Jonathan Kay, MD


July 01, 2014

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Coming to a Market Near You: Biosimilars

Hello. I am Dr. Jonathan Kay, Professor of Medicine and Director of Clinical Research in the Division of Rheumatology at UMass Memorial Medical Center and the University of Massachusetts Medical School, both in Worcester, Massachusetts.

Welcome to Medscape. I am in Paris at the 2014 European League Against Rheumatism (EULAR) Annual Scientific Meeting. I am going to talk about several of the presentations that were quite significant here.

The topic that I am going to discuss today is biosimilars. Biosimilars are coming to the market. These have already been approved in the European Union (EU) and are available in several member states of the EU. There were several presentations at the EULAR meeting about biosimilars.

HD203: Biosimilar Etanercept

The first was Prof. Bae[1] from Seoul, South Korea, who presented data from a randomized, double-blind phase 3 equivalence trial comparing a biosimilar etanercept HD203 with Enbrel®, the reference etanercept, in combination with methotrexate in patients with rheumatoid arthritis. The objective of this study was to evaluate the equivalence in effectiveness between the 2 drugs, and also to compare safety of HD203 with that of Enbrel. They studied 294 patients, 147 of whom were randomly assigned to the biosimilar and another 147 who were randomly assigned to Enbrel.

The proportion of patients who achieved the primary endpoint, the American College of Rheumatology (ACR)-20 score at week 24, was not significantly different between the 2 groups. Equivalence in effectiveness was demonstrated within predefined margins. There were no statistically significant differences in the proportions of patients who achieved an ACR20 at week 12 or at week 48. Similar trends were seen for the ACR50 and the ACR70. The proportion of patients who achieved an ACR50 at week 24 and at week 48 was higher with HD203 than with Enbrel, but not outside of the prespecified equivalence margins. There were no statistically significant differences between the groups for secondary endpoints. The study met its primary endpoint of demonstrating equivalence in effectiveness of HD203 compared with that of the reference product, Enbrel. HD203 was well tolerated, with a safety profile comparable with that of Enbrel in this population of all Korean patients with rheumatoid arthritis.

Thus, this phase 3 study suggests that the biosimilar etanercept is essentially equivalent to Enbrel. In the United States, the patent for Enbrel was extended to 2028, so we are not going to see biosimilar etanercept in the United States. But in other countries, when the patent for etanercept expires, this medication likely will be introduced if it meets with regulatory approval. These data suggest that regulatory support will be anticipated.

BOW015: Biosimilar Infliximab

The second oral presentation at that session was my own presentation[2] about a biosimilar infliximab (BOW015) compared with reference infliximab (Remicade®). This study was conducted in India at 23 sites in 189 patients who were randomly assigned 2 to 1, with twice as many patients on the biosimilar as on the reference infliximab. This was a phase 3, double-blind, active comparator clinical trial which also compared effectiveness and safety of the biosimilar with the reference product.

This study is significant in that we measured early time points, before the primary endpoint at 16 weeks. We were able to present a time-response curve that demonstrated very close similarity between the biosimilar and the reference product at each of these time points. The study met its primary endpoint, which was the ACR20 at week 16, with ACR20s being 89.9% and 86.4% in the biosimilar and reference infliximab groups, respectively. This was well within the prespecified equivalence margin of 23%, and it also met the equivalence margins of 15% which are used in several of the other biosimilar trials, most notably that of the Celltrion CTP-13 infliximab biosimilar. The maximum treatment difference for the per-protocol population was only 3.4%, and for the intent-to-treat population it was 6.4% at week 2.

The safety profile for both of these medications was similar in this population at high risk of developing tuberculosis. There were 3 cases of tuberculosis in the biosimilar-treated group, and none were observed up to week 16 in the reference infliximab group, but this being a rare event, the difference was not statistically significant. There was no statistically significant difference in adverse event incidence by body system. Infectious adverse events occurred in 15.8% of the biosimilar-treated patients and in 9.5% of the reference product-treated patients, but this difference was not statistically significant. Immunogenicity was similar, with antibodies detected in 22% of the BOW015-treated and 35.5% of the reference infliximab-treated patients at week 14. There was high concurrence between the BOW015-specific and reference infliximab-specific amino acids among all patients, regardless of treatment. This did not seem to influence effectiveness in either of the groups. In summary, this study showed equivalent effectiveness and safety, as well as equivalent potency in the biosimilar infliximab BOW015. This is the first clinical trial of a biosimilar infliximab to demonstrate and report the kinetics of response to treatment prior to the plateau phase.

This early phase, when the sensitivity to change over time is greatest, is the most sensitive timeframe in which to compare a biosimilar with a reference product, and the comparable proportion of responders at each of these early time points and at week 16 (which was the primary endpoint) provides convincing evidence of therapeutic equivalence. The high ACR20 response rates are consistent with those observed in other rheumatoid arthritis clinical trials, such as the TICORA trial,[3] in which patients who had not failed methotrexate were all treated with an active drug. This trial design sets a new paradigm for comparison of biosimilars with reference products, looking at early time points as a sensitive window in which to look for the equivalence of the 2 molecules.

CTP-13: Biosimilar Infliximab

Two more studies were presented in poster form, which I will mention briefly. One was a study[4] looking at structural progression in patients treated with CTP-13, the biosimilar infliximab produced by Celltrion, which is approved in the EU and Canada. This study, PLANETRA, compared patients treated with either the biosimilar CTP-13 or innovator infliximab and was presented by Prof. Yoo from South Korea.

In the PLANETRA study, 606 patients were randomly assigned to receive either CTP-13 or reference infliximab in a 1:1 randomization, and were treated for 54 weeks. Of these patients, 336 had radiographs both at baseline and at week 54, and the mean changes from baseline in joint space narrowing and erosion at week 54 were not significantly different between the 2 groups.

This is not surprising, given that CTP-3 has been demonstrated to be biosimilar to reference infliximab in in vitro, pharmacokinetic, and pharmacodynamic assays and in 2 large clinical trials. One is the PLANETRA study in rheumatoid arthritis, and the other was the PLANETAS study[5] conducted in ankylosing spondylitis. It's unclear whether radiographic progression needs to be examined in studies comparing a biosimilar with a reference product, because we know that the reference biological agents inhibit structural progression.

PF-05280586: Biosimilar Rituximab

The final study[6] that was presented was a poster comparing the pharmacokinetics of PF-05280586, a potential biosimilar rituximab produced by Pfizer, with rituximab from the United States or from the EU. This study looked at the pharmacokinetic profiles of the biosimilar rituximab compared with US-sourced rituximab and EU-sourced rituximab in 198 patients who were randomly assigned to 1 of 3 groups.

In this study, the pharmacokinetic and safety profiles were similar for each of the 3 groups, suggesting the pharmacokinetic similarity of PF-05280586 with that of rituximab sourced either from the US or the EU, and that the low incidence of treatment-related adverse events and discontinuations suggests similar safety.

In summary, at this meeting, 4 abstracts were presented that looked at biosimilar infliximab, biosimilar etanercept, and biosimilar rituximab, and continue to show similarity of the biosimilars to the reference products. The increasing number of biosimilars that are being studied and presented shows promise for biosimilars as a new paradigm in the treatment of patients with rheumatic diseases.

Thank you very much for you attention. I look forward to seeing you again on Medscape.


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