Journal of the Neurological Sciences 197 (2002) 51 – 55
`
`www.elsevier.com/locate/jns
`
`Comparison of glatiramer acetate (CopaxoneR) and interferon h-1b
`(BetaferonR) in multiple sclerosis patients: an open-label 2-year follow-up
`S. Flechter a,*,1, J. Vardi b, L. Pollak a, J.M. Rabey a
`
`aThe MS Clinical Research and Therapy Service, Department of Neurology, Assaf Harofeh Medical Center, Zerifin 70300, Israel
`bDepartment of Neurology, Shaare Zedek Medical Center, Jerusalem, Israel
`
`Received 2 August 2001; received in revised form 11 February 2002; accepted 12 February 2002
`
`Abstract
`
`Objective: To compare the clinical efficacy, as expressed by relapse rate and disability accumulation, and safety profile of glatiramer
`acetate (CopaxoneR; COP-1) and Interferon h-1b (BetaferonR; IFNh-1b) administered to multiple sclerosis patients during a 2-year follow-
`up on an open-label parallel design, as compared to their clinical condition in the 2-year period prior to treatment. Background: Copaxone
`and IFNh-1b have been recently introduced for the treatment of relapsing forms of MS. Both medications have been proven to have a
`relatively safe profile and are used extensively world-wide. Methods: 58 consecutive patients with relapsing forms of MS were enrolled from
`the MS out-patient clinic, during three months. After being informed in detail of the two approved treatment options existing at the time in
`Israel, the patients chose by themselves to receive either: (a) Copaxone 20 mg subcutaneously (sc) daily (Copaxone dly, 20 patients), or (b)
`Copaxone 20 mg sc alternate-day (Copaxone alt, 18 patients) or (c) IFNh-1b 8 MIU sc in alternate day (20 patients). Mean relapse rate/year
`and mean EDSS/year were calculated for each group of patients during the 2 years prior to the onset of treatment, and during the year prior to
`the onset of treatment. Statistical significance was observed in the relapse rate in the year prior to the onset of treatment between the IFNh-1b
`group and the two Copaxone groups ( p = 0.05). This statistical difference has no effect on the overall data of the 2 years prior to starting the
`treatment and on the results. No statistical significance was observed in the total number of relapses, and on the 2-year relapse rate, prior to
`the onset of treatment. Mean relapse rate/year and mean EDSS/year were calculated for each group during the first and second year of
`treatment. Wilcoxon anaylsis for clinical data and chi-square for adverse events were applied. Results: The three groups were statistically
`comparable concerning mean relapse/year in the 2 years before the trial started and no statistical significance was observed among the three
`groups. A statistically significant reduction in the mean relapse rate in the 2 years after onset of treatment was observed in the three group of
`patients: Copaxone daily (dly) 1.1 F 0.6 ( p = 0.0001); Copaxone alternate (alt) 0.9 F 0.6 ( p = 0.0004) and IFNh-1b 1.2 F 0.7 ( p = 0.0001).
`Disability as expressed by EDSS score prior to the onset of treatment and after 2 years of treatment showed deterioration in the three groups
`although more significant in the Copaxone groups: Copaxone dly 3.3 F 1.4 to 3.8 F 1.6 ( p = 0.007); Copaxone alt 2.4 F 1.1 to 2.8 F 1.3
`( p = 0.04); IFNh-1b 3.1 F 1.3 to 3.3 F 2.0 (N.S.). The most common adverse events reported were: (1) flu-like symptoms 7 pts (35%) in the
`IFNh-1b group; 10 pts (26%) of the two Copaxone groups; (2) increased spasticity of lower limbs 3 pts (15%), only in the IFNh-1b group;
`(3) site injection reaction (SIR): 16 SIR (80%) in the IFNh-1b group; 12 SIR (67%) in the Copaxone alt group; 14 SIR (70%) in the
`Copaxone dly group; and (4) systemic reaction 3 pts (15%) in the IFNh-1b group; 4 pts (22%) in the Copaxone alt group; 6 pts (30%) in the
`Copaxone dly group. Premature termination occurred in five patients treated with Copaxone (3 in the alternate group and 2 in the daily
`group). Conclusion: The present study, despite the limitations of an open-label study, shows that Copaxone dly, Copaxone alt and IFNh-1b
`treatment seem to be equally effective for the control of exacerbations in MS. The adverse event profile, as reported by the patients, was also
`similar. However, the adverse events profile registered indicated that Copaxone is somewhat less detrimental, whereas disability as measured
`by EDSS accumulation showed that the interferon h-1b patients demonstrated a slower progression of the disability. D 2002 Elsevier Science
`B.V. All rights reserved.
`
`Keywords: Multiple sclerosis; Glatiramer acetate; Interferon h-1b; Follow-up
`
`1. Introduction
`
`* Corresponding author. Tel.: +972-8-9779878; fax: +972-8-9779879.
`1 Affiliated with Tel-Aviv University Sackler School of Medicine, Tel-
`Aviv, Israel.
`
`Multiple sclerosis (MS) is an inflammatory demyelinating
`immune mediated disease which may present in relapsing or
`progressive form. The prime task of therapy in the relapsing
`
`0022-510X/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved.
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`52
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`S. Flechter et al. / Journal of the Neurological Sciences 197 (2002) 51–55
`
`forms of MS is to prevent the relapses and to slow down the
`neurological deterioration.
`Recently, Interferon h-1b (BetaferonR), Interferon h-1a
`(RebifR, AvonexR) and Copolymer-1 (COP-1, Glatiramer
`Acetate, CopaxoneR) were shown to decrease the relapse
`rate [1 – 7] and to slow down the accumulation of the neuro-
`logical disability [as measured by the expanded disability
`status scale (EDSS)] [8 – 12]. All three products have been
`approved for the treatment of relapsing MS. Since the
`decision of injecting Copaxone 20 mg sc on a daily basis
`was an arbitrary one based on pre-clinical studies [13,14], we
`have decided to compare the effect of alternate-day injection
`vs. daily injection. Moreover, we assume that the effect of
`Copaxone is not dose related, but is related to the exposure of
`the immune system to its presence.
`We report the results of a 2-year open-label prospective
`follow-up with Copaxone and IFNh-1b in relapsing forms of
`MS. The study was performed in an open-label design aimed
`at evaluating the clinical course of the disease, as expressed
`by re lapse rate and disability accumulation and to evaluate
`the long-term safety, in a population of 58 relapsing MS
`patients divided into three groups, 2 years prior to starting
`the treatment and within 2 years of treatment; two groups of
`patients receiving 20 mg of Copaxone sc on a daily or
`alternate-day basis, and a third group of patients, each patient
`received 8 MIU of IFNh-1b sc on an alternate-day basis.
`
`2. Patients and methods
`
`Fifty-eight consecutive MS patients with clinically defi-
`nite MS [15], who were followed in our MS clinic for more
`that 2 years before enrolling to the study, were enrolled on a
`randomly basis in a 3-month period. In order to be eligible for
`entry into the study, the patients had to meet the following
`inclusion criteria: patients were of both genders; 18 years and
`older, no significant neurological, psychiatric, hematologic,
`renal, hepatic, endocrinological, cardiovascular, cerebro-vas-
`cular, active malignancy and auto-immune diseases had to be
`present. Women of child-bearing potential had to practice a
`clinically accepted method of contraception. No immune-
`modulating drug should be used in the three months prior to
`entering the study. The drugs available at that time in Israel,
`namely: Copaxone and Betaferon, were presented by the
`treating neurologist in detail to each patient, explaining very
`carefully the diversity between the two drugs. In addition,
`patients were given the opportunity to choose between
`Copaxone on daily injection or on every other day. After
`considering the possible benefits and adverse events of each
`drug, the patient alone decided on which of the options to take
`and a written consent for the treatment was obtained. Once
`each arm was filled, by the patients free election, it was
`closed. The enrolment period lasted 3 months. A pre-con-
`dition to inclusion in the study was at least two exacerbations
`documented by a neurologist, and by reviewing the medical
`charts, during the 2 years prior to starting the treatment. The
`
`EDSS in every patient had to be stable for at least six months
`before starting the treatment. Patients’ evaluation was per-
`formed on scheduled visit every 3 months by a qualified
`neurologist on the MS out-patient clinic, and included phys-
`ical neurological and laboratory examinations (haematologic,
`urinalysis, blood chemistry). During each visit, adverse
`events were recorded. In the case of the appearance of an
`acute relapse (which was defined as the appearance of a new
`neurological symptom, or severe deterioration in a pre-exist-
`ing symptom that lasted for at least 24 h causing the
`deterioration in the EDSS with 1 point), the patient was
`examined on an unscheduled visit within 1 to 3 days after the
`onset of symptoms and was treated with corticosteroids
`according to the severity of the presenting symptom (1 g of
`prednisolone intravenous for five consecutive days). Symp-
`tomatic therapy was permitted if required. Assessment of the
`course of the disease was done by monitoring the annual
`relapse rate and the change of the EDSS score. Once an acute
`relapse occurred, the EDSS registered on the unscheduled
`visit was not taken into account on the statistical evaluation.
`Compliance of the treatment was assessed by specialised
`nurses who were involved with each patient from the begin-
`ning of the treatment. The data obtained during the 2-year
`follow-up period were compared with the data of the same
`patients registered in our files during the 2 years of follow-up
`in the MS clinic, prior to starting the treatment.
`The medication was supplied to each patient by the
`respective medical insurance company.
`According to the methods described, 58 consecutive
`patients, comprising 43 females (74%) and 15 males
`(26%), were assigned into three groups. Group 1 comprised
`20 patients, 15 females (75%) and 5 males (25%), who
`received IFNh-1b 8 MIU sc by alternate-day injection;
`group 2 comprised 18 patients, 15 females (83%) and 3
`males (17%), who received Copaxone 20 mg sc by alter-
`nate-day injection and group 3 comprised 20 patients, 13
`females (65%) and 7 males (35%), who received 20 mg sc
`Copaxone by daily injection.
`
`2.1. Statistics
`
`Statistical analysis using the Wilcoxon and chi-square
`analysis was carried out to evaluate changes in the param-
`eters during the course of the treatment. Changes in the
`annual relapse rate and in the EDSS score were compared,
`to evaluate whether the results differed significantly among
`groups.
`
`3. Results
`
`All three groups were comparable considering gender,
`mean age, mean disease duration prior to the onset of treat-
`ment, mean total number of relapses 2 years prior to the onset
`of treatment and mean EDSS score prior to the inclusion in
`this study.
`
`Page 2 of 5
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`S. Flechter et al. / Journal of the Neurological Sciences 197 (2002) 51–55
`
`53
`
`Fig. 1. Difference in relapse rate 2 years and 1 year prior to the onset of treatment and 1 year and 2 years after the onset of treatment.
`
`3.1. Exacerbations during the treatment
`
`Fig. 1 demonstrates the differences in number of relapses,
`as well as the differences in relapse rate, prior to and after the
`onset of the treatment. The difference between the total
`number of relapses in the year prior to the onset of treatment
`and the number of relapses during the first year of treatment
`was statistically significant for all groups (INFh-1b mean
`1.6 F 1.3 p = 0.0001; Copaxone alternate day mean 1.1 F 0.7
`p = 0.0005; Copaxone daily mean 1.0 F 0.9 p = 0.0007). The
`mean difference between relapse rate in the 2 years prior to
`the onset of treatment and the 2 years after starting the
`treatment was significant for all groups (IFNh-1b mean 1.2
`F 0.7 p = 0.0001; Copaxone daily mean 1.1 F 0.6 p = 0.0001,
`Copaxone alternate day mean 0.9 F 0.6 p = 0.0004). Fifty
`relapses were registered during the 2 years of follow-up;
`
`22 on the Betaferon group, 16 on the Copaxone alternate-day
`group, and 12 on the Copaxone daily group. Twenty-six
`relapses were considered of clinical significance (10 in the
`Betaferon group, 9 in the Copaxone alternate group and 7 in
`the Copaxone daily group) and required hospitalisation and
`treatment with a course of prednisolone according to the
`protocol mentioned above.
`
`3.2. Disability
`
`Analysis conducted on the differences between EDSS
`scores are presented in Fig. 2. EDSS registered during un-
`scheduled visit because of an acute relapse was not included
`in the statistical evaluation. EDSS scores 2 years after onset of
`treatment were significantly higher than EDSS scores prior
`to the onset of treatment for the Copaxone daily group
`
`Fig. 2. Difference in EDSS score prior to and after 1 year and 2 years of treatment.
`
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`54
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`S. Flechter et al. / Journal of the Neurological Sciences 197 (2002) 51–55
`
`( p = 0.007), and Copaxone alternate-day group ( p = 0.04).
`No significant difference was observed in the EDSS score in
`the IFNh-1b ( p = 0.3). The results demonstrated have to be
`considered carefully, since the groups were composed of a
`small number of patients and the duration of the follow-up
`was 2 years.
`
`treated group, and two patients from the Copaxone daily
`treated group. No drop-outs were observed in the IFNh-1b
`group. The five patients who dropped-out were assigned for
`interferon treatment, but were not
`included in the final
`analysis.
`
`3.3. Adverse events
`
`4. Discussion
`
`A chi-square analysis was applied for analysis of the
`major adverse events occurring at least once per patient and
`at least in 5% of patients in each group. The results were
`summarised in Table 1. No statistically significant differ-
`ences were found among the three groups. Flu-like symp-
`toms were observed in 7 (35%) in the IFNh-1b group;
`increased spasticity of lower limbs occurred in 3 (15%) in
`the IFNh-1b group. Local injections site reactions were
`reported as 16 (80%) in the IFNh-1b group, 12 (67%) in the
`Copaxone alternate-day group, and 14 (70%) in the Copax-
`one daily group. Depression was observed in 11 patients, 4
`(20%) in the IFNh-1b group, and 7 (18%) in the Copaxone
`groups. A systematic adverse reaction, manifested by chest
`pain, palpitations and tachypnea was reported by 3 patients
`(15%) in the IFNh-1b group, 4 (22%) in the Copaxone
`alternate-day group, and 6 (30%), in the Copaxone daily
`group. These reactions occurred immediately following
`drug administration, and resolved without any treatment.
`Some other systematic reactions such as lymphadenopathy
`were observed in 2 patients (10%) in the Copaxone daily
`group. Lypodystrophy was observed in 3 patients (15%) in
`the Copaxone daily group. Adverse reactions were reported
`especially during the first six months of treatment. The
`majority of them resolved in a short time. Routine labora-
`tory examinations showed no clinically significant changes.
`
`3.4. Premature termination
`
`Table 1 summarises the reasons for termination in all
`three groups of patients. Of the 58 patients who started the
`treatment, 5 patients dropped out during the first 2 years of
`treatment. Three patients from the Copaxone alternate-day
`
`Both IFNh-1b and Copaxone in well-designed studies
`(double blind placebo control) were found to be effective in
`the treatment of multiple sclerosis reducing the number of
`exacerbations, and modulating the course of the disease as
`shown by EDSS accumulation [3,4,7,10].
`In the present study, we report a 2-year follow-up of an
`open-label parallel design follow-up, comparing Copaxone
`(daily and alternate-day administration) and IFNh-1b. Our
`follow-up shows that there was a significant benefit in
`decreasing the relapse rate in MS in all three groups, without
`any difference among them. These data, despite the rela-
`tively small number of patients in each group and the open-
`label design, show similar results with those published in
`the previous studies of IFNh-1b and the Copaxone [9,17].
`The data presented here showing that Copaxone on
`alternate-day injection is equally effective to Copaxone
`daily injection have to be evaluated very carefully since
`the study performed was an open-label uncontrolled one,
`and further studies should be considered to confirm results.
`The safety profile observed during our follow-up was
`similar to that registered in previous studies [4,10,16].
`Adverse experiences were reported by 16 (80%) patients
`of the Copaxone daily injected group, 14 (78%) patients of
`the Copaxone alternate-day injected group and 17 (85%)
`patients of the IFNh-1b group. The most frequent being the
`local injection site reaction observed in all three groups,
`followed by flu-like symptoms reported by the IFNh-1b
`injected group, transient self-limited systematic reactions
`(i.e. flushing, tachycardia, tachypnea, dyspnea, chest pain)
`which resolved spontaneously within a short time. Three
`patients (16.6%) of the Copaxone alternate-day injection
`group withdrew from the treatment because of increasing
`
`Table 1
`Major adverse events and* premature termination, occurring at least one per patient and at least in 5% of patients in each group
`
`Adverse events
`
`Group
`
`Betaferon
`
`Copaxone alternate day
`
`Copaxone daily
`
`P value
`
`Flu-like symptoms
`Increased spasticity of the lower limbs
`Site of injection reaction
`Systemic reaction
`Lymphadenopathy
`Lypodystrophy
`Severe clinical deterioration *
`Patient’s decision *
`Adverse events *
`Acute relapse+* severe deterioration
`Low compliance *
`
`No. (%)
`No. (%)
`No. (%)
`No. (%)
`No. (%)
`No. (%)
`No. (%)
`No. (%)
`No. (%)
`No. (%)
`
`7 (35.5)
`3 (15.0)
`16 (80.0)
`3 (15.0)
`–
`–
`
`1 (5.5)
`–
`12 (67.0)
`4 (22.2)
`–
`–
`1 (5.5)
`1 (5.5)
`
`1 (5.5)
`
`N.S
`
`N.S
`N.S
`
`2 (10.0)
`–
`14 (70.0)
`6 (30.0)
`2 (10.0)
`3 (15.0)
`
`1 (5.0)
`1 (5.0)
`
`Page 4 of 5
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`S. Flechter et al. / Journal of the Neurological Sciences 197 (2002) 51–55
`
`55
`
`disability and poor compliance. Two patients (10%) of the
`Copaxone daily injection group stopped the treatment
`because of adverse events and acute relapse. No withdrawal
`was observed in the IFNh-1b group. The frequency of the
`adverse events decreased after a few months of treatment in
`all three groups.
`Although our follow-up label prospective uncontrolled
`study and its results should be considered carefully, it still
`demonstrates that Copaxone on alternate-day injection has
`the same beneficial effect as daily injection on the relapse
`rate, and is equally effective as IFNh-1b considering this
`parameter, as it was shown in previous studies [3,4,7,10]. On
`the other hand, assessment of disability accumulation as
`demonstrated by the EDSS score shows that in the Copaxone
`groups disability accumulation was higher than Betaferon-
`treated patients. This change may not necessarily reflect
`disease progression (since there are many reasons for EDSS
`to fluctuate in a small sample, particularly in the 2.5 – 4.0
`range); that observation, too, has to be considered carefully
`since the follow-up is an open one. Adverse events were
`manageable in most of the patients on both medications.
`In summary, although our study is an open-label one, it
`shows that IFNh-1b injected subcutaneously on alternate
`day, and Copaxone injected subcutaneously either daily or
`on alternate day, may modulate disease activity in a similar
`way and to a similar extent.
`The choice of the appropriate medication for each patient
`still remains an individual decision since the effects of
`IFNh-1b and Copaxone seem to be similar [17,18]. The
`fact that Copaxone injected on alternate day seems to be
`equally effective as the Copaxone injected daily is important
`to patients with injection-related adverse events and, from
`an economic point of view, as a cost-effective measure.
`Moreover, considering that there is no available data sup-
`porting daily vs. alternate-day Copaxone injection, in our
`view a well-designed post-marketing study is required, in
`order to confirm or refute the results obtained in our study.
`
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