WO2000020010A1 - Administration en jours alternes de copolymer 1 destine au traitement de maladies autoimmunes - Google Patents

Administration en jours alternes de copolymer 1 destine au traitement de maladies autoimmunes Download PDF

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Publication number
WO2000020010A1
WO2000020010A1 PCT/US1999/022836 US9922836W WO0020010A1 WO 2000020010 A1 WO2000020010 A1 WO 2000020010A1 US 9922836 W US9922836 W US 9922836W WO 0020010 A1 WO0020010 A1 WO 0020010A1
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WO
WIPO (PCT)
Prior art keywords
copolymer
disease
autoimmune
composition
present
Prior art date
Application number
PCT/US1999/022836
Other languages
English (en)
Inventor
Shlomo Flechter
Bettina Steiner-Birmanns
Edna Kott
Puiu Nisipianu
Joseph M. Rabey
Amos D. Korczyn
Original Assignee
Yeda Research And Development Co., Ltd.
Teva Pharmaceuticals Usa, Inc.
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 Yeda Research And Development Co., Ltd., Teva Pharmaceuticals Usa, Inc. filed Critical Yeda Research And Development Co., Ltd.
Priority to AU62815/99A priority Critical patent/AU6281599A/en
Publication of WO2000020010A1 publication Critical patent/WO2000020010A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials

Definitions

  • the present invention provides compositions and methods for treating an autoimmune disease which include administering a single dose of a therapeutically effective amount of Copolymer 1 (Cop 1 ) on alternate days.
  • autoimmune diseases This self-tolerance process breaks down when autoimmune diseases develop.
  • autoantigens the organism's own tissues and proteins are recognized as "autoantigens" and are attacked by the organism's immune system.
  • multiple sclerosis is believed to be an autoimmune disease occurring when the immune system attacks the myelin sheath, whose function is to insulate and protect nerves. It is a progressive disease characterized by demyelination, followed by neuronal and motor function loss.
  • Rheumatoid arthritis (“RA") is also believed to be an autoimmune disease which involves chronic inflammation of the synovial joints and infiltration by activated T cells, macrophages and plasma cells, leading to a progressive destruction of the articular cartilage. It is the most severe form of joint disease.
  • the nature of the autoantigen(s) attacked in rheumatoid arthritis is poorly understood, although collagen type II is a candidate.
  • HLA histocompatibility locus antigens
  • MHC major histocompatibility complex
  • the MHC region expresses a number of distinctive classes of molecules in various cells of the body, the genes being, in order of sequence along the chromosome, the Class 1, 11 and III MHC genes.
  • the Class I genes consist of HLA genes, which are further subdivided into A, B and C subregions.
  • Patients were enrolled in four medical centres, after obtaining the approval of the ethical committees. All patients signed an informed consent form. Patients had clinically definite or laboratory-supported definite MS, with a relapsing- remitting or relapsing-progressive type and with at least two exacerbations during the two years prior to study entry. Patients had to be clinically stable for at least one month before entry. No steroids and other immuno-modulators could be used during six months prior to study entry. The Expanded Disability Status Scale (EDSS) score at baseline had to be less than 6.0. Both males and females aged 18 and over were eligible. Existence of any other chronic disease or pregnancy excluded patients from the study. Patients evaluation included physical and neurological examinations, laboratory evaluation (haematology, blood chemistry, urinalysis) and vital signs.
  • EDSS Expanded Disability Status Scale
  • Table 1 demonstrates demographic and clinical characteristics of the 68 patients who were enrolled, consisting of 51 females (75%) and 17 males (25%).
  • Mean age was 35.5 years (SD ⁇ 9.8), ranging from 19 to 61 years.
  • the mean age when MS symptoms first appeared was 28.5 years (SD ⁇ 8.9) ranging from 14 to 52 years.
  • the total number of self reported exacerbations prior to trial entry ranged from 2 to 20 (mean 5.8, SD ⁇ 3,8).
  • the mean number of exacerbations reported during the two years prior to trial entry was 2.9 (SD ⁇ 1.5), ranging from 1 to 12.
  • the mean baseline EDSS score was 2.7 (SD ⁇ 1.5), ranging from 1 to 8.
  • Table 2 summarizes the distribution of termination reasons. According to the open-label design of the study, discontinuation was allowed after one or two years. Of the 68 patients enrolled, 27 patients dropped out during the first two years of treatment: 8 (11.8%) due to adverse experience; 5 (7.3%) were lost to follow-up; 5 (7.3%) withdrew voluntarily; 6 (8.8%) due to investigator's judgement;
  • Table 6 displays all adverse experiences recorded, coded according to the COSTAR system. More than 17% of all patients participating in the trial (12/68) did not report any adverse event during the study. Local injection site reactions were reported as 36.1 % of the total number of reports (Table 6). An idiosyncratic, systemic adverse reaction, manifested by chest pain, palpitations and tachypnea was reported as 16.6% of the total number of adverse events reported. These sporadic, brief (2-20 minutes) reactions occurred immediately following drug administration and resolved without any treatment. Additional systemic reactions, such as rash (1.8%) and lymphadenopathy (1.8%) were rarely reported. Most of the adverse experiences reported were considered to be mild (51.5%) or moderate (29.5%) in nature.
  • treatment with Cop1 on alternate days is as effective as daily treatment and can have even fewer side effects and be more benign than is treatment with IFN ⁇ .
  • 12MIU were not significantly better than 6MIU, indicating that the 6MIU IFN ⁇ dosage is the maximum effective dosage - and that interferon has a ceiling effect.
  • the present studies indicate that 20 mg of Cop 1 on alternate days has a "ceiling effect.”
  • the biological effect of Cop 1 is not dose related but is time related to the exposure of the immune system to its presence and the continuity of administering the drug with rechallenging the immune system, thus making daily injection unnecessary.
  • Cop 1 is a safe drug. Most of the adverse events reported were mild and transient. Adverse experiences were reported by 56 (82.4%) of the patients, the most frequent being mild local injection site reactions, which were reported by 34 patients (50%). Sixteen patients reported 38 episodes of one or more symptoms of transient self-limited reactions (i.e., palpitations, flushing, dyspnoea or chest pain) which resolved spontaneously within a short time. These symptoms were also reported in placebo-controlled Cop 1 studies, and did not follow any recognizable pattern of appearance, recurrence and disappearance. Placebo patients reported similar reactions but less frequently. Such adverse reactions are likely due, at least in part, to anxiety reactions. Eight patients (11.8%) withdrew from the study because of adverse experiences. Seven of them were felt to be possibly or probably related to treatment with Cop 1. There were no deaths during the study. The frequency of adverse experiences reported decreased after the first 6 months of therapy.

Abstract

Dans une précédente étude sous surveillance, le Copolymer 1 donné à une dose journalière de 20 mg a eu pour résultat une diminution du taux de rechute de la sclérose en plaques (SEP) d'environ 30 % par rapport à un placebo. Dans nos études cliniques, une administration journalière sous-cutanée (SC) a permis de diminuer le taux de rechute de 73,4 % par rapport à la ligne de base. Dans la présente étude, les patients rechutant pour la sclérose en plaques ont reçu une administration en jours alternés de 20 mg de Copolymer 1. Soixante huit patients ont été recrutés dont 51 et 40 ont respectivement été traités pendant une et deux années. Le taux de rechute du traitement ayant duré deux années a décru de 80,8 % en comparaison du traitement précédent sur deux années (moyennes 0,56±1,02 contre 2,91±1,10, respectivement, P<0,0001). L'échelle d'incapacité étendue (EDSS) ne diffère pas de la ligne de base au cours de la première année de traitement, mais augmente quelque peu à la fin de la seconde année (ligne de base=2,72±1,55, une année 2,71±1,59, deux années 2,97±1,80, P<0,008). Le médicament était très bien toléré. Cette étude suggère que la thérapie en jours alternés présente des effets bénéfiques et qu'elle est bien tolérée dans la rechute de la sclérose en plaques, avec une comparaison favorable par rapport aux effets obtenus avec des injections journalières de Copolymer 1.
PCT/US1999/022836 1998-10-02 1999-10-01 Administration en jours alternes de copolymer 1 destine au traitement de maladies autoimmunes WO2000020010A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU62815/99A AU6281599A (en) 1998-10-02 1999-10-01 Alternate day administration of copolymer 1 for treating autoimmune diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10296198P 1998-10-02 1998-10-02
US60/102,961 1998-10-02

Publications (1)

Publication Number Publication Date
WO2000020010A1 true WO2000020010A1 (fr) 2000-04-13

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AU (1) AU6281599A (fr)
WO (1) WO2000020010A1 (fr)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001060392A1 (fr) * 2000-02-18 2001-08-23 Yeda Research And Development Co., Ltd. At The Weizmann Institute Of Science Formes posologiques a administration par voie orale, nasale et pulmonaire du copolymere 1
US6800285B2 (en) 2000-06-20 2004-10-05 Moses Rodriguez Treatment of central nervous system diseases by antibodies against glatiramer acetate
US6800287B2 (en) 1998-09-25 2004-10-05 Yeda Research And Development Co., Ltd. Copolymer 1 related polypeptides for use as molecular weight markers and for therapeutic use
WO2005025596A1 (fr) * 2003-09-16 2005-03-24 Hadasit Medical Research Services & Development Ltd. Acetate de glatiramer utilise en tant qu'agent immunomodulateur
WO2004064717A3 (fr) * 2003-01-21 2005-10-13 Yeda Res & Dev Copolymere 1 pour le traitement de maladies enteriques inflammatoires
US7022663B2 (en) 2000-02-18 2006-04-04 Yeda Research And Development Co., Ltd. Oral, nasal and pulmonary dosage formulations of copolymer 1
US7033582B2 (en) 2000-06-05 2006-04-25 Teva Pharmaceutical Industries, Ltd. Use of glatiramer acetate (copolymer 1) in the treatment of central nervous system disorders
US7279172B2 (en) 1998-07-23 2007-10-09 Yeda Research And Development Co., Ltd. Treatment of autoimmune conditions with copolymer 1 and related copolymers
US7425332B2 (en) 1998-07-23 2008-09-16 Yeda Research And Development Co., Ltd. Treatment of autoimmune conditions with Copolymer 1 and related Copolymers
US7429374B2 (en) 2001-12-04 2008-09-30 Teva Pharmaceutical Industries, Ltd. Process for the measurement of the potency of glatiramer acetate
US7655221B2 (en) 2004-05-07 2010-02-02 Peptimmune, Inc. Methods of treating disease with random copolymers
US8232250B2 (en) 2009-08-20 2012-07-31 Yeda Research & Development Co., Ltd. Low frequency glatiramer acetate therapy
US9155775B1 (en) 2015-01-28 2015-10-13 Teva Pharmaceutical Industries, Ltd. Process for manufacturing glatiramer acetate product
US9499868B2 (en) 2011-10-10 2016-11-22 Teva Pharmaceutical Industries, Ltd. Determination of single nucleotide polymorphisms useful to predict response for glatiramer acetate
US9617596B2 (en) 2012-10-10 2017-04-11 Teva Pharmaceutical Industries, Ltd. Biomarkers predictive for clinical response for glatiramer acetate
US9625473B2 (en) 2010-10-11 2017-04-18 Teva Pharmaceutical Industries Ltd. Cytokine biomarkers as predictive biomarkers of clinical response for glatiramer acetate
US9702007B2 (en) 2013-10-21 2017-07-11 Teva Pharmaceuticals Industries, Ltd. Genetic markers predictive of response to glatiramer acetate
US11167003B2 (en) 2017-03-26 2021-11-09 Mapi Pharma Ltd. Methods for suppressing or alleviating primary or secondary progressive multiple sclerosis (PPMS or SPMS) using sustained release glatiramer depot systems
USRE49251E1 (en) 2010-01-04 2022-10-18 Mapi Pharma Ltd. Depot systems comprising glatiramer or pharmacologically acceptable salt thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5668117A (en) * 1991-02-22 1997-09-16 Shapiro; Howard K. Methods of treating neurological diseases and etiologically related symptomology using carbonyl trapping agents in combination with previously known medicaments
US5800808A (en) * 1994-05-24 1998-09-01 Veda Research And Development Co., Ltd. Copolymer-1 improvements in compositions of copolymers

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5668117A (en) * 1991-02-22 1997-09-16 Shapiro; Howard K. Methods of treating neurological diseases and etiologically related symptomology using carbonyl trapping agents in combination with previously known medicaments
US5800808A (en) * 1994-05-24 1998-09-01 Veda Research And Development Co., Ltd. Copolymer-1 improvements in compositions of copolymers

Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7279172B2 (en) 1998-07-23 2007-10-09 Yeda Research And Development Co., Ltd. Treatment of autoimmune conditions with copolymer 1 and related copolymers
US7425332B2 (en) 1998-07-23 2008-09-16 Yeda Research And Development Co., Ltd. Treatment of autoimmune conditions with Copolymer 1 and related Copolymers
US7615359B2 (en) 1998-09-25 2009-11-10 Yeda Research And Development Co., Ltd. Copolymer 1 related polypeptides for use as molecular weight markers and for therapeutic use
US6800287B2 (en) 1998-09-25 2004-10-05 Yeda Research And Development Co., Ltd. Copolymer 1 related polypeptides for use as molecular weight markers and for therapeutic use
US8399211B2 (en) 1998-09-25 2013-03-19 Yeda Research And Development Co., Ltd. Copolymer 1 related polypeptides for use as molecular weight markers and for therapeutic use
US7074580B2 (en) 1998-09-25 2006-07-11 Yeda Research And Development Co., Ltd. Copolymer 1 related polypeptides for use as molecular weight markers and for therapeutic use
US7163802B2 (en) 1998-09-25 2007-01-16 Yeda Research And Development Co., Ltd. Copolymer 1 related polypeptides for use as molecular weight markers and for therapeutic use
WO2001060392A1 (fr) * 2000-02-18 2001-08-23 Yeda Research And Development Co., Ltd. At The Weizmann Institute Of Science Formes posologiques a administration par voie orale, nasale et pulmonaire du copolymere 1
US7022663B2 (en) 2000-02-18 2006-04-04 Yeda Research And Development Co., Ltd. Oral, nasal and pulmonary dosage formulations of copolymer 1
US7033582B2 (en) 2000-06-05 2006-04-25 Teva Pharmaceutical Industries, Ltd. Use of glatiramer acetate (copolymer 1) in the treatment of central nervous system disorders
US6800285B2 (en) 2000-06-20 2004-10-05 Moses Rodriguez Treatment of central nervous system diseases by antibodies against glatiramer acetate
US8389228B2 (en) 2001-12-04 2013-03-05 Teva Pharmaceutical Industries, Ltd. Process for the measurement of the potency of glatiramer acetate
US7429374B2 (en) 2001-12-04 2008-09-30 Teva Pharmaceutical Industries, Ltd. Process for the measurement of the potency of glatiramer acetate
US7923215B2 (en) 2001-12-04 2011-04-12 Teva Pharmaceutical Industries, Ltd. Process for the measurement of the potency of glatiramer acetate
US8008258B2 (en) * 2003-01-21 2011-08-30 Yeda Research And Development Co. Ltd. Cop 1 for treatment of inflammatory bowel diseases
AU2004206120B2 (en) * 2003-01-21 2009-09-24 Yeda Research And Development Co. Ltd. COP 1 for treatment of inflammatory bowel diseases
WO2004064717A3 (fr) * 2003-01-21 2005-10-13 Yeda Res & Dev Copolymere 1 pour le traitement de maladies enteriques inflammatoires
WO2005025596A1 (fr) * 2003-09-16 2005-03-24 Hadasit Medical Research Services & Development Ltd. Acetate de glatiramer utilise en tant qu'agent immunomodulateur
US7655221B2 (en) 2004-05-07 2010-02-02 Peptimmune, Inc. Methods of treating disease with random copolymers
US8475779B2 (en) 2004-05-07 2013-07-02 Ares Trading Sa Methods of treating disease with random copolymers
US8969302B2 (en) 2009-08-20 2015-03-03 Yeda Research & Development Co., Ltd. Low frequency glatiramer acetate therapy
US8399413B2 (en) 2009-08-20 2013-03-19 Yeda Research & Development Co., Ltd. Low frequency glatiramer acetate therapy
EP2630962B1 (fr) 2009-08-20 2018-06-27 Yeda Research & Development Company, Ltd. Thérapie d'acétate de glatiramère à basse fréquence
US9155776B2 (en) 2009-08-20 2015-10-13 Yeda Research & Development Co., Ltd. Low frequency glatiramer acetate therapy
US9402874B2 (en) 2009-08-20 2016-08-02 Yeda Research & Development Co., Ltd. Low frequency glatiramer acetate therapy
EP2949335B1 (fr) 2009-08-20 2017-01-04 Yeda Research & Development Company, Ltd. Thérapie à l'acétate de glatiramère à basse fréquence
US8232250B2 (en) 2009-08-20 2012-07-31 Yeda Research & Development Co., Ltd. Low frequency glatiramer acetate therapy
EP3199172B1 (fr) 2009-08-20 2018-07-11 Yeda Research and Development Co., Ltd. Regime posologique pour la sclerose en plaques
USRE49251E1 (en) 2010-01-04 2022-10-18 Mapi Pharma Ltd. Depot systems comprising glatiramer or pharmacologically acceptable salt thereof
US9625473B2 (en) 2010-10-11 2017-04-18 Teva Pharmaceutical Industries Ltd. Cytokine biomarkers as predictive biomarkers of clinical response for glatiramer acetate
US9499868B2 (en) 2011-10-10 2016-11-22 Teva Pharmaceutical Industries, Ltd. Determination of single nucleotide polymorphisms useful to predict response for glatiramer acetate
US9617596B2 (en) 2012-10-10 2017-04-11 Teva Pharmaceutical Industries, Ltd. Biomarkers predictive for clinical response for glatiramer acetate
US9702007B2 (en) 2013-10-21 2017-07-11 Teva Pharmaceuticals Industries, Ltd. Genetic markers predictive of response to glatiramer acetate
US9763993B2 (en) 2015-01-28 2017-09-19 Teva Pharmaceutical Industries Ltd. Process for manufacturing glatiramer acetate product
US9155775B1 (en) 2015-01-28 2015-10-13 Teva Pharmaceutical Industries, Ltd. Process for manufacturing glatiramer acetate product
US11167003B2 (en) 2017-03-26 2021-11-09 Mapi Pharma Ltd. Methods for suppressing or alleviating primary or secondary progressive multiple sclerosis (PPMS or SPMS) using sustained release glatiramer depot systems

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