Clinical Neuropharmacology
`Vol. 25, No. 1, pp. 11–15
`© 2002 Lippincott Williams & Wilkins, Inc., Philadelphia
`
`Copolymer 1 (Glatiramer Acetate) in Relapsing Forms of
`Multiple Sclerosis: Open Multicenter Study of
`Alternate-Day Administration
`
`*Shlomo Flechter, †Edna Kott, ‡Bettina Steiner-Birmanns, §Puiu Nisipeanu, and
`储Amos D. Korczyn
`
`*Assaf-Harofeh Medical Center, Zerifin; †Sapir Medical Center, Kefar-Sava; ‡Hadassa Ein-Kerem Medical Center, Jerusalem;
`§Hillel-Jaffe Medical Center, Hedera; and 储Sieratzki Chair of Neurology, Tel-Aviv University, Tel-Aviv, Israel
`
`Summary: Daily 20-mg doses of Copolymer 1 have been shown to significantly de-
`crease the relapse rate in patients with multiple sclerosis (MS). In the present open-label
`study, patients with relapsing MS were treated with the same dose of Copolymer 1
`administered on alternate days. Sixty-eight patients were recruited: fifty-one and forty-
`one patients completed 1 and 2 years of treatment respectively. The relapse rate during
`the 2 years of treatment decreased by 80.8% compared with the 2 years before treatment
`(means, 0.56 ± 1.02 versus 2.91 ± 1.10, respectively; p < 0.0001). This lower rate is
`comparable with that obtained with daily open-label administration previously reported
`by the authors. The score on the Expanded Disability Status Scale did not differ from that
`at baseline after the first year of treatment, although it increased somewhat at the end of
`the second year (baseline = 2.72 ± 1.55, 1 year = 2.71 ± 1.59, 2 years = 2.97 ± 1.80; p <
`0.008). The drug was very well tolerated. This preliminary open-label study suggests
`that alternate-day therapy has beneficial effects and is well tolerated, comparing favor-
`ably with the effects of daily injections of Copolymer 1 in patients with relapsing MS.
`These results should be confirmed by randomized double-blind examinations. Key
`Words: Multiple sclerosis—Copolymer-1—Alternate-day therapy—Glatiramer ac-
`etate—Treatment—Mechanisms
`
`Multiple sclerosis (MS) is a common chronic neuro-
`logic disease of unknown etiology. This inflammatory
`demyelinating disease may present with a relapsing-
`remitting (RR) or a chronic-progressive course. In the
`more common RR form, the relapses may leave pa-
`tients with residual deficits, causing neurologic disabil-
`ity that accumulates over time. The aim of therapy in
`patients with RR MS is to prevent exacerbation and the
`accumulation of disability. Recently, in double-blind,
`placebo-controlled studies, interferon ␤-1a, interferon
`␤-1b, and Copolymer 1 (glatiramer acetate) were
`shown to decrease the relapse rate (1–5) and possibly
`slow down the accumulation of disability in patients
`with MS (6–8). All three agents have been approved in
`several European countries and in the U.S. for the treat-
`ment of patients with RR MS. Copolymer 1 is a syn-
`thetic polypeptide with a molecular weight of 4.700–
`
`Address correspondence and reprint requests to Dr. S. Flechter, The
`MS Clinical Research and Therapy Service, Assaf-Harofeh Medical
`Center, Zerifin 70300, Israel.
`
`11
`
`13.000 Dalton; it is composed of four amino acids: ala-
`nine, glutamic acid, lysine, and tyrosine. Copolymer 1
`prevents the induction of experimental autoimmune en-
`cephalomyelitis and may reverse or ameliorate neuro-
`logic deficits in animal models (9,10). Clinical double-
`blind, placebo-controlled studies with Copolymer 1
`showed beneficial effects of this drug when it was
`given by daily, subcutaneous (SC) injections of 20 mg.
`In these studies, Copolymer 1 reduced the relapse rate
`and slowed the accumulation of disability (2,11–13).
`The safety profile of Copolymer 1 compares favorably
`with the safety profile of interferons (14). However, the
`dose and frequency of administration of Copolymer 1
`were rather arbitrarily selected. We report here the re-
`sults of a long-term, multicenter, phase III, open-label
`study of RR MS. The objectives of this study were to
`evaluate the long-term neurologic course of the disease
`and the long-term safety of Copolymer 1 in patients in
`whom 20 mg was administered SC on an alternate-day
`basis. Using a protocol identical to that used by us in a
`previous open-label study of daily Copolymer 1 admin-
`istration, analyses were performed on two efficacy pa-
`
`Page 1 of 5
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`Coalition Exhibit 1059
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`

`
`12
`
`S. FLECHTER ET AL.
`
`rameters: frequency of exacerbations and score on the
`Expanded Disability Status Scale (EDSS) (15).
`
`TABLE 1. Demographic and clinical characteristics of
`patients treated with Copolymer 1
`
`MATERIALS AND METHODS
`
`Patients
`
`After obtaining the approval of the respective ethical
`committees and individual informed consents, sixty-
`eight patients were enrolled in dedicated MS clinics at
`four medical centers. The inclusion criteria were iden-
`tical to those of our previous open-label study with
`daily Copolymer 1 injections (15). Patients had clini-
`cally definite or laboratory-supported definite MS.
`Fifty-eight were of the relapsing-remitting type and ten
`were of the relapsing-progressive type with at least two
`exacerbations during the 2 years before study entry. Pa-
`tients had to be clinically stable for at least 1 month
`before entry. No steroids or other immuno-modulators
`could be used during 6 months before study entry. The
`EDSS score at baseline had to be less than 6.0. Men and
`women ages 18 and over were eligible, but existence of
`any other chronic disease or pregnancy excluded pa-
`tients from the study. Evaluations included physical
`and neurologic examinations, laboratory data (hema-
`tology, blood chemistry, urinalysis), and vital signs.
`
`Drug Supply
`
`Copolymer 1 was manufactured and supplied by
`Teva Pharmaceuticals (Petah Tikva, Israel). It was sup-
`plied as a sterile lyophilized material in single-dose vi-
`als containing 22 mg of the active drug and 40 mg of
`mannitol. Patients or family members were instructed
`how to prepare and administer the drug. New supplies
`of Copolymer 1 were provided at 3-month intervals
`during scheduled visits. On each scheduled and un-
`scheduled visit, adverse events were recorded. The an-
`nual relapse rate and the change of the EDSS score
`were monitored to assess the neurologic course of the
`disease.
`
`Premature Discontinuation
`
`Treatment was discontinued in any of the following
`circumstances: serious or intolerable adverse events,
`
`Gender: Male/Female
`Age (years)
`Mean ± SD
`Range
`Age when first symptom appeared (years)
`Mean ± SD
`Range
`Total number of relapses reported before trial entry
`Mean ± SD
`Range
`Number of relapses reported 2 years before trial entry
`Mean ± SD
`Range
`EDSS score before onset of treatment
`Mean ± SD
`Range
`
`EDSS, Expanded Disability Status Scale.
`
`17/51
`
`35.4 ± 9.8
`19–61
`
`28.5 ± 8.9
`14–52
`
`5.8 ± 3.8
`2–20
`
`2.9 ± 1.5
`1–12
`
`2.7 ± 1.5
`1–8
`
`patient’s decision to discontinue treatment for any rea-
`son, investigator’s judgment that continuation of treat-
`ment was not in the best interest of the patient, poor
`compliance (fewer than 75% of scheduled injections),
`disease progression (EDSS progression over 6.0), and
`loss to follow-up.
`
`Statistics
`
`The aim of the statistical analysis was to assess
`changes in efficacy parameters during the course of the
`treatment. Comparison of changes in EDSS scores and
`in annual relapse rates was performed. Paired t-tests
`were conducted to examine whether the results differed
`significantly from zero. In addition, we compared the
`results of this study to those of the previous open-label
`study in which daily injections were performed in the
`same centers by the same investigators (15). For these
`comparisons we used an unpaired t-test or ␹2 test, as
`appropriate.
`
`RESULTS
`
`Table 1 shows demographic and clinical character-
`istics of the sixty-eight patients who were enrolled
`(consisting of fifty-one females [75%] and seventeen
`males [25%]). Mean age was 35.4 years (± SD 9.8) and
`ranged from 19 to 61 years. The mean age when MS
`
`TABLE 2. Distribution of exacerbations
`
`Number of
`patients
`
`Total number of
`exacerbations
`
`Mean ± SD
`
`Range
`Min–Max
`
`Two years before trial entry
`Two–year completers
`
`68
`41
`
`195
`23
`
`2.9 ± 1.1* (41/68)
`0.56 ± 1.02 (41/41)
`
`1–12
`0–4
`
`* p = 0.0001, comparing baseline relapse frequency in 41 patients who completed 2 years of treat-
`ment with that during the study.
`
`Clin. Neuropharmacol., Vol. 25, No. 1, 2002
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`Page 2 of 5
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`

`
`COP-1 EFFECTIVENESS IN MS ON ALTERNATE DAYS
`
`13
`
`TABLE 3. EDSS scores and difference in EDSS scores at yearly intervals
`
`N Mean
`
`SD Min Max
`
`Mean
`difference
`
`SD
`
`P-value
`
`Screening (first day of study)
`After first year of treatment (last visit of first year-12 months of study)
`After second year of treatment (last visit of second year-24 months of study)
`Screening vs. first year of treatment
`Screening vs. second year of treatment
`First year of treatment vs. second year of treatment
`
`68
`53
`41
`53
`41
`41
`
`2.72
`2.71
`2.79
`
`1.55
`1.59
`1.80
`
`1
`1
`0
`
`8
`7.5
`6.5
`
`0.132
`0.426
`0.29
`
`0.54
`0.99
`0.78
`
`0.084
`0.008
`0.021
`
`EDSS, Expanded Disability Status Scale.
`
`symptoms first appeared was 28.5 years (± SD 8.9) and
`ranged from 14 to 52 years. The total number of self-
`reported exacerbations before trial entry ranged from
`2–20 (mean 5.8 ± SD 3.8). The mean number of exac-
`erbations reported during the 2 years before trial entry
`was 2.9 (± SD 1.5) and ranged from 1 to 12. The mean
`baseline EDSS score was 2.7 (± SD 1.5) and ranged
`from 1 to 8. (One patient with an EDSS score of 8 was
`included in the study by mistake, as well as one patient
`with only a single relapse in the 2-year period before
`entry. Inclusion of these cases did not change the re-
`sults or their significance).
`
`Premature Discontinuation
`
`According to the open-label design of the study, dis-
`continuation was allowed after 1 or 2 years. Of the
`sixty-eight patients enrolled, fifty-three (77.9%) com-
`pleted the first year and forty-one (60.3%) completed
`the second year of treatment. Twenty-seven patients
`(39.7%) dropped out during this period: eight (11.8%)
`as a result of adverse experience, six (8.8%) withdrew
`voluntarily, seven (10.3%) as a result of investigator’s
`judgment, five (7.3%) were lost to follow-up, and one
`(1.5%) as a result of poor compliance and disease pro-
`gression.
`
`Relapses During the Study
`
`Table 2 displays mean values and ranges of the num-
`ber of exacerbations per patient before the study and
`during the first 2 years of the study. At the end of the
`first year, 65% of the patients who were still being
`
`treated remained relapse-free (33/51), corresponding to
`49% of the total cohort. At the end of the second year
`(Fig. 1), 71% of the patients who continued the treat-
`ment throughout the second year (29/41) remained re-
`lapse-free. The annual relapse rate during succeeding
`years decreased. The mean relapse rate for these pa-
`tients who completed 2 years of treatment (n = 41) de-
`creased from 2.9 (± 1.1) in the 2 years before study
`entry to 0.56 (± 1.02) at the end of the second year. This
`represents an 80.8% reduction in relapse rate and is
`highly statistically significant (p = 0.0001).
`
`Disability Accumulation
`
`Evaluation of EDSS scores during the study revealed
`that the condition of most of the forty-one patients who
`completed 2 years of treatment remained stable, and
`that of only a few deteriorated. Table 3 displays EDSS
`scores at screening and after each year of treatment and
`mean differences between EDSS scores at screening
`and after 1 and 2 years of treatment. Differences were
`computed by subtracting the value at an earlier interval
`from the value obtained at the later interval. The results
`obtained show that EDSS scores remained stable dur-
`ing the first year of treatment (p = 0.084) and subse-
`quently mildly deteriorated (Fig. 2).
`
`Adverse Experiences
`
`Table 4 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 events during the study. The
`most frequent adverse event, injection-site reaction,
`
`TABLE 4.
`
`Incidence and frequency of adverse experiences
`
`Number of
`reports
`
`% of
`reports
`
`Number of
`patients
`
`% of
`patients
`
`Total
`Injection site reaction*
`Idiosyncratic systemic adverse reaction
`Rash
`Lymphadenopathy
`
`332
`120
`38
`6
`6
`
`100
`36.1
`11.4
`1.8
`1.8
`
`56
`34
`16
`4
`1
`
`82.4
`60.7
`28.6
`7.1
`1.8
`
`* Including local sensitivity (10.5%), pain (7.8%), edema (6.0%), mass (4.8%), atrophy
`(3.6%), inflammation (0.6%), hemorrhage (0.6%), cyst (0.3%), and other local site reactions
`(1.8%).
`
`Clin. Neuropharmacol., Vol. 25, No. 1, 2002
`
`Page 3 of 5
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`

`
`14
`
`S. FLECHTER ET AL.
`
`TABLE 5. Disease characteristics and results of alternate and daily-treated patients with MS
`
`Number of patients
`Mean disease duration in years (± SD)
`Mean annual relapse rate before 2 years (± SD)
`Mean EDSS score before onset of treatment (± SD)
`Mean relapse rate in the first 2 years of treatment (± SD)
`Mean EDSS score at the end of the second year of treatment (± SD)
`Number of patients who completed two years of treatment (%)
`Number of patients relapse-free at the end of second year of treatment (%)
`Premature terminations (total)
`Due to voluntary withdrawal
`Due to adverse events
`Loss to follow up
`Others
`
`MS, multiple sclerosis; EDSS, Expanded Disability Scale.
`* Data from Meiner et al. (1997).
`
`Alternate-day
`treatment
`
`68
`6.9 (± 0.9)
`1.4 (± 0.6)
`2.7 (± 1.6)
`0.56 (± 1.02)
`2.97 (± 1.80)
`41/68 (60.3%)
`29/41 (70.7%)
`27/68 (39.7%)
`6/27 (22.2%)
`8/27 (29.6%)
`5/27 (18.5%)
`8/27 (29.6%)
`
`Daily
`treatment*
`
`271
`8.3 (± 6.4)
`1.4 (± 0.7)
`3.3 (± 1.8)
`0.3 (± 0.5)
`Not available
`107/271 (39.5%)
`58/107 (54.2%)
`99/271 (36.5%)
`29/99 (29.3%)
`24/99 (34.2%)
`26/99 (26.3%)
`20/99 (20.2%)
`
`was reported in 36% of the total number of reports. A
`self-limited idiosyncratic systemic adverse reaction
`manifested through transient chest pain, palpitations,
`and tachypnea was reported as 16.6% of the total num-
`ber of adverse events reported. These sporadic, brief
`(2–20 minutes) reactions occurred immediately after
`drug administration and resolved without any treat-
`ment. No clinically significant changes were observed
`in any of the routine laboratory examinations.
`In the design of the study, patients were supposed to
`have an EDSS score of 6 or lower; one patient with an
`EDSS of 8, however, was erroneously included. The
`same holds true for another patient who had only a
`single relapse in the 2-year period preceding random-
`ization. We decided to include these patients in the final
`analysis and presentation. However, their exclusion did
`not change the results of the study.
`
`Comparison of Daily with
`Alternate-Day Treatment
`
`The results of the present alternate-day treatment
`were slightly better than those of the previous study
`
`with daily treatment; results were not significantly dif-
`ferent, except for a lower dropout rate in the present
`study (Table 5).
`
`DISCUSSION
`
`Copolymer 1 was introduced for the management of
`MS based on a specific scientific assumption and
`proved useful in animal models of the disease (9,10). Its
`introduction into therapeutic studies, however, has by-
`passed the usual dose-finding phase, and the dose and
`frequency of administration have been slightly arbi-
`trarily determined. Double-blind, placebo-controlled
`studies of Copolymer 1 demonstrated efficacy and
`safety (2,13), and the results of parallel, large-scale,
`open-label studies conducted in Israel support the long-
`term safety of the drug (15). Clinical data that were me-
`ticulously collected in these open-label studies showed
`an impressive reduction in exacerbation rate when
`compared with that in a 2-year period before entry into
`
`FIG. 1. Mean number of exacerbations for the 2 years before
`and the 2 years during treatment.
`
`FIG. 2. Mean differences in Expanded Disability Status Scale
`(EDSS) scores relative to screening score. Ninety-five percent
`confidence intervals are given.
`
`Clin. Neuropharmacol., Vol. 25, No. 1, 2002
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`

`
`COP-1 EFFECTIVENESS IN MS ON ALTERNATE DAYS
`
`15
`
`the study (15). These open-label studies are important
`because they are more similar than Phase IV studies to
`the clinical situation that will occur when the drug
`reaches the open market.
`The study reported here was uncontrolled; therefore,
`all conclusions cannot be used to prove efficacy. Nev-
`ertheless, it should be emphasized that the design of the
`present study was methodologically identical to that of
`the previous open-label study performed by us (15), ex-
`cept that injections were administered on alternate days
`rather than daily. The results of the two studies were
`surprisingly similar in terms of efficacy and tolerability
`as is demonstrated in Table 5; in particular, although
`the populations of both studies were roughly similar,
`the disease severity was reduced by the same degree
`(Table 5). It should be stressed that the dropout rate was
`lower in the alternate-day group than in the daily-
`injection regime (39.7% versus 60.3%, p < 0.01). The
`high rate of premature termination was not necessarily
`caused by inefficacy or an adverse event. During the
`same period, an aggressive campaign for the introduc-
`tion of ß-interferons had a significant effect as well. If
`these results are confirmed, treatment with Copolymer
`1 will become even more desirable than interferon
`therapy, as the side-effect profile is more benign than
`that of IFN-␤. Our results may indicate that the dose of
`20 mg of Copolymer 1 on alternate days already has a
`maximal effect, and daily injections are unnecessary. It
`is possible that the biologic effect of Copolymer 1 is not
`dose-related but is related to the exposure of the im-
`mune system to its presence by the continuity of admin-
`istering the drug with rechallenging the immune sys-
`tem, thus making daily injections unnecessary.
`The results of this study support previous reports
`concerning the safety of Copolymer 1 (2,12–15). The
`majority of adverse events reported were mild and tran-
`sient, most frequently consisting of local injection-site
`reactions, which were reported by thirty-four patients
`(50%). Sixteen patients (23.5%) reported 38 episodes
`of one or more symptoms of the transient self-limited
`reactions (i.e., palpitations, flushing, dyspnea, or chest
`pain), which resolved spontaneously within a short
`time. These events, which were previously reported in
`placebo-controlled Copolymer 1 studies (2,14), did not
`follow any recognizable pattern of appearance, recur-
`rence, and disappearance. Eight patients (11.8%) with-
`drew from the study because of adverse experiences;
`seven of these experiences are believed to be possibly
`or probably related to treatment with Copolymer 1.
`There were no deaths during the study. The frequency
`of adverse experiences reported decreased after the first
`6 months of therapy.
`We recorded very few relapses in patients who
`stayed in the trial. These results are similar to those of
`
`the previously reported phase II double-blind study
`(13), those of our own open-label study (15), and those
`of the multicenter phase III double-blind study con-
`ducted in the U.S. (2).
`
`CONCLUSION
`
`The results of this trial suggest that alternate-day
`treatment with Copolymer 1 is safe, well tolerated, and
`probably as effective as daily Copolymer 1 in reducing
`relapse rate and slowing neurologic deterioration.
`However, these preliminary observations will have to
`be examined in larger studies, preferably comparing
`daily with alternate-day administration of Copolymer 1
`in a blinded manner.
`
`Acknowledgment: The authors are grateful to Martin Rabey
`for reviewing the manuscript.
`
`REFERENCES
`
`1. Interferon beta-1b is effective in relapsing-remitting multiple scle-
`rosis. I. Clinical results of a multicenter, randomized, double-blind,
`placebo-controlled trial. The IFN␤-1b Multiple Sclerosis Study
`Group. Neurology 1993;43:655–61.
`2. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer 1 reduces the
`relapse rate and improves disability in relapsing-remitting multiple
`sclerosis. Results of a phase III multicenter, double-blind, placebo-
`controlled trial. Neurology 1995;45:1268–76.
`3. Jacobs LD, Cookfair DL, Rudick RA. Intramuscular interferon:
`ß-1a for disease progression in relapsing-remitting multiple sclero-
`sis. Ann Neurol 1996;l39:285–94.
`4. Ebers GC, Oger J, Paty DW, et al. The prisms study group preven-
`tion relapses and disability by Interferon: ß-1a subcutaneously in
`multiple sclerosis. Ann Neurol 1997;42:986.
`5. Rudik RA, Cohen JA, Weinstock-Guttman B, et al. Management of
`multiple sclerosis. New Engl J Med 1997;337:1604–11.
`6. Clark W. Therapeutic advances: ß-Interferon for multiple sclerosis.
`J Clin Pharm Therap 1996;21:195–9.
`7. Lublin FD, Whitaker JN, Eideman BH, et al. Management of pa-
`tients receiving interferon: ß-1b for multiple sclerosis: report of a
`consensus conference. Neurology 1996;46:12–8.
`8. Goodkin DE, Rudick RA. Multiple sclerosis: advances in clinical
`trial design, treatment and future prespectives. Berlin, Germany:
`Springer-Verlarg, 1996:153–172.
`9. Arnon R, Teitelbaum D, Sela M. Suppression of experimental aller-
`gic encephalomyelitis by Cop 1: relevance to multiple sclerosis. Isr
`J Med Sci 1989;25:686–9.
`10. Teitelbaum D, Arnon R, Sela M. Copolymer 1: from basic research
`to clinical application. Cell Mol Life Sci 1997;53:24–8.
`11. Borenstein MB, Miller A, Teitelbaum D, et al. Multiple sclerosis:
`trial of a synthetic polypeptide. Ann Neurol 1982;11:317–9.
`12. Borenstein MB, Miller A, Slagle S, et al. A pilot trial of Cop 1 in
`exacerbating-remitting multiple sclerosis. New Engl J Med 1987;
`317:408–14.
`13. Borenstein 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;41:533–9.
`14. Korczyn AD and Nisipeanu P. Safety profile of Copolymer 1:
`Analysis of cumulative experience in the United States and Israel. J
`Neurol 1996;243:23–6.
`15. Meiner Z, Kott E, Schechter D, et al. Copolymer 1 in relapsing-
`remitting multiple sclerosis: a multicenter trial. In: Abramsky O and
`Ovadia H, ed. Frontiers in Multiple Sclerosis London: Martin Dun-
`itz, 1997:213–21.
`
`Clin. Neuropharmacol., Vol. 25, No. 1, 2002
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`Page 5 of 5