BOSTON — A new generic version of glatiramer acetate for multiple sclerosis (MS) has shown similar results to the branded agent (Copaxone, Teva Pharmaceuticals) in terms of reduction in lesions on brain imaging and adverse effects in a 700-patient clinical trial.

The data were deemed sufficient to show equivalence to the Copaxone branded product, as stipulated in the design of the study, lead investigator, Jeffrey Cohen, MD, from the Cleveland Clinic in Ohio, reported during his presentation here at MS Boston 2014, the 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS) meeting.

Commenting on the data for Medscape Medical News, session cochair Tanuja Chitnis, MD,Brigham and Women's Hospital, Boston, said: "I think this study did show comparable effects of the new generic with Copaxone but I would ask whether it was sufficiently powered in all aspects in terms of duration of exposure. I personally would like to see more data on clinical efficacy as well as pharmacodynamics. It is important to know if the drugs are working in the same way, and longer term MRI data would be helpful."

But Jerry Wolinsky, MD, from the University of Texas Health Science Center at Houston, who has been involved in many trials with glatiramer acetate, said he did not think it should be necessary for biosimilars of complex molecules like this to show absolute equivalence on long-term outcomes. "Just as long as it looks the same, behaves the same and has similar effects on reasonable biomarkers, then I would say it is a viable generic," he told Medscape Medical News.

Dr. Cohen explained that the generic product, which has been developed by the Dutch company Synthon, is 1 of 3 generic versions of Copaxone that are ready to hit the market. The other 2 formulations have been submitted for approval without clinical trials, as is usual for generic drugs.

Dr. Cohen noted that unlike most drugs, which are relatively simple molecules and can be easily copied, glatiramer acetate is a complex mixture of peptides, so it is more difficult to make an identical product. "Minor changes in the manufacturing process may have significant changes in safety or benefits, so this generates many problems for generic manufacturers. This begs the question as to how much testing should a new generic product be submitted to," he said.

The US Food and Drug Administration has not decided yet what standards are needed for generic versions of such drugs, but the European Medicines Agency (EMA) has requested a clinical trial showing equivalence, and the GATE study was developed with the EMA, Dr. Cohen reported.

Dr. Cohen said that generic versions of the older MS drugs such as glatiramer acetate and the beta-interferons were much needed to make treatment more affordable. "All MS medications are very expensive, and patients struggle to afford the medications. In the US patients have substantial co-pays even if they are insured and some insurers restrict which drugs can be prescribed."

He explained that a compromise was reached in terms of the outcomes used in the GATE trial. "It was recognised that this is a generic agent which needs to be cheaper than the branded product so a very large trial with clinical outcomes is not really feasible. But at the same time we need enough patients to get some meaningful efficacy results. It was therefore agreed to use MRI lesions as the primary endpoint. This is not accepted for new branded drugs which have to show reduction of clinical relapses rates."

Equivalence Demonstrated

The GATE study involved 735 patients with relapsing-remitting MS who had had at least 1 relapse in the prior year (mean 1.8) and had 1–15 T1 gadolinium-enhancing lesions on screening MRI (mean 2.5). They were randomized to generic glatiramer acetate (n = 353), the branded Copaxone (n = 357), or placebo (n = 84).

Results showed that at months 7 to 9 (end of the randomized treatment phase) patients on both generic and branded Copaxone had about half the amount of T1 gadolinium-enhancing lesions (the primary endpoint) as those on placebo, with a geometric mean ratio for the combined active treatments of 0.48. The placebo patients had an estimated mean of 0.8 gadolinium-enhancing lesions compared with 0.42 for the generic product and 0.39 for Copaxone.

Dr. Cohen reported that the new generic formulation was equivalent to the branded Copaxone according to the criteria stipulated, with a geometric mean ratio of 1.097. The 95% confidence limits of 0.884–1362, were within those stipulated (0.727–1.375) to show equivalence. Other MRI endpoints showed similar results.

Other MRI Results: Median Values (Min-Max)

Endpoint Generic Glatiramer Acetate Copaxone Placebo
Cumulative unique active lesions 6.0 (0–151) 5.0 (0–92) 8.0 (0–59)
Change in T2 number 5.0 (-1.0–147.0) 4.0 (-2.0–71.0) 7.0 (0–50)
Change in T2 volume (mm3) 277 (-22481–10426) 163 (-9892–9084) 443 (-38374–13006)
Change in T1-hypo lesion volume (mm3) 0.0 (-280–1444.0) 0.0 (-372–816) 0.0 (0–3610)
Change in brain volume (cm3) -0.5 (-4.5–2.8) -0.5 (-4.3–2.1) -0.6 (-3.6–1.4)


Dr. Cohen said the clinical endpoints were also consistent with the expected profile of glatiramer acetate.

Clinical Results

Endpoint Generic Glatiramer Acetate Copaxone Placebo
Annualized relapse rate (95% CI) 0.31 (0.20–0.48) 0.41 (0.27–0.63) 0.39 (0.22–0.67)
Subjects without relapse (%) 281 (79.6%) 263 (73.7%) 62 (73.8%)
Change in EDSS (Median (min-max) 0.0 (-2.5–2.0) 0.0 (-3.0–4.5) 0.0 (-2.0–1.5)
Free from disease activity (%) 33 (9.3%) 32 (9.0%) 6 (7.1%)

CI = confidence interval; EDSS = expanded disability status scale

Adverse events also showed a very similar profile between the 2 active treatments.

During the discussion, the lack of difference in annualized relapse rates between the active treatments and placebo was highlighted, and this was said to be surprising given that Copaxone was associated with a 30% reduction in relapse rate vs placebo in its original trial. Dr. Cohen said he could not explain why the impressive reduction in MRI endpoints with both formulations was not shown in these relapse rate results.

A question from the audience addressed whether the study looked at black holes — small holes in the brain seen in MS that have been reduced with glatiramer acetate. Dr. Cohen said they hadn't looked at this endpoint.

Another question focused on the exclusion of patients without a gadolinium-enhancing lesion at baseline, with the implication that this may limit applicability of the results. But Dr. Wolinsky said he thought it was a reasonable approach to enrich the population like this to make it easier to show an effect.

The study was sponsored by Synthon. Dr. Cohen reports the following disclosures: consulting with EMD Serono, Genentech, Genzyme, Innate Immunotherapeutics, Novartis, Vaccinex; contracted research for Genzyme, Novartis, Receptos, Synthon, Teva, Vaccinex. Dr. Wolinsky has received compensation for service on steering committees or data monitoring boards for Novartis, Roche, Sanofi, and Teva; reimbursement for services as consultant to AbbVie, Alkermes, Athersys, Bayer HealthCare, Celgene, EMD Serono, Genentech, Genzyme, Novartis, Roche, Janssen R&D, Teva, and XenoPort; royalty payments through the University of Texas Health Science Center at Houston for monoclonal antibodies outlicensed to Chemicon International; and research support from Genzyme, Sanofi, and the National Institutes of Health through the University of Texas Health Science Center at Houston.

MS Boston 2014: 2014 Joint Americas and European Committees for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS). Abstract FC1.2 Presented September 12, 2014.


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