the fingers, and slight weakness or wasting of the hand muscles.
  • Cramping and fasciculations of the muscles of the forearm, upper arm, and shoulder girdle muscles also appears. With time, the other hand and arm may be similarly affected.
  • a patient exhibits atrophic weakness of the hands and forearms, slight spasticity of the legs, and generalized hyperreflexia.
  • the patient may walk about with useless, dangling arms. Later the atrophic weakness spreads to the neck, tongue, pharyngeal and laryngeal muscles.
  • 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, particularly the superior frontal gyri, and the 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.
  • ALS has been observed in conjunction with presenile and senile dementia, and with Parkinsons disease.
  • the course of ALS irrespective of its particular mode of onset and pattern of evolution, is inexorably progressive.
  • Half of the patients die within 3 years and 90% within 6 years (Adams and Victor (1989) in Principles of Neurology. 4th ed.. McGraw- Hill, Inc., New York.)
  • CPK creatine phosphokinase
  • Serum CPK levels are used to monitor muscle damage in certain neuromuscular diseases, and as a marker for effective treatment.
  • serum CPK levels may be elevated up to 2-3 times normal. This phenomenon, occurring in almost half of all patients with ALS, probably represents ongoing muscle damage secondary to progressive denervation.
  • a standardized test has been developed to measure the clinical deficit and progression of ALS.
  • the test battery developed by the Neuromuscular Research Unit at the New England Medical Center is referred to as the Tufts Quantitative Neuromuscular Exam or TQNE. See, Andres et al. Neurology 38: 409-413 (1988).
  • the TQNE is a validated test battery specifically designed to measure the motor function and strength of ALS patients as the disease progresses.
  • the battery includes testing of five major functional areas: bulbar, respiratory, arm, leg, and fine motor activities.
  • the present invention includes the use of the protein neurotrophic factor ciliary neurotrophic factor (CNTF) to treat ALS.
  • CNTF protein neurotrophic factor ciliary neurotrophic factor
  • Neurotrophic factors are naturally occurring proteins that promote the survival and functional activities of nerve cells. 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. Although the biological role of CNTF has not been conclusively established, CNTF appears to be released upon injury to the nervous system and may limit the extent of injury or neuronal damage.
  • 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.
  • ciliary neurotrophic factor CNTF
  • 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 administration in order to treat patients suffering from ALS.
  • 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.
  • a method for treating a patient suffering from ALS by administering to that patient the human neurotrophic factor CNTF.
  • preferred embodiment of this invention preferred
  • 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 Structure, vol. 5, p. 124 (1972) , National Biochemical Research Foundation, Washington, D.C., specifically incorporated herein by reference) as well as possessing comparable biological activity.
  • Substantially equivalent proteins of this invention includes proteins that have a significant degree of homology with the naturally occurring protein, but have been modified to contain a limited number of mutations or deletions within the amino acid sequence. Only such modified proteins retaining the biological activity of the naturally occurring proteins are included within the definition. Those skilled in the art are competent to prepare mutated proteins based on the known sequence of the naturally occurring proteins according to well known procedures without undue experimentation. The biological activity of such mutations may also be determined (without undue experimentation) according to the procedures described herein by those skilled in the art.
  • Bio activity refers to the natural 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.
  • CNTF is modified by attachment of one or more polyethylene glycol (PEG) or other repeating polymeric moieties.
  • PEG polyethylene glycol
  • the CNTF used is naturally-occurring recombinant human CNTF (rhCNTF) .
  • 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 invention. Recombinant DNA methods are preferred in part because they are capable of achieving comparatively higher amounts at greater purity.
  • 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 States patent 4,997,929. It is to be recognized, however, that derivatives of CNTF may have different specific activities.
  • 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.
  • the therapeutic composition of the present invention is preferably administered parenterally by injection.
  • the 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 envisioned.
  • 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.
  • the manner of parenterally administering the formulations containing CNTF is via a subcutaneous or intramuscular route.
  • the most preferred administration is parenterally via a subcutaneous route.
  • 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 administration of doses of greater than lOmg/kg/day may have undesirable side effects.
  • the dose of CNTF is between 0.5-50 ⁇ g/kg/day.
  • the periodic administrations may constitute monthly, bi-weekly, weekly, daily or hourly regimes. The required frequency of administration will be apparent to those treating the patient based on standard observational techniques.
  • 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.
  • the most positive trends were seen in the patient group which had been administered 2 ⁇ g/kg/day.
  • 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 formulated with or without those carriers customarily used in the compounding of solid dosage forms.
  • 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 approximate body weight or surface area of the patient. Further refinement of the calculations necessary to determine the appropriate dosage for treatment involving each of the above mentioned formulations is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them without undue experimentation, especially in light of the dosage information and assays disclosed herein. These dosages may be ascertained through use of the established assays for determining dosages utilized in conjunction with appropriate dose-response data.
  • a patient in need of a treatment for ALS is administered a therapeutically effective amount of CNTF.
  • the dosage sufficient to deliver a "therapeutically 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. It is understood that the application of teachings of the present invention to a specific problem or environment will be within the capabilities of one having ordinary skill in the art in light of the teachings contained herein. Examples of representative uses of the present invention appear in the following examples.
  • ALS amyotrophic lateral sclerosis
  • rhCNTF recombinant human CNTF
  • the rhCNTF was prepared in an E. coli expression system as described in U.S. patent numbers 4,997,929 and 5,141,856 and U.S. patent application serial no. 07/753,176).
  • 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 white blood cells
  • differential, hemoglobin, hematocrit, platelets, serum electrolytes, SGOT, SGPT, alkaline phosphatase, BUN an creatinine, total bilirubin, and urinalysis were within clinically acceptable limits.
  • 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, 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 predicted. 3.
  • the patient has evidence for GM1 antibodies, paraproteinemia, familial ALS, or "pure" motor syndromes (Spinal muscular atrophy, etc.) 4.
  • the patient is lactating or pregnant. 5.
  • the patient has received another investigational drug within the past 30 days.
  • the patient has any other major neurologic disease in addition to ALS.
  • the patient has had a major surgical operation or severe infection within one month prior to the day of dosing.
  • 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 procedures.
  • the rhCNTF was supplied in a sterile solution ready for injection.
  • This solution was comprised of a Tris (lOmM) and sodium phosphate buffered solution (lOmM) 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 L 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.
  • D represents patients who received CNTF
  • P represents patients who received placebo
  • the number represents the dosage of CNTF in mg/kg/day.
  • serum CPK levels decreased in 5 of 6 patients, receiving 0.005 mg/kg/day of rhCNTF, 6 of 6 patients receiving 0.01 mg/kg/day of rhCNTF and 3 of 3 patients receiving 0.02 mg/kg/day.
  • Patients receiving placebo showed no obvious correlations to a decrease in serum CPK levels.
  • 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.
  • TQNE Tufts Quantitative Neuromuscular Exam
  • 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 treatment in patients receiving daily subcutaneous injections of rhCNTF.
  • 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 demonstrates a 28-day score worse than the baseline score.
  • " ⁇ " signifies no changes.
  • Table 4 shows a summary table of megascore improvement per 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).
EP94908700A 1993-02-08 1994-02-03 Procedes permettant le traitement de la sclerose laterale amyotrophique avec le cntf Withdrawn EP0682525A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US1521893A 1993-02-08 1993-02-08
US11644093A 1993-09-03 1993-09-03
US116440 1993-09-03
PCT/US1994/001227 WO1994017818A1 (fr) 1993-02-08 1994-02-03 Procedes permettant le traitement de la sclerose laterale amyotrophique avec le cntf
US15218 2001-11-19

Publications (1)

Publication Number Publication Date
EP0682525A1 true EP0682525A1 (fr) 1995-11-22

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EP94908700A Withdrawn EP0682525A1 (fr) 1993-02-08 1994-02-03 Procedes permettant le traitement de la sclerose laterale amyotrophique avec le cntf

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EP (1) EP0682525A1 (fr)
AU (1) AU6169894A (fr)
CA (1) CA2155540A1 (fr)
WO (1) WO1994017818A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6444201B1 (en) * 1995-05-12 2002-09-03 The Rockefeller University Treatment of alzheimer disease by modulation of synapsins
WO1997012635A1 (fr) * 1995-10-02 1997-04-10 Cytotherapeutics, Inc. Procede de traitement de la sclerose laterale amyotrophique
AU8021098A (en) * 1997-06-13 1998-12-30 Roche Diagnostics Gmbh Improvement of the regeneration of myelin sheaths
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
LT2558499T (lt) 2010-04-16 2017-07-25 Biogen Ma Inc. Antikūnai prieš vla-4

Family Cites Families (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
IE903130A1 (en) * 1989-09-15 1991-03-27 Regeneron Pharma Ciliary neurotrophic factor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9417818A1 *

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CA2155540A1 (fr) 1994-08-18
AU6169894A (en) 1994-08-29
WO1994017818A1 (fr) 1994-08-18

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