FRONTIERS IN
`MULTIPLE SCLEROSIS:
`CLINICAL RESEARCH
`AND THERAPY
`
`Edited by
`
`ODED ABRAMSKY MD PhD
`Professor and Head, Department of Neurology,
`Hadassah Hebrew University Hospital,
`Jerusalem, Israel
`
`HAIM OVADIA PhD
`Associate Professor, Department of Neurology,
`Hadassah Hebrew University Hospital,
`Jerusalem, Israel
`
`Published in association with the European
`Committee for Treatment and Research in
`Multiple Sclerosis (ECTRIMS)
`
`~T~ Mosby
`
`St. Louis Baltimore Boston Carlsbad Chicago Naples New York Philadelphia Portland
`London Madrid Mexico City Singapore Sydney Tokyo Toronto Wiesbaden
`
`MARTIN DU NITZ
`
`MYLAN INC. EXHIBIT NO. 1009 Page 1
`
`

`

`© Martin Dunitz Ltd 1997
`
`First published in the United Kingdom in 1997 by
`
`Martin Dunitz Ltd
`The Livery House
`7-9 Pratt Street
`London NWl OAE
`
`Mosby
`
`Dedicated to Publishing Excellence
`
`llllf'1ll A Times Mirror
`l!.il1 Company
`
`Distributed in the U.S.A. and Canada by
`Mosby-Year Book
`11830 Westline Industrial Drive
`St. Louis, Missouri 63146
`
`Times Mirror Professional Publishing Ltd.
`130 Flaska Drive
`Markham, Ontario L6G 188
`
`All right reserved. No part of this publication may be reproduced, stored
`in a retrieval system, or transmitted, in any form or by any means,
`electronic, mechanical, photocopying, recording or otherwise, without
`the prior permission of the publisher or in accordance with the provisions
`of the Copyright Act 1988, or under the terms of any licence permitting
`limited copying issued by the Copyright Licensing Agency, 33-34 Alfred
`Place, London WClE 7DP.
`
`A CIP catalogue record for this book is available from the British Library
`
`ISBN 1-85317-384-3
`
`Composition by Keyword Typesetting Services Limited, Wallington, Surrey
`Printed and bound in Great Britain by Biddles Ltd, Guildford and King's Lynn
`
`MYLAN INC. EXHIBIT NO. 1009 Page 2
`
`

`

`25
`Copolymer 1 in relapsing-remitting
`multiple sclerosis: a multi-centre trial
`
`Zeev Meiner, Edna Kott, Dalia Schechter, Puiu Nisipanu, Amos D Korczyn, Shlomo Fiechter and
`Oded Abramsky
`
`INTRODUCTION
`
`Multiple sclerosis (MS) is a chronic neurological
`disease, affecting mainly young adults.1 The dis(cid:173)
`ease is caused by inflammation and demyelina(cid:173)
`tion of various areas of the central nervous
`system (CNS) and has diverse clinical manifesta(cid:173)
`tions, such as impairment of motor, sensory,
`cerebellar, visual, cognitive, urogenital and men~
`tal functions,2 in a relapsing-remitting (RR) or
`chronic-progressive (CP) course. The cause and
`pathogenesis of the disease are still not known
`although the leading hypothesis is of an autoim(cid:173)
`mune attack on CNS myelin.3'4 Multiple thera(cid:173)
`peutic
`interventions have failed
`to reduce
`significantly the relapse rate or the progression
`of disability.5 Recently, however, interferon
`beta-lb (IFN~-lb), was shown to reduce the
`'7 and IFN~-lb has
`relapse rate in RR patients,6
`been approved in the U.S. for the treatment of
`ambulatory RR MS patients.
`Copolymer 1 is the acetate salt of a controlled
`mixture of synthetic polypeptides with an aver(cid:173)
`age molecular weight of 4700 to 13 000 Daltons.
`It is composed of four L-amino acids: alanine,
`glutamic acid, lysine and tyrosine, and has
`been shown to cross-react with the myelin
`basic protein (MBP) on both the humoral and
`cellular levels.8
`9 Copolymer 1 was shown to pre(cid:173)
`'
`vent the induction and to reduce the clinical
`score of EAE as well as brain pathology induced
`by CNS material in a variety of rodents and to
`
`cure the disease in monkeys without any evi(cid:173)
`dence of encephalitogenic activity.10 The pro(cid:173)
`posed mechanism of action for copolymer 1
`involves binding to the class II major histocom(cid:173)
`patibility complex molecules on antigen-present(cid:173)
`'12 followed by stimulation of antigen(cid:173)
`ing cells,11
`specific suppressor T-cells13'14 and/ or inhibition
`of the activation of antigen-specific effector T(cid:173)
`cells.1s-17
`Preliminary studies, including a previous
`phase II double-blind, placebo-controlled clinical
`trial, showed a marked beneficial effect of co(cid:173)
`polymer 1, given by daily s.c. injections of
`20 mg, in reducing the relapse rate and slowing
`- 20
`progression of disability in RR MS patients.18
`A second double-blind study revealed a poten(cid:173)
`tial, though not conclusive, effect in slowing pro(cid:173)
`gression of disease
`in chronic-progressive
`patients administered 30 mg (15 mg b.i.d.) of
`copolymer 1 daily.21 In these studies copolymer
`1 was found to be safe, with only minimal and
`well-tolerated adverse effects. These results were
`recently corroborated by a phase III double(cid:173)
`blind, placebo-controlled, multi-centre study in
`RRMS.22
`Here we report interim results of a long-term
`multi-centre, open-label, phase III clinical trial of
`copolymer 1 in RR and relapsing-progressive
`(RP) MS patients. The objectives of this trial
` were to evaluate the long-term safety of copoly(cid:173)
`mer 1 and to monitor the course of the disease in
`the treated patients.
`
`MYLAN INC. EXHIBIT NO. 1009 Page 3
`
`

`

`214 FRONTIERS IN MULTIPLE SCLEROSIS
`
`METHODS
`
`Patients
`
`Patients were enrolled in four medical centres in
`Israel. The study was approved by the tespective
`institutional review boards and the Israeli health
`ministry, and all patients gave informed consent.
`All patients had clinically definite or laboratory(cid:173)
`supported definite MS.23 Subjects of both
`sexes had to be between 18 and 60 years of age,
`be ambulatory with an BOSS score not greater
`than 6, and should have had at least two docu(cid:173)
`mented exacerbations during the two years prior
`to study entry. Patients had to be clinically stable
`for at least one month before entry with no
`steroid treatment during this period. A washout
`period of six months from any previous immu(cid:173)
`nosuppressive or immunomodulating treatment
`was required. Existence of any other chronic dis(cid:173)
`ease or pregnancy excluded patients from par(cid:173)
`ticipating in the trial, as well as significant
`in ECG, chest X-rays, blood
`abnormalities
`VORL, ANF, HIV, vitamin B12 and folic acid.
`
`BAE in mice. Copolymer 1 for injection was sup(cid:173)
`plied as a sterile, lyophilized material, in single(cid:173)
`dose vials containing 20 mg of the active drug
`and 40 mg of mannitol. The medication was
`reconstituted before administration with sterile
`water for
`injection supplied conc01nitantly.
`Patients· or their companions were instructed
`how to prepare and administer the medication
`subcutaneously. The first three injections were
`administered at the medical centre under. close
`observation for six hours. Thereafter, new sup(cid:173)
`plies were provided at three-month intervals
`and patients continued to self-administer daily.
`
`Follow-up visits schedule
`
`Adverse experiences were recorded every three
`months. In addition the patients were evaluated
`every six months. Each visit included general
`and neurological examinations, establishment
`of the functional system (FS) and BOSS scores,25
`routine blood and urine tests, recording of
`adverse events and patients' self-evaluations.
`
`Preparation, characterization and
`administration of copolymer 1 for injection
`(Copaxone)
`
`Copolymer 1, the active ingredient of Copaxone,
`was manufactured by Teva Pharmaceutical
`Industries Ltd in Israel, essentially as previously
`described,24 by reacting the protected and acti(cid:173)
`vated derivatives of L-alanine, L-glutamic acid,
`L-lysine and L-tyrosine in the appropriate ratios.
`The molar fraction ranges for each amino acid
`residue in the final product are, L-ala: 0.392-
`0.462; L-glu; 0.129-0.153; L-lys: 0.30-0.374, and
`L-tyr; 0.086-0.10. The average molecular mass is
`4700-13 000 Oaltons. Each batch was rigorously
`controlled during its production and the final
`product was quality-controlled for its amino
`acid composition, molecular weight distribution
`and chromatographic profile, as well as by var(cid:173)
`ious other quality control tests. Some batches
`were also monitored for cross-reactivity with
`myelin basic protein using four different mono(cid:173)
`clonal antibodies and for their capacity to block
`
`Monitoring of safety and of the neurological
`course of disease
`
`The safety of copolymer 1 was evaluated by
`monitoring the occurrence and severity of
`adverse events (AEs) as reported by the patients
`or observed by the treating physician during
`each visit. Haematological analysis, levels of
`serum electrolytes, liver and kidney functions,
`as well as other serum chemistries and urine
`analysis, were performed to monitor metabolic
`changes and disturbances in organ function
`throughout the trial.
`The neurological course of the disease was
`assessed by monitoring the annual relapse rate,
`the proportion of relapse-free patients and the
`time to first relapse as well as the change in
`BOSS score from baseline, with a significant
`change defined as a change of 1.0 unit or more
`in any direction relative to the baseline value. In
`addition, progression of disease was defined as a
`sustained (;:::90 days) increase of at least 1.0 unit
`in the BOSS score relative to baseline.
`
`MYLAN INC. EXHIBIT NO. 1009 Page 4
`
`

`

`COPOLYMER l IN RE LAPSING-REMITTING MUL TTPLE SCLEROSIS 215
`
`Premature discontinuation
`
`Treatment was discontinued in any of the fol(cid:173)
`lowing circumstances: intoleral?le AEs; patient's
`decision to discontinue treatment for any reason;
`investigator's judgment that continuation of
`treatment is not in the best interest of the patient;
`poor compliance, i.e. failure to administer the
`drug for more than 25 per cent of the time (com(cid:173)
`pliance less than 75 per cent), pregnancy, with
`patient planning to carry it to term, and loss to
`follow-up.
`
`Exacerbations
`
`An exacerbation was defined as the appearance
`of a new symptom or a marked worsening of an
`old symptom attributable to MS, accompanied
`by new neurological signs. A minimal duration
`of 24 hours for these symptoms was required,
`and they had to be preceded by a minimum of
`30 days of stabilization or improvement to be
`considered a new relapse. The patients were
`instructed to report immediately any symptoll).
`suggesting a relapse and were evaluated within
`4-7 days. Patients were subsequently examined
`every 2-4 weeks until they returned to baseline
`or stabilized. A short course (up to 28 days) of
`steroids was allowed during exacerbations.
`
`Statistical methods
`
`Analysis included all patients enrolled (n=271),
`with subgroup analysis of those who were trea(cid:173)
`ted for at least 12, 24 or 36 months. Improvement
`or worsening in the EDSS score was defined as a
`change of at least 1 unit in either direction rela(cid:173)
`tive to the baseline value.
`Comparison of changes in EDSS score and in
`the annual relapse rate were performed using
`the Wilcoxon test. The life-table estimates of sur(cid:173)
`vival curves (Kaplan-Meier analysis) were used
`to determine time to disease progression and
`time to first relapse. The Wilcoxon test for homo(cid:173)
`geneity was applied to test differences in survi(cid:173)
`val curves between patients who continued
`treatment and those who withdrew prema-
`
`turely. Analyses were performed using the
`V6.09 SAS statistical softvvare with an Ultrix
`Dec Station. All p-values denoted are two-tailed.
`
`RESULTS
`
`Demographic and baseline disease
`characteristics
`
`Two hundred and seventy one patients were
`enrolled in four centres (Table 25.1), 155 (57.2
`per cent) females and 116 (42.8 per cent) males.
`The patients' age range was 18-59 years, with a
`mean of 36.7 (±9.9) years. Mean disease dura(cid:173)
`tion was 8.3 (±6.4) years. The mean baseline
`EDSS score was 3.3 (±1.8), and the annual
`relapse rate in the two years prior to study
`entry, calculated from historical data, was 1.4
`(±0.7). To date, 188, 107 and 45 patients have
`completed one, two and three years of treat(cid:173)
`ment, respectively.
`
`Premature terminations
`
`the distribution of
`Table 25.2 summarizes
`patients with regard to their reason for with(cid:173)
`drawal. Due to the open-label design of the
`trial, which enabled normal conclusion after
`one, two or three years, a relatively high propor(cid:173)
`tion of patients are categorized as 'normal con(cid:173)
`clusion' (11.8 per cent of the total). Only 24
`patients (8.8 per cent) were reported to have
`AEs at the time of premature termination, after
`a mean duration of treatment of 6.9 (±6.5)
`months. The AEs associated with treatment dis(cid:173)
`continuation were usually those observed at the
`highest incidence (see next section). In addition,
`three patients withdrew due to symptoms that
`could be associated with an allergic reaction
`(rash, urticaria).
`
`Adverse events and laboratory studies
`
`The administration of copolymer 1 was asso(cid:173)
`ciated with relatively minor AEs. More than 30
`per cent of all patients participating in the trial
`(102/271) did not report any AE during the
`
`MYLAN INC. EXHIBIT NO. 1009 Page 5
`
`

`

`216 FRONTIERS IN MULTIPLE SCLEROSIS
`
`Table 25.1 Demographic and baseline disease characteristics of all
`enrollees (n=271)
`
`Characteristics
`Gender
`male
`female
`Mean age in years (±SD)
`Mean disease duration in years (±SD)
`Mean baseline EDSS (±SD)
`Mean annual relapse rate in prior two years (±SD)
`
`116
`155
`36.7
`8.3
`3.3
`1.4
`
`(42.8%)
`(57.2%)
`(±9.9)
`(±6.4)
`(±1.8)
`(±0.7)
`
`Table 25.2 Distribution of patients by reason for premature termination
`
`Termination reason
`
`Normal conclusion (at 12, 24, 36 months)
`Voluntary withdrawal
`DuetoAE
`Loss to follow up
`Others*
`Total
`
`N
`
`32
`29
`24
`26
`20
`131
`
`% of discontinued
`(n=131)
`
`% of total
`(n=271)
`
`24.4
`22.9
`18.3
`19.9
`14.5
`100
`
`11.8
`11.0
`8.8
`9.6
`7.1
`48.3
`
`*Continuation of treatment in the US (12); Compliance less than 75% (2); Surgery that affects MS treatment (1); Investigator's judgment (2);
`Disease progression (2); Personal problems (1).
`
`reactions were
`injection-site
`study. Local,
`resported by 44.0 per cent of the patients
`(Table 25.3). These included erythema (12.1 per
`cent), hypersensitivity (10.7 per cent), induration
`(9.2 per cent), inflammation (8.8 per cent) and
`pain (8.8 per cent). Five patients reported these
`reactions as cause for withdrawal. An idiosyn(cid:173)
`cratic, systemic adverse reaction, manifested
`by chest tightness or flushing, together with
`dyspnoea, palpitations and/ or anxiety, was
`reported by 13.6 per cent of the patients. These
`reactions occurred immediately following drug
`administration, lasted for 10-30 minutes and
`resolved without treatment or sequelae. Most
`patients experienced these reactions only once,
`sporadically and unpredictably. The maximum
`number of episodes for a single patient was six
`(in three patients). Fifteen patients (5.5 per cent)
`
`who experienced more than two such episodes,
`were discontinued from the trial. Additional sys(cid:173)
`temic reactions deemed related to treatment,
`such as lymphadenopathy (2.2 per cent) and
`rash (3.7 per cent) were also reported.
`A cumulative presentation of the proportion
`of patients reporting AEs as a function of time
`on
`treatment revealed
`that most patients
`reported the AEs within the first six months
`(Figure 25.1). The proportion of patients report(cid:173)
`ing AEs after the first six months of treatment
`declined significantly. Only one out of 19 serious
`AEs reported in this study-an Arthus phenom(cid:173)
`enon-was deemed by the investigator to be
`highly probably related to drug treatment. Two
`deaths occurred during the study, none of which
`was deemed by the investigators to be reason(cid:173)
`ably associated with the use of copolymer 1.
`
`MYLAN INC. EXHIBIT NO. 1009 Page 6
`
`

`

`COPOLYMER l IN RELAPSING-REMITTING MULTIPLE SCLEROSIS 217
`
`Table 25.3. Adverse effects of copolymer 1 occurring In at least 5% of the patients
`
`AEgroup
`
`Injection-site reactions
`Systemic post-injection reaction*
`Systemic (other)t
`Asthenia
`Pruritus
`Dizziness
`
`No. of patients reporting % patients reporting at
`at least once
`least once
`
`119
`37
`19
`16
`17
`15
`
`44.0
`13.6
`7.0
`5.9
`6.3
`5.5
`
`*Temporarily related to treatment administration, includes chest pain or flushing together with dyspnoea, palpitation and/or anxiety.
`tlncludes any of the above symptoms, appearing not In combination with the others.
`
`No clinically significant changes were noted
`in any of the routine laboratory examinations,
`including haematology, blood electrolytes, and
`liver and kidney function, as well as in a variety
`of other routine serum chemistry tests and
`urinalysis.
`
`Relapses during study
`
`In the group of 107 patients who completed two
`years of treatment, 54.2 per cent remained
`relapse-free after two years (Table 25.4 and
`Figure 25.2), 23.4 per cent experienced one
`relapse and 12.2 per cent had two relapses. The
`
`100
`
`a
`
`111
`
`•
`
`Any AE
`
`1r - - -tr - - "'
`
`Local reactions
`
`80
`
`o--G--o SPIR
`
`60
`
`~ Q)
`''la
`a.
`0
`~
`~ 40
`Q) a.
`
`Q)
`
`20
`
`0
`
`6
`
`12
`
`18
`
`24
`
`30
`
`36
`
`Month in trial
`
`Figure 25.1 Cumulative proportion of patients reporting adverse events as a function of time in trial. The data
`includes all patients enrolled (n=271). Results presented are for the total (AE), local and systemic post-injection
`reactions (SPIR).
`
`MYLAN INC. EXHIBIT NO. 1009 Page 7
`
`

`

`218 FRONTIERS IN MDL TIP LE SCLEROSIS
`
`annual relapse rate for the patients who com(cid:173)
`pleted two years on treatment (n=107) dropped
`from 1.4 (±0.60) in the two years prior to study
`entry to 0.3 (±0.5) during the study. This repre(cid:173)
`sents a 73.4 per cent reduction in annual relapse
`rate and is highly statistically significant (Wil(cid:173)
`coxon, p=0.0001). The time to first relapse was
`10.3 (±10.8) months. The majority of the patients
`developed their relapses during the first six
`months (Figure 25.2). The annual relapse rate
`during each succeeding year decreased (Figure
`25.3), with a concomitant increase in the propor(cid:173)
`tion of relapse-free patients: while during the
`first year of treatment 69.2 per cent of the
`patients were relapse-free (74 of the 107 who
`were followed-up for at least two years), 77.6
`per cent (83 of 107) were relapse-free during
`the second year. This trend was also observed
`during the third year, where 84.4 per cent of the
`patients (38 of 45) were relapse-free.
`
`Tabte25.4 Relapses In patients who
`completed two years in study
`
`Number .of relapses
`
`N
`
`%
`
`0 (Relapse-free)
`1
`2
`3
`4
`5-6
`Total
`
`58
`25
`13
`6
`3
`2
`107
`
`54.2
`23.4
`12.2
`5.6
`2.8
`1.9
`100
`
`There was no statistically significant differ(cid:173)
`ence
`in the number of on-study relapses
`reported by patients who withdrew from the
`study and those who continued treatment. As
`is apparent from the survival curves presented
`
`1.0
`
`0.9
`
`0.8
`
`0.7
`
`tr - - -tr - -6 Patients in trial
`
`•
`
`•
`
`• Withdrawers
`
`c
`
`.0
`
`0 s 0.6
`~
`'5
`~
`·~
`::I
`(/)
`
`0.5
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0.0
`
`0
`
`6
`
`12
`
`18
`Time to first relapse (months)
`
`24
`
`30
`
`36
`
`Figure 25.2 Kaplan-Meier analysis of the probability of remaining relapse-free during treatment. Results are
`shown for patients in trial (n=140) and for patients who withdrew prematurely (n=131).
`
`MYLAN INC. EXHIBIT NO. 1009 Page 8
`
`

`

`COPOLYMER 1 IN RELAPSING-REMITTING MULTIPLE SCLEROSIS 219
`
`2.5
`
`2
`
`<ll
`T§
`<ll
`(/) 1.5
`0..
`C<J
`~
`(ii
`::i
`c:
`c:
`<(
`
`0.5
`
`0
`
`Prior
`
`1st
`Year of treatment
`
`2nd
`
`Figure 25.3 Effect of treatment duration on relapse
`rate. The difference between the first year and prior two
`years relapse rate is statistically significant (Wilcoxon,
`p<0.0001). The difference between the first and
`second years of treatment is not statistically significant.
`
`in Figure 25.2, the time to first relapse was also
`similar for these two groups (Kaplan-Meier,
`p=0.2982).
`
`Changes in EDSS score
`
`Evaluation of the EDSS score during the study
`revealed that most of the patients who com(cid:173)
`pleted two or three years of treatment remained
`stable or improved, and only 28 patients wor(cid:173)
`sened. Only slight changes in the mean EDSS
`score relative to baseline were observed. As
`can be seen from Figure 25.4, there was no dif(cid:173)
`ference in the time to progression of disease,
`defined as a sustained (~90 days) increase of at
`least one point on the EDSS, between the
`patients who continued treatment and those
`who withdrew (Kaplan-Meier, p=0.2646).
`
`DISCUSSION
`
`The results of this study lend support to previous
`21
`reports on the safety of copolymer 1.18
`-
`Although 70 per cent of the patients reported
`AEs, these were mostly mild and transient.
`This favourable profile was also observed in
`
`the phase III double-blind study with copoly(cid:173)
`mer-1 recently completed in the U.S.22 The
`most common adverse events reported were
`injection-site reactions. Their occurrence, how(cid:173)
`ever, was not consistent, and it was unpredict(cid:173)
`able whether they would appear, or recur, in any
`given patient. Studies performed on a small sub(cid:173)
`group of our patients seem to imply that these
`local reactions may involve a direct histamine(cid:173)
`releasing effect of copolymer 1 on dermal mast
`cells (M. Shalit et al, unpublished data). The sec(cid:173)
`ond most common AE consisted of a transient
`feeling of chest tightness or flushing together
`with dyspnoea, palpitations, and/ or anxiety.
`These events, which were previously reported
`in placebo-controlled copolymerl studies,20
`21
`,
`did not follow any recognizable pattern of
`appearance, recurrence or disappearance. In the
`large double-blind studies with copolymer 1,
`placebo patients reported these systemic post(cid:173)
`injection reactions too.21
`22 Therefore, we inter(cid:173)
`'
`pret them as being, at least in part, anxiety reac(cid:173)
`tions rather than true physiological AEs. The
`totally unpredictable pattern of these reactions
`rules out the possibility of an allergic reaction
`and, indeed, no IgE reactive copolymer 1 was
`found in a sub-group of our patients who experi(cid:173)
`enced these AEs (M. Shalit et al, unpublished
`data). Other AEs were remarkably rare. Only
`one drug-related serious adverse event, an
`Arthus phemonenon, was reported in our series,
`expanding over 500 patient-years. Of note is our
`observation that the frequency of AEs reporting
`decreases after the first six months of therapy.
`This may represent a real-time effect or may
`result from patients becoming accustomed to
`the AEs and failing to report them, attesting to
`their benign nature.
`Since this was an open-label study, the results
`cannot be used to determine efficacy, particu(cid:173)
`larly in view of the natural history of MS and
`20
`the well-known placebo effects.6
`22 None(cid:173)
`'
`'
`theless, it is remarkable that our patients had a
`largely stable course of the disease with very few
`relapses during treatment. In this resped our
`results are very similar to those of the previously
`reported phase II double-blind study of copoly(cid:173)
`mer 1 in RR MS.20 The beneficial effect of co(cid:173)
`polymer 1 in RR MS patients was corroborated
`
`MYLAN INC. EXHIBIT NO. 1009 Page 9
`
`

`

`220 FRONTIERS IN MULTIPLE SCLEROSIS
`
`1.0
`
`0.9
`
`0.8
`
`0.7
`
`Patients in trial
`
`e
`
`"'
`
`e Withdrawers
`
`c
`
`..a
`
`0 s 0.6
`:~ 'O
`"Cii >
`·~
`::i
`(/)
`
`0.5
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0.0
`
`0
`
`6
`
`12
`
`18
`
`24
`
`30
`
`36
`
`Time to progression (months)
`
`Figure 25.4 Kaplan-Meier analysis of the probability of remaining progression-free during treatment. Progression
`was defined as a sustained (;;::90 days) increase of at least 1 point on the· EDSS. Results are shown for patients in
`trial (n=140) and for patients who withdrew prematurely (n=131).
`
`by the results of a multi-centre double-blind
`phase III trial recently completed in the U.S.22
`Another support for the validity of our results
`is the fact that the results for the four participat(cid:173)
`ing centres in Israel are similar (data not shown).
`A most interesting observation was that over
`the course of treatment the proportion of
`patients remaining relapse-free increased, indi(cid:173)
`cating that the beneficial effects of copolymer-1
`are maintained and even enhanced with time on
`treatment. Similar results were obtained in the
`trial.22 The reduced
`double-blind phase III
`relapse rate and the fact that a large number of
`patients remained relapse-free, changed the
`quality of life of many subjects at a low cost of
`adverse reactions (E. Kott et al, unpublished
`data).
`In summary, we can conclude that copoly(cid:173)
`mer-1 is a safe, well-tolerated medication and
`that the AEs observed are minor. Our results
`
`support and extend the safety and efficacy of
`copolymerl, reported in several controlled trials,
`for the treatment of RR MS.
`
`ACKNOWLEDGEMENTS
`
`The following persons contributed to the success
`of this multi-centre trial: Michal Mor RN, Hanna
`A vrahami, Hadassah University Hospital, Ein
`Karem, Jerusalem. Jehuda Yochai RN, Bianca
`Gutman MD, Naomi Shilman, Meir Hospital,
`Kfar-Saba. Emma Bakaleinik RN, Tel-Aviv Med(cid:173)
`ical Center, Ichilov Hospital, Tel-Aviv. Leora
`Ben-Bassat, Assaf Harofeh Medical Centre, Zri(cid:173)
`fin. Yafit Stark PhD, Irit Pinchasi PhD, Rivka
`Riven-Kreitman PhD, Paul Bendeheim MD,
`Shaul Kadosh MS, Baim Singal MS, Maria Gur(cid:173)
`evich RN, Teva Pharmaceutical Industries Ltd,
`Pethah Tiqva, Israel.
`
`MYLAN INC. EXHIBIT NO. 1009 Page 10
`
`

`

`COPOLYMER l IN RE LAPSING-REMITTING MULTIPLE SC LE ROS IS 221
`
`REFERENCES
`
`1. Kurtzke JF, Epidemiologic contribution to multiple
`sclerosis-an overview, Neurologtj (1980) 30: 61-79.
`2. Kelly R, Clinical aspects of ntultiple sclerosis. In:
`Vinken PJ, Bruyn GW (eds), Handbook of Clinical
`Neurologtj (Amsterdam: Elsevier Science, 1985)
`pp 49-78.
`3. Waksman BH, Mechanism in multiple sclerosis,
`Nature (1985) 318: 104-105.
`4. Bernard CCA, Kerlero de Rosbo N, Multiple
`sclerosis: an autoimmune disease of multifactoral
`etiology, Curr Opin Immunol (1992) 4: 760-765.
`5. Weiner HL, Hafler DS, Immunotherapy for MS,
`Ann Neural (1988) 23: 211-222.
`6. The IFNB multiple sclerosis study group. Inter(cid:173)
`feron beta-lB is effective in relapsing-remitting
`multiple sclerosis. I. Clinical results of a multi-cen(cid:173)
`ter, randomized double-blind placebo-controlled
`trial, Neurology (1993) 43: 655-661.
`7. Paty DW, Li DKB, the UBC MS/MRI study group
`and the IFNB MS group, interferon beta-lb is
`effective in relapsing-remitting multiple sclerosis.
`II. MRI results of a multi-center randomized
`double-blind placebo-controlled trial, Neurologtj
`(1993) 43: 662-667.
`8. Webb C, Teitelbaum D, Amon R et al, In vivo and
`in vitro immunological cross-reactions betwee~
`basic encephalitogen and synthetic basic polypep(cid:173)
`tides capable of suppressing experimental allergic
`encephalomyelitis, Eur J Immunol (1973) 3: 279-
`286.
`9. Teitelbaum D, Aharoni R, Sela Met al, Cross reac(cid:173)
`tions and specificities of monoclonal antibodies
`against myelin basic protein and against synthetic
`copolymer-1, Proc Natl Acad Sci USA (1991) 88:
`9528-9532.
`10. Amon R, Teitelbaum D, Desensitization of experi(cid:173)
`mental allergic encephalomyelitides with synthetic
`peptide analogues. In: Davidson AM, Cuzner ML
`(eds) The Suppression of Experimental Allergic Ence(cid:173)
`phalomyelitides and Multiple Sclerosis (Academic
`Press: New York, 1980) 105-117.
`11. Fridkis-Hareli M, Teitelbaum D, Gurevich E et al,
`Direct binding of myelin basic protein and syn(cid:173)
`thetic copolymer-1 to class II major histocompat(cid:173)
`ibility complex molecules on living antigen
`presenting cells-specificity and promiscuity,
`Proc Natl Acad Sci USA (1994) 91: 4872-4876.
`12. Fridkies-Hareli M, Teitelbaum D, Amon R et al,
`Synethetic copolymer-1 and myelin basic protein
`do not require processing prior to binding to class
`II major histocompatibility complex molecules on
`
`living antigen presenting cells, Cell I111111unol (1995)
`163: 229-236.
`13. Lando Z, Teitelbaum D, Amon R, Effect of cyclo(cid:173)
`phosphamide on suppressor cell activity in mice
`unresponsive to EAE, J Immunol (1979) 123: 2156-
`2160.
`14. Aharoni R, Teitelbaum D, Amon R, T Suppressor
`hybridomas and interleukin-2 dependent lines
`induced by copolymer-1 or by spinal cord homo(cid:173)
`genate down-regulate experimental allergic ence(cid:173)
`phalomyelitis, Eur J Immunol (1993) 23: 17-25.
`15. Teitelbaum D, Aharoni R, Amon R et al, Specific
`inhibition of the T-cell response to myelin basic
`protein by the synthetic copolymer, COP-1, Proc
`Natl Acad Sci USA (1988) 85: 9724-9728.
`16. Teitelbaum D, Milo R, Amon R et al, Synthetic
`copolymer-1 inhibits human T-cell lines specific
`for myelin basic protein, Proc Natl Acad Sci USA
`(1992) 89: 137-141.
`17. Milo R, Panitch H, Additive effects of COP-1 and
`INF-beta on the immune responses to myelin basic
`protein, Neuroimmunologtj (1995) 61: 185-193.
`18. Abramsky 0, Teitelbaum D, Amon R, Effect of a
`synthetic polypeptide (COP-1) on patients with
`multiple sclerosis and with acute disseminated
`encephalomyelitis. Preliminary report, J Neural
`Sci (1977) 31: 433-438.
`19. Bornstein MB, Miller A, Teitelbaum D et al, Mul(cid:173)
`tiple sclerosis: trial of a synthetic polypeptide,
`Ann Neural (1982) 11: 317-319.
`20. Bornstein MB, Miller A, Slagle Set al, A pilot trial
`of COP-1
`in exacerbating-remitting multiple
`sclerosis, N Engl J Med (1987) 317: 408-414.
`21. Bornstein MB, Miller A, Slagle S et al, A placebo
`controlled double-blind randomized two center,
`pilot trial of COP-1 in chronic progressive multiple
`sclerosis, Neurology (1991) 41: 533-539.
`22. Johnson KP, Brooks MD, Cohen JA et al, Copoly(cid:173)
`mer-1 reduces the realpse rate and improves dis(cid:173)
`ability in relapsing-remitting multiple sclerosis.
`Results of a phase III multi-center double-blind,
`trial, Neurology
`placebo-controlled
`(1995) 45:
`1268-1276.
`23. Poser CM, Paty DW, Scheinberg Let al, New diag(cid:173)
`nostic criteria for multiple sclerosis: guidelines for
`research protocols, Ann Neural (1983) 13: 227-231.
`24. Teitelbaum D, Meshorer A, Hirshfeld T et al, Sup(cid:173)
`pression of experimental allergic encephalomyeli(cid:173)
`tis by a synthetic polypeptide, Eur J Immunol
`(1971) 1: 242-248.
`25. Kurtzke JF, Rating neurological impairment in
`multiple sclerosis: an expanded disability status
`scale (EDSS), Neurologtj (1983) 33; 1444-1452.
`
`MYLAN INC. EXHIBIT NO. 1009 Page 11
`
`