Drugs
`of the
`
`Future
`
`Drugs of the Future is published monthly. A pharmacostructural index appears annually in the December issue. Cumulative
`chemical formula and general indices are published separately and mailed to subscribers in January.
`
`Subscription Rates
`
`Calendar year subscription price for Volume 21, 1996 is US $ 950. Airmail additional (optional): America $ 70. Asia 3: 120,
`Europe 3 40.Back volumes are available in book form, offering an Encyclopedia of drugs in various stages of research. contin-
`uously updated as new information becomes available.
`
`Subscription InformationISample Copies
`
`Remittances and orders tor subscriptions. notices of change of address, claims for missing numbers and requests for sam ple
`copies should be sent to the Subscription Service Department, Apartado de Correos 540. 08080 Barcelona. Spain. Street
`address: Provenza 388, 03025 Barcelona. Tel. (34+3} 459-2220. Fax (34+3) 458-1 535. Please indicate the code numbertrom
`mailing labels in all correspondence relating to your subscription.
`
`Computerized Databases
`CIPSLINE PC®. a series of structural databases, are available for use with Molecular Design Ltd.’s graphic chemical data
`management system for personal computer ChemBase®. These databases comprise drugs selected from Drugs of the
`Future and Drug Data Report.
`
`Online and CD-ROM versions of Drugs of the Future are available. For more inlorrnation contact Prous Science Online Publi-
`cations.
`
`Authorization to photocopy items for internal or personal use, or the internal use of specific clients, is granted by J.Fi. Prous. 8A., for users
`registered with the Copyright Clearance Center (000) Transactional Reporting Service. For those organizations that have been granted a
`photocopy license by 000. a separate system has been arranged.
`Copyright 1996, J.Fi. Prous, SA. Publishers. Reproduction in whole or part is not permitted except by written permission from the publisher.
`
`FIPP Member oi the International Federation of Periodical Press.
`APP publication not sumac! to mandatory control ol circulation because advenising pages are less than 10% ot the total number of pages.
`————‘___________________—__
`
`Tile Editor has made a reasonable ellort to supply complete and accurate information, but does not assume any liability tor errors or omissions.
`ISBN: (DH-0262 - Depdsrlo Legal: [3-4.1 54-1 .9?6 — Printed in Spain. . COMGRAFIC—INDUGFIAF - Barcelona
`
`MYLAN INC. EXHIBIT NO. 1022 Page 1
`
`MYLAN INC. EXHIBIT NO. 1022 Page 1
`
`

`

`Drugs of the Future 1996, 21(2): 131-134
`Copyrighl PHOUS SCIENCE
`
`
`
`Copolymer-1
`
`Copaxone®
`COP-1
`
`Agent for Multiple Scierosis
`
`Polylt-Glu13‘15.L-Ala39'45,L-Tyr3‘5'10,L-Lys30‘37],nCH3000H
`n: '| 5-24
`
`
`l
`
`'\
`
`MOI wt: 4700-1 3,000
`
`GAS: 147245-92-9
`OAS: 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 information 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-t, 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 encephalomyelitis {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-
`Iymer—1 had a marked suppressive and preventive effect on
`EAE in the various species studied, including primates (7).
`Fiecently. it was demonstrated that copolymer—t can also
`suppress chronic-relapsing (C-Ft) EAE, induced by either
`proteolipid protein (PLP) or myelin oligodendrocyte glyco-
`protein (M06) (8, 9). Thus. it was shOwn that copolymer-1
`does not manifest species specificity. either for the source
`of the encephalitogen or for 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-i 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-celt level with monoclonal antibodies (1 3) and atthe T-ceII
`level with cell-mediated 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-t 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-copoiymer-t . a copolymer of identical
`amino acid composition as that of copolymer-t, 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-
`Iymer-t 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-y
`secretion by copolymer—1 was restricted to MBP-specific
`T-celi lines and clones, interferon-[3 exhibited a non-specific
`immunosuppressive activity {22).
`Interestingly,
`copo-
`Iymer-t plus interferon-l3 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-celt lines in vitro, as well as prevent active
`induction of EAE (26).
`These findings support the hypothesis that binding of
`copolymer-t to the MHC II groove may lead to two effects
`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 MSsspecific.
`
`Pharmacokinetics
`
`Radioiodinated copolymer—‘l has been extensively used
`to decipher the fate of the administered drug in mice, rats
`and monkeys (27). After subcutaneous administration,
`
`
`E. Lobel. H. Riven-Kreitman, A. Amselem. I. Pinchasi. Research
`& Development Division, Teva Pharmaceutical Industries Ltd,
`P.O. Box 8077. Kiryat Nordau Industrial Zone. Netanya. Israel.
`
`MYLAN INC. EXHIBIT NO. 1022 Page 2
`
`MYLAN INC. EXHIBIT NO. 1022 Page 2
`
`

`

`132
`
`Copolymer-1
`
`copolymer-t was readily absorbed and only a small fraction
`was retained atthe 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 178 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-l are presumed to be low 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-t
`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 (2B).
`
`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.. iv). A
`chronic toxicity study 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-
`apeuticdose. exceptforsome 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.
`Immunogenicity and immunotoxicity studies were also
`performed. Following daily subcutaneous injections to rats
`and monkeys,
`copolymer-t-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 tevels of B-lymphocytes. T-lymphocytes. CD4+ T-Iym-
`phocytes. CDB+ T-Iymphocyte and CD4+rCD8+ ratio. No
`changes were observed also in natural killer cells and in the
`level of antinuclear antibodies or lgG 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
`COPOIYmer-l.
`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 or systemic adverse reactions. Furthermore, the
`clinical efficacy of copolymer-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 biological activity, either in
`vitro or in vivo.
`
`Clinical Studies
`
`The results of a phase III multicenter, double-blind, place-
`bo-control led trial, demonstrating efficacy and safety of
`Copaxone":i have been published (29). This was a 2-year
`study, involving 251 patients who daily self-injected subcu-
`taneously either Copaxone’l‘i 20 mg in = 125) or placebo (n
`= 126). The primary end point was the number of relapses
`reported during the treatment period. The final 2-year
`relapse rate was 1.19 i- 0.13 for patients receiving copo-
`Iymer-1 and 1.68 i 0.1 3 for those 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 21 E088 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. 20.3%) worsened (p = 0.037).
`Fiepeated measures analysis also demonstrated a signifi-
`cant effect in favor of Copaxone"9 for mean change in EDSS
`score (p 2 0.023). Patient withdrawals were 19 (15.2%)
`from the c0polymer-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. Rarely. a transient
`self-limited systemic reaction followed the injection in
`15.2% of those receiving copolymer-t and 3.2% of those
`receiving placebo‘. This reaction is characterized by vaso-
`dilatation or tightness of the chest with palpitations, anxiety
`andfor dyspnea. These symptoms generally resolve with-
`out sequelae. Studies of blood and urinefor 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 copoiymer-1 treatment can sig-
`nificantly and beneficially alter the course of relapsing~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 i 0.1 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 iniections to patients receiv-
`ing Copaxone’” and those receiving placebo, the number of eye-
`temic reaction episodes is very low. 0.037% and 0.0035%,
`respectively.
`
`MYLAN INC. EXHIBIT NO. 1022 Page 3
`
`MYLAN INC. EXHIBIT NO. 1022 Page 3
`
`

`

`Drugs Fut 1998. 21(2)
`
`133
`
`significant manner. A group of 27 patients in one center was
`also followed by serial quantitative MFll throughout treat-
`ment
`(32). A preliminary
`study. measuring Gd2+
`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-free
`patients (33}.
`
`Summary
`
`is effective in relapsing-remitting multiple
`Copolymer-l
`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.
`
`Manufa ctu rer
`
`Teva Pharmaceutical Industries Ltd. (IL).
`
`References
`
`1.Prous. J.. Meaty. N.. Castafier. J. Copolymen t : Agent formultiple
`sclerosis. Drugs Fut 1995. 20: 139-41.
`2. Paterson. P.Y. Autoimmune neurological disease: Experimental
`animal systems and applications for multiple sclerosis. in: Autoim-
`munity. Genetic. immunologic. Virologlc and Clinical Aspects. N.
`Talal (Ed). Academic Press. New York, 1977. 643-92.
`3. Alvord. E.C. Species-restricted encephalitogenic determinants.
`in: Experimental Allergic Encephalomyelitis: A Useful Model for
`Multiple Sclerosis. EC. Alvord. MW. Kies and A.J. Suckling (Eds).
`Alan Fl. Liss, New York. 1984. 523-31
`
`4. Driscoll. B.F.. Kies. l'vl.W.. Alvord. E.C.J. Successful treatment of
`experimental allergic encephafomyelitis in guinea pigs with homol-
`ogous myelin basic protein. J Immunol 1974. 112: 393-5.
`5. Bitar. D.. Withacre. C.C. Suppression of experimental autoim-
`mune encephalomyelitis by the oral administration of myelin basic
`protein. Cell Immunol 1988. 112: 364-79.
`6. Arnon. Ft. Experimental allergic encephalomyelitis - Susceptibil-
`ity and suppression. Immunol Flev 1981. 55: 5-30,
`7. Teitelbaum. D.. Webb. 0.. Bree. M. et al. Suppression of exper-
`imental allergic encephalomyelitis in rhesus monkeys by a syn-
`thetic basic copolymer. Olin lmmunol
`lmmunopathol 19M. 3:
`256-62.
`
`8. Teitelbaum. D.. Fridk'rs-Hareli. Fl.. Arnon. Fl.. Sela. M. Copo-
`lymer-t inhibits the onsetol chronic relapsing experimental autoim-
`mune encephaiomyelitis and interleres with T-cell responses to
`encephalitogenicpeptides of myelin proteolrpid protein. J Neuroim«
`munol 1996. in press.
`
`9. Ben-Nun. A.. Mendel, |.. Bakirner. H. et al. The effect of cops-
`lymer~l on encephalitogenic MUG-reactive T-cells. Eur J Neurol
`1996. in press.
`
`10. Sela. M. Polymeric drugs as immunomodulatory vaccines
`against multiple sclerosis. Makromol Chem Macromol Symp 1993.
`70l7‘l: 147-55.
`
`11. Sela. M.. Arnon. FL, Teitelbaum. D. Suppressive activity of
`COP-l in EAE andits relevance to multiple sclerosis. Bull Inst Pas-
`teur 1990. 88: 303-14.
`
`12. Teitelbaum. D.. Meshorer. A.. Hirshfeld. T. et al. Suppression of
`experimentalallergic encephalomyelitis bya synthetic polypeptide.
`Eur J Immunol 1971. 1: 242-8.
`13.Teite|baum. D.. Aharoni. R, Sela. M.. Arnon. R. Gross-reactions
`andspecificities ofmonoclonalantibodies against myelin basic pro-
`tein and against the synthetic copolymer- 1. Proc Natl Acad Sci USA
`1991. 88: 9528-32.
`14. Webb. C..Teitelbaurn, D.. Arnon. H, Sela. M. ln-vivo andin-vi—
`tro immunological cross—reactions between basic encephalitogen
`and synthetic basic polypeptides capable of suppressing exper-
`imentalallergic encephalomyelitis. EurJ lmmunol 1973. 3: 279-86.
`15. Teitelbaum. D.. Aharonl. R. Alnon, FL. Sela. M. Specific inhibi~
`tion of the T-cell response to myelin basic protein by synthetic copo~
`lymer COP- 1. Proc Natl Acad Sci USA 1988, 85: 9724-8.
`16, Fridkis-Hareli. M. Teitelbaum. D.. Gurevich. E. et at. Direct
`binding of myelin basic protein and synthetic copolymer-l to class
`ll major histocompatibility complex molecules on living antigen
`presenting cells. Specificity and promiscuity. Proc Natl Acad Sci
`USA 1994, 91: 4872-6.
`17. Fridkis~Hareli. M.. Teitelbaum. D.. Gurevr'ch, E. et al. Specific
`and promiscuous binding olsynthetic copolymer- 1 to class it major
`histooompatibility complex molecules on living antigen presenting
`cells. Annu Meet Isr Biochem Mol Biol {March 21 -22) 1994, Abst.
`18. Fridkis-Hareli. M, Tellelbaum. D.. Kerlero De Flosbo, N.. Arnon.
`Ft.. Sela. M. Syn thelic copolymer— 1 inhibits the binding ofMBP, PLP
`and M06 peptides to class it major histocompatibility complex mol-
`ecules on antigen presenting cells. J Neurochem 1994, 63(Suppl.
`1): 8-610.
`19. Fridkis-Hareli. M.. Teitelbaum. D.. Arnon, FL. Sela. M. Copo-
`lymeret displaces MBl—‘i PLP and MUG but can not be displaced by
`these antigens from the MHC class if binding site. 9th Int Cong
`Immunol (July 23-29. San Francisco) 1995. Abst 2408.
`20. Fridkis-Hareli. M.. Teitelbaum, D.. Arnon. R. Sela. M. Synthetic
`copolymer-l and myelin basic protein do not require processing
`prior to binding to class it major histocompetibiiity complex mole-
`cules on living antigen presenting cells. Cell Immunol 1995. 163:
`229-36.
`
`21. Teitelbaum, D.. Milo. FL. Arnon. Ft.. Sela. M. Synthetic copo-
`lymer-t inhibits human T-cell lines specific for myelin basic protein.
`Proc Natl Acad Sci USA 1992. 89: 137-41.
`
`22. Milo. FL. Panitch. H. Additive effects of copoh’mer-l and inter-
`feron beta- lb on the immune response to myelin basic protein. J
`Neuroimmunol 1995. 61: 185-93.
`
`23. Lando, Z.. Teitelbaum. D.. Amon. B. Effect of cyclophospha-
`mide on suppressor cell activity in mice unresponsive to EAE. J
`|mmun0l1979. 123: 2156-60.
`24. Lando. Z.. Teitelbaum. D.. Amon. H. The immunological
`response in mice unresponsive to expenmentalallergic encephalo-
`myelitis. J Neuroimmunol 1981. 126: 1526-8.
`25. Lando. Z.. Dori. Y.. Teitelbaum. D.. Arnon, R. Unresponsiveness
`to experimental allergic encephalomyelitis in mice - Replacement
`of suppressor cells by a soluble factor. J Immunol 1981. 121':
`1915-9.
`
`25. Aharoni. Fl. Teitelbaum. D.. Arnon. Ft. T—suppressor hybrido-
`mas and interleukin-z-dependent lines induced by copolymer-t or
`by spinal cord homogenate down-regulate experimental allergic
`encephalomyelilis. Eur J Immunol 1993. 23: 17-25.
`27. Teva Pharmaceutical Industries Ltd.. Internal Reports.
`28. Johnson. K.P.. Teitelbaum. D.. Arnon. Ft.. Sela. M. Antibodies
`to copolymer-l do not interfere with its clinical effect. 120th Annu
`Meet Amer Neurol Assoc (Oct 2225. Washington DC) 1995. Abst.
`29. Johnson, K.P.. Brooks. 8.9.. Cohen. J. et al. Copolyrner—t
`reduces relapse rate and improves disability in relapsing-remitting
`multiple sclerosis: Results of a phase lll multicenter. double-blind
`placebo-controlled trial. Neurology 1995. 45: 1268-76.
`
`MYLAN INC. EXHIBIT NO. 1022 Page 4
`
`MYLAN INC. EXHIBIT NO. 1022 Page 4
`
`

`

`134
`
`Copolymer-1
`
`30. Kunzke.J.F. Haringneurologicimpairmentinmuitipiescierosie'
`An expanded disabitity status soate (E085). Neurology 1983. 33:
`1444-52.
`31. Bernstein. M.B., Miller. A, Slagle. S. et al. A pita! trtaiotCOPnl
`in exacerbating-remitting muitipie scierosis. New Engl J Med 1 987,
`317: 408-1 4.
`
`:32. Johnson. KP. Copoiymer-f: Mufti-center muiripte sclerosis
`(Ms) Mat extension shows improved effects on reiapse rate and
`disabiiity Ann Neurol 1995, 38: 971 (Abst).
`33. Cohen, J.A., Grossman. Fl.l.. Udupa. J.K. et el. Assessmenror
`the efficacy of copoMner—f in the treatment of muibpte seierosts by
`quantitative MRI. Neurology 1995,4591. Suppt 4): Abs! 9178.
`
`MYLAN INC. EXHIBIT NO. 1022 Page 5
`
`MYLAN INC. EXHIBIT NO. 1022 Page 5
`
`