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`
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`EXHIBIT NO. 1022 Page 1
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`
`Drugs of the Future 1996, 21 (2): 131-134
`Copyright PROUS SCIENCE
`
`
`
`Copolymer-1
`
`Copaxone®
`COP-1
`
`Agent for Multiple Sclerosis
`
`Polyli.-Glu‘3“5,L-Ala39'45,i.-Tyr5-51°,L-Lys3°“37].nCH3COOH
`n= 15-24
`
`
`MOI wt: 4700-1 3.000
`
`CAS: 147245-92-9
`CAS: 028704-27-0 (as free base)
`
`EN: 199999
`
`Introduction
`
`This article is an update of the monograph on copo-
`lymer-1. published in Drugs of the Future a year ago (1). it
`includes additional lniormation based on unpublished data
`that were not available to the publishers at that time and on
`recent publications of scientific and clinical data.
`‘
`This update summarizes the mechanism of action of
`copolymer-1, the toxicology and safety studies and the
`results of the pivotal phase III clinical trial recently com-
`pleted.
`
`Pharmacological Actions and Proposed Mechanism
`
`The effect of copolymer-1 on the prevention, suppression
`and blocking of acute and chronic-relapsing experimental
`allergic encephalomyelilis (EAE) was_studied in several
`animal species. EAE is the most extensively studied exper-
`imental autoimmune disease which ‘serves as the primary
`animal model for multiple sclerosis (MS)
`(2-6). Copo-
`lymer—1 had a marked suppressive and preventive eflect on
`EAE in the various species studied, including primates (7).
`Recently. it was demonstrated that copolymer-1 can _also
`suppress chronic-relapsing (C-R) EAE, induced by either
`proteolipid protein (PLP) or myelin oligodendrocyte glyco-
`protein (MOG) (8. 9). Thus, it was shown that copolymer-1
`does not manifest species specificity. either for the source
`of the encephalitogen ortor the test animal (10, 11).
`The mechanism of action of copolymer-_1 has not been
`fully elucidated, but laboratory experiments indicate that the
`effect of copolymer-1 may be disease-specific. Copo-
`lymer-1 was originally synthesized to mimic suppressive
`determinants in the MBP molecule (12) and cross-reactivity
`with epitopes of MBP has been demonstrated both at the
`B-cell level with monoclonal antibodies (13) and atthe T-cell
`level with cell-rnediated responses (14).
`A study of MBP-specific clones showed that copo-
`lymper-1 can directly block T-cell responses to MBP in an
`
`antigen-specific but not MHC-restricted fashion (15). It was
`demonstrated that copolymer-1 binds directly and avidly to
`class II MHC on living human antigen presenting cells of
`various HLA haplotypes (16. 17). inhibits the binding of
`MBP, PLP and MOG peptides to MHC class II on antigen
`presenting cells (18), and even displaces them from the
`MHC II groove (19). Processing of copolymer-1 is not
`required prior to its binding to the MHC (20). Interestingly,
`binding to MHC II, although required for copolymer-1 activ-
`ity, is not sufficient. D-copolymer-1. a copolymerof identical
`amino acid composition as that of copolymer-1, but com-
`posed of D-amino-acids, while binding to the MHC II, fails
`to suppress EAE.
`Suppression of MBP-specific T-cell activation by copo-
`lymer-1 was observed both in murine (15) and human cells
`(21). In the latter, it was demonstrated that while the sup-
`pression of proliferation.
`interleukin-2 and interferon»;
`secretion by copolymer-1 was restricted to MBP-specific
`T-cell lines and clones, interferon-[3 exhibited a non-specific
`immunosuppressive activity (22).
`interestingly, copo-
`lymer-1 plus interferon-[3 had additive and sometimes syn-
`ergistic suppressive effects (22).
`Studies of murine EAE have shown that copolymer-1 can
`induce MBP specific suppressor cells which mediate
`protection from EAE (23-25). T-cell hybridomas and T-cell
`lines induced with copolymer-1 were found to have
`suppressive properties and could inhibit the responses of
`MBP~specific T-cell lines in vitro. as well as prevent active
`induction of EAE (26).
`These findings support the hypothesis that binding of
`copolymer-1 to the MHC ll groove may lead to two eilects
`that ameliorate the pathogenesis of EAE and multiple scle-
`rosis: 1) copolymer-1 induces specific suppressor T-cells
`and 2) copolymer-1 inhibits specific effector T-cells. Based
`on the available data, it was concluded that copolymer-1
`works through a unique mechanism and is MS-specific.
`
`Pharmecoklnetics
`
`Fladioiodinated copolymer-1 has been extensively used
`to decipher the fate of the administered drug in mice. rats
`and monkeys (27). After subcutaneous administration,
`
`
`E. Lobel. Fl. Riven-Kreilman, A. Amselem, I. Pinchasi. Research
`& Development Division, Teva Pharmaceutical Industries Ltd..
`P.O. Box 8077, Kiryat Nordau Industrial Zone. Netanya, Israel.
`
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`EXHIBIT NO. 1022 Page 2
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`
`132
`
`Copolymer-1
`
`copolymer-1 was readily absorbed and only a small fraction
`was retained at the injection site. The amount absorbed was
`proportional to the administered dose and maximal plasma
`concentrations were reached within 2-4 hours in monkeys
`and 1-2 hours in rats. Chronic exposure to daily drug injec-
`tions for periods up to 1 78 days did not alter the basic phar-
`macokinetic parameters of a single radioactive dose.
`Following subcutaneous injection, radiolabelled copo-
`lymer-1 is rapidly degraded into smaller molecular weight
`fragments. In skin and muscle homogenates a rapid protec-
`lytic degradation of copolymper-1 to small oligopeptides
`and free amino acids was observed in vitro.
`
`Based on animal studies. serum concentrations of copo-
`lymer-1 are presumed to below or not detectable following
`subcutaneous administration of 20 mg once daily to man.
`Consequently, pharmacokinetic information in patients
`receiving the recommended dose is not available. How-
`ever, several effects of copolymer-1 in man provide Indirect
`evidence that subcutaneous copolymer-1 is bioavailable
`and biologically active. This evidence includes its efficacy
`in patients as demonstrated by the results of the clinical
`trials (29, 31) and the formation of systemic antibodies to
`copolymer-1 (28).
`
`Toxicology and Safety Studies
`
`Acute and chronic toxicity studies (27) have been com-
`pleted in mice. rats, dogs and monkeys and several routes
`of administration have been used (s.c., i.p., i.m., i.v.). A
`chronic toxicitystudy in cynomolgus monkeys that lasted 52
`weeks demonstrated that copolymer-1, injected s.c. daily,
`was well tolerated at doses up to 100 times the human ther-
`apeutic dose. except for some inflammatory reactions at the
`injection site.
`Other studies showed no evidence of adverse effects of
`copolymer-1 on reproductive function. The drug was devoid
`of any mutagenic potential and was not genotoxic.
`lmmunogenicity and immunotoxicity studies were also
`performed. Following daily subcutaneous injections to rats
`and monkeys,
`copolymer-1-reactive antibodies were
`formed. The titers of copolymer-1 reactive antibodies
`peaked at 3 months and declined at 6 months. Selected
`additional parameters were chosen for immunotoxicity
`studies. No treatment-related changes were observed in
`the ievt‘-‘IS Oi B-lymphocytes, T-lymphocytes. CD4+ T-Iym-
`phocytes, CD8+ T-lymphocyte and CD4+/CD8+ ratio. No
`changeswere observed also in natural killer cells and inthe
`level of antinuclear antibodies or IgG and lgM. No treat-
`ment-related changes were observed in microscopic
`examination of lymphoid organs.
`Serial antibody studies were performed (28) In the con-
`text of the recently completed U.S. phase III study with
`c0D0|Vmer-1.
`in
`relapsing-remitting multiple sclerosis
`patients (29). No correlation was found between the level or
`time-dependent profile of antibodies and the occurrence of
`relapses 0' Systemic adverse reactions. Furthermore, the
`clinical efficacy ofcopolymer-1 in reducing the MS relapse
`rate and slowing progression of disability was maintained
`throughout more than two years of treatment, regardless of
`the antibody profile. In addition, the copolymer-1 reactive
`
`antibodies did not neutralize its biolo9l°a' acliVl1Y. cither in
`vitro or in vivo.
`
`Clinical Studies
`
`The results of a phase III multicenter, double-blind, place-
`bo-controlled trial, demonstrating efficacy and safety of
`Copaxone’~‘3‘ have been published (29). This was a 2-year
`study, involving 251 patients who daily self-injected subcu-
`taneously either Copaxoneg’ 20 mg (rt = 125) 0|’ Placebo in
`= 126). The primary end point was the number of relapses
`reponed during the treatment period. The final 2-year
`relapse rate was 1.19 i 0.13 for patients receiving copo-
`lymer-1 and 1.68 i 0.13forthose receiving placebo, a 29%
`reduction in favor of copolymer-1 (p = 0.007).
`Trends in the proportion of relapse-free patients and
`median time to first relapse also favored copolymer-1.
`Disability was measured by the Expanded Disability Sta-
`tus Scale (EDSS) (30). using a two-neurologist (examining
`and treating) protocol. When the proportion of patients who
`improved, were unchanged, orworsened by 2 1 EDSS step
`from baseline to conclusion (2 years) was evaluated. signifi-
`cantly more patients (24.8% vs. 15.2%) receiving copo-
`lymer-1 were found to have improved and more patients
`receiving placebo (28.8% vs. 20.8%) worsened (p = 0.037).
`Repeated measures analysis also demonstrated a signifi-
`cant effect in favor of Copaxone"’ for mean change In EDSS
`score (p = 0.023). Patient withdrawals were 19 (15.2%)
`from the copolymer-1 group and 17 (13.5%) from the pla-
`cebo group at approximately the same intervals. The treat-
`ment was well tolerated. The most common adverse experi-
`ences were injection-site reactions. Ftarely, a transient
`self-limited systemic reaction followed the Injection in
`15.2% of those receiving copolymer-1 and 3.2% of those
`receiving placebo‘. This reaction is characterized by vaso-
`dilatation ortightness of the chest with palpitations, anxiety
`and/or dyspnea. These symptoms generally resolve with-
`out sequelae. Studies of blood and urine for common meta-
`bolic changes or hematologic abnormalities showed no dif-
`ferences between groups and ECGs were unchanged. This
`rigorous study confirmed the findings of a previous pilot trial
`(31) and demonstrated that copolymer-1 treatment can sig-
`nificantly and beneficially alter the course of relapslng-re-
`mitting MS in a well-tolerated fashion.
`The above double-blind trial was extended beyond the
`planned 24 months for an additional average of 5.2 months
`for copolymer-1 patients and 5.9 months for placebo
`patients (32). The final relapse rates over the entire course
`of the double-blind study were 1.34 i 0.15 for patients
`receiving copolymer~1 and 1 .98 10.1 4 for those on placebo
`(p = 0.002), which represents a reduction of 32% in favor of
`copolymer-1. Annualized relapse rates, proportion of
`relapse-free patients, median time to first relapse and the
`proportion of patients who were improved, unchanged or
`worsened by 21 EDSS score between baseline and con-
`clusion all favored copolymer-1 treatment, in a statistically
`
`
`
`‘When relating to the total number of injections to patients receiv-
`ing Copaxone” and those receiving placebo. the number of sys-
`temic reaction episodes is very low, 0.037% and 0.0035%,
`respectively.
`
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`EXHIBIT NO. 1022 Page 3
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`Drugs Fut 1995, 21(2)
`
`133
`
`significant manner. A group of 27 patients In one center was
`also followed by serial quantitative MFt| throughout treat-
`ment
`(32). A preliminary
`study, measuring Gd?‘
`enhanced-T1 lesions. showed a trend towards a beneficial
`effect of copolymer-1 treatment on both the number of
`enhancing lesions and the proportion of enhancement-tree
`patients (33).
`
`Summary
`
`Copolymer-1 is effective in relapsing-remitting multiple
`sclerosis in reducing the frequency of relapses and slowing
`progression of disability. This clinical efficacy is maintained
`and even enhanced upon prolonged treatment. Its benign
`safety profile and good level of tolerance were repeatedly
`reported. It acts In MS via a unique and disease-specific
`mechanism.
`
`Manufacturer
`
`Teva Pharmaceutical Industries Ltd. (IL).
`
`References
`
`1. Prous, J., Meaty, N.,Castar‘1er,J. Copolymer-1:Agentlormultiple
`sclerosis. Drugs Fut 1995, 20: 139-41.
`2. Paterson, P.Y. Autoimmune neurological disease: Experimental
`animal systems and eppfications for multiple sclerosis. In: Autoim-
`munity, Genetic. Immunologic. Virologic and Clinical Aspects, N.
`Talal (Ed.), Academic Press, New York, 1977, 643-92.
`3. Aivord. E.C. Species-restricted encephalitogenic determinants.
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`Alan Ft. Liss, New York, 1984, 523-37.
`
`4. Driscoll, B.F., Kies, M.W., Aivord. E.C.J. Successful treatment of
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`ity and suppression. lmmunol Rev 1981, 55: 5-30.
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`imentel allergic encephalomyelitis in rhesus monkeys by a syn-
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`lmmunopathol 1974. 3:
`256-62.
`
`8. Teitelbaum. D., Fridkis-Hareli, Ft., Arnon. R.. Sela, M. Copo-
`lymer-1 inhibits the onsetofchronic relapsing experimental autoim-
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`encephalitogenicpeptides olmyelinproteolipidprotein. J Neu reim-
`munol 1996, in press.
`9. Ben-Nun, A.. Mendel, l., Bakimer, R. et al. The effect olcopo-
`lymer-1 on encephalitogenic MOG-reactive T-cells. Eur J Neurol
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`10. Sela, M. Polymeric drugs as immunomodulatory vaccines
`against multiple sclerosis. Makromol Chem Macromol Symp 1993,
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`
`11. Sela, M., Amon, FL, Teitelbaum. D. Suppressive activity of
`COP-1 in EAE andits relevance to multiple sclerosis. Bull Inst Pas-
`teur 1990, 88: 303-14.
`
`12.Tellelbaum, D., Meshorer. A.. Hirshfeld, T. et al. Suppression of
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`13. Teitelbaum. D., Aharonl, R., Sela. M., Arnon, R. Cross-reactions
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`1991 . 88: 9528-32.
`14. Webb. C., Teitelbaum, D., Amon, F-l., Sela, M. In-vivo and in-vi.
`tro immunological cross-reactions between basic encephalitogen
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`lmentalallergic encephalomyelitis. EurJ lmmunol 1973. 3: 279-86.
`15. Teltelbaum, D., Aharonl, R., Arnon. R., Sela, M. Specilic inhibi-
`tion of the 7'-cell response to myelin basicprotein by synthetic copo-
`lymer COP- 1. Proc Natl Acad Sci USA 1988. 85: 9724-8.
`16. Fridkis-Hareli, M., Teitelbaum, D., Gurevich. E. et al. Direct
`binding ofmyelin basic protein and synthetic copolymer-1 to class
`ll major histocompatibility complex molecules on living antigen
`presenting cells. Specilicity and promiscuity. Proc Natl Acad Sci
`USA 1994, 91: 4872-6.
`
`17. Fridkis-Hareli, M., Teitelbaum. D., Gurevich. E. et al. Specific
`andpromiscuous binding ofsynthetic copolymer-1 to class II major
`histocompatibility complex molecules on living antigen presenting
`cells. Annu Meet lsr Biochem Mol Biol (March 21-22) 1994, Abst.
`18. Fridkis-Hareli, M., Teitelbaum. D., Kerlero De Rosbo, N., Amon,
`R. , Sela, M. Synthetic copolymer- 1 inhibits the binding ofMBP, PLP
`and M06 peptides to class ll majorhistocompatibility complexmol-
`ecules an antigen presenting cells. J Neurochem 1994, 63(Suppl.
`1): S-610.
`19. Fridkis-Hareli, M., Teitelbaum. D., Arnon, Fl.. Sela. M. Copo-
`lymer-1 displaces MBR PLP and MOG but can not be displaced by
`these antigens from the MHC class ll binding site. 9th Int Cong
`lmmunol (July 23-29, San Francisco) 1995, Abst 2408.
`20. Fridkis-Hareli, M., Teitelbaum. D., Arnon, Ft., Sela, M. synthetic
`copolymer-1 and myelin basic protein do not require processing
`prior to binding to class II major histocompatibility complex mole-
`cules on living antigen presenting cells. Cell lmmunol 1995. 163:
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`
`21. Teitelbaum. D., Milo, R., Arnon. Ft.. Sela. M. Synthetic copo-
`lymer-1 inhibits human T-cell lines specific tor myelin basicprotein.
`Proc Natl Acad Sci USA 1992. 89: 137-41 .
`
`22. Mile, Ft.. Panitch, H. Additive effects of copolymer-1 and inter-
`teron beta- 1b on the immune response to myelin basic protein. J
`Neuroimmunol 1995, 61: 185-93.
`23. Lando, 2., Teitelbaum. D., Amon, Ft. Ellect of cyclophospha-
`mide on suppressor cell activity in mice unresponsive to EAE. J
`lmmunol 1979, 123: 2156-60.
`24. Lando, 2., Teitelbaum, D., Amon, R. The immunological
`response in mice unresponsive to experimentalallergic encephalo-
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`25. Lando, 2., Don‘, Y., Teitelbaum. D., Arnon, R. Unresponsiveness
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`
`26. Aharonl, R., Teitelbaum. D., Amon, R. 7'-suppressor liybrlclo-
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`by spinal cord homogenate down-regulate experimental allergic
`encephalomyelitis. Eur J Immunol 1993, 23: 17-25.
`27. Teva Pharmaceutical Industries Ltd.. Internal Reports.
`28. Johnson, K.P., Teitelbaum. D., Arnon. R., Sela. M. Antibodies
`to copolymer-1 do not interfere with its clinical effect. 120th Annu
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`29. Johnson, K.P., Brooks, B.R., Cohen, J. et al. Copolymer-1
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`
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