Comparative Clinical Efficacy and Safety of the Proposed Biosimilar ABP 710 With Infliximab Reference Product in Patients With Rheumatoid Arthritis

Mark C. Genovese; Juan Sanchez-Burson; MyungShin Oh; Eva Balazs; Jeffrey Neal; Andrea Everding; Tomas Hala; Rafal Wojciechowski; Gary Fanjiang; Stanley Cohen

Disclosures

Arthritis Res Ther. 2020;22(60) 

In This Article

Discussion

In this study, we have established similarity of efficacy of ABP 710 and infliximab RP in patients with moderate to severe RA by demonstrating no clinically meaningful differences between the proposed biosimilar ABP 710 and the infliximab RP. This study design met FDA and EMA guidelines contributing to the development and approval of biosimilar agents. The primary efficacy endpoint was RD of ACR20 at week 22. The 2-sided 90% CI of the RD of ACR20 between ABP 710 and infliximab RP was within the lower bound of the prespecified equivalence margin but exceeded the upper bound by 0.96%. An additional analysis was performed to account for an imbalance in baseline demographic and disease characteristics, which may have contributed to the observed difference between the ABP 710 and RP treatment groups. When covariates identified to be predictive of ACR20 by a stratified conditional logistic regression were selected for adjustment, the resulting estimates of RD of ACR20 at week 22 and the associated 90% CIs were narrowed such that it was contained within the prespecified equivalence margin.

ACR20 is a dichotomous measure used as the primary efficacy endpoint for this study based on consistency with the originator and precedence from prior studies evaluating biosimilars. However, continuous endpoints such as DAS28-CRP and hybrid ACR may be more sensitive for a comparison of two active and very similar products as is the case during clinical evaluation of a proposed biosimilar with its RP. Based on results obtained at week 22 and over the entire study, both DAS28-CRP and hybrid ACR showed minimal differences between treatment groups and are supportive of similarity of ABP 710 and RP. Specifically, at week 22, the difference between treatment groups of ABP 710 and infliximab RP in the DAS28-CRP mean change from baseline was − 0.01 with a 90% CI of − 0.20, 0.17 and a 95% CI of − 0.24, 0.21. This difference of less than 0.6 is consistent with no clinically meaningful difference and aligns with EULAR definition, which states that a change in DAS28-CRP of up to 0.6 points within an individual constitutes no improvement.[13]

Further evaluations of efficacy were also consistent with similarity of ABP 710 and RP. When analyzed across time, the maximum RD of ACR20 occurred at the week 22 time point and was the only time point where the upper bound of the prespecified equivalence margin was exceeded. RD CIs were narrow at time points before and after. At weeks 14 and 30, which are also frequent pre-determined time points of primary analysis in RA efficacy studies, the RD of ACR20 is fully contained within the prespecified equivalence margin. These results of RD of ACR20 across time points are consistent with both non-inferiority and non-superiority. In addition, overlapping 95% CIs for RD of ACR50 and ACR70 at all points across time further demonstrate similarity in efficacy. Considering that, for biosimilars, the purpose of clinical evaluation is to confirm similarity with the RP (and not demonstrate efficacy per se), the inconsistent observation at week 22 may not be considered clinically meaningful.

In addition to similarity of efficacy, we have demonstrated further safety and PK similarity for the comparison of ABP 710 and RP. As was consistent with previous results in healthy patients, serum concentrations as well as the subject incidence rates of developing ADAs of ABP 710 and RP were similar between the two treatment groups or the three re-randomized treatment groups throughout the entire study. The frequency, type, and severity of AEs were similar between treatment groups with no clinically meaningful differences. Safety events were consistent with the known safety profile of infliximab with no new or unexpected safety signals and no impact of a single transition from RP to ABP 710.

Several biosimilars of infliximab have been approved in various countries (Remsima™, Celltrion, South Korea; Inflectra™, Pfizer, USA; Infimab, Reliance Life Sciences, India; Renflexis®, Samsung Bioepis Co. Ltd./Merck Sharp & Dohme Corp., USA; Flixabi®, Biogen, USA).[14–16] As an example, efficacy in RA for CT-P13 (Remsima™, Inflectra™) was also demonstrated in a comparative efficacy study in patients with active disease despite MTX as evaluated by ACR20 but with the primary endpoint evaluated at week 30. In an extension of the study up to week 54 that included efficacy, radiographic progression, immunogenicity, safety, and PK, the conclusion of similarity to infliximab RP was unchanged.[17,18]

Although this study successfully demonstrated that there were no clinically meaningful differences between ABP 710 and the RP with respect to efficacy, exceeding the upper bound margin for the demonstration of efficacy may be considered a limitation. The upper bound margin for the primary endpoint RD of ACR20 at week 22 was 15.96%, which exceeded the prespecified upper limit of 15% by 0.96%. Therefore, while it may be questioned whether this study met its objective, it is important to understand that biosimilarity is based on the totality of evidence that also includes the demonstration of similarity in analytical and preclinical assessments and clinical pharmacology, safety, and immunogenicity. ABP 710 has been successfully shown to be similar to the RP for all of these aspects.

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