AB0377\u2005CLINICAL SIMILARITY OF ABP 710 WITH INFLIXIMAB (REFERENCE PRODUCT) IN SUBJECTS WITH MODERATE TO SEVERE RHEUMATOID ARTHRITIS

Abstract

Background ABP 710 is being developed as a biosimilar to infliximab. Both ABP 710 and infliximab reference product (RP) inhibit tumor necrosis factor-alpha and have been shown to be structurally and functionally similar in analytical assessments. In a phase 1 clinical pharmacokinetic (PK) study both were shown to be bioequivalent for PK parameters. The final step in the demonstration of biosimilarity is a comparative phase 3 clinical trial in a representative indication Objectives The objective of this study was to evaluate the similarity of ABP 710 compared to RP with respect to efficacy and safety. Methods In this multicenter, randomized, double-blind study, the efficacy and safety of ABP 710 was compared with the RP in subjects with moderate to severe rheumatoid arthritis. Subjects were maintained on a stable 7.5 to 25 mg/week dose of methotrexate and received 3 mg/kg infusions of the investigational products (IPs) at predetermined intervals. The primary endpoint of the study was risk difference (RD) of ACR20 at week 22; secondary endpoints included DAS28-CRP and safety at week 22. The confidence intervals (CI) for RD of ACR20 were estimated using the intention-to-treat analysis set with non-responder imputation based on the subject’s randomized treatment. Clinical equivalence was evaluated by comparing the 2-sided 90% CI with the equivalence margin of (-15%, 15%) of the RD of ACR20. For change of DAS28-CRP at week 22 from baseline, the CI of the mean difference was estimated using an analysis of covariance model with relevant baseline values and stratification factors as covariates. Results Of the 558 randomized subjects, 556 were treated (ABP 710 n=278; RP n=278). For ACR20, the RD was 9.3% and the lower bound of the 90% CI (2.67%, 15.96%) was within the pre-specified criteria, thus confirming non-inferiority; the upper bound slightly exceeded the pre-specified criteria such that superiority cannot be ruled out statistically. In post-hoc analysis when the impact of random imbalance in baseline demographic and disease characteristic between the 2 treatment arms was adjusted, the RD was reduced to 7.18% and the 90% CI was narrowed to (0.75%, 13.62%). Results of change of DAS28-CRP at week 22 showed a difference in mean change from baseline of -0.01 with 90% CI of (-0.20, 0.17). Since this difference is less than the suggested EULAR threshold of 0.6 for clinically meaningful difference, the result supports both non-inferiority and non-superiority. Through week 22, percentage of subjects reporting any serious adverse events was 4.1 (ABP 710=3.2; RP=5.0) and the binding/neutralizing antibody positive post-baseline in subjects were 58.9/19.4 (ABP 710=57.1/18.0; RP=60.6/20.8). Conclusion The results of this study indicate that ABP 710 is similar to the RP. Although we were unable to statistically confirm non-superiority, post-hoc analysis is supportive of non-superiority. The DAS28-CRP difference of less than 0.6 is believed to not be clinically meaningful. These efficacy and safety results support similarity between ABP 710 and infliximab RP. Acknowledgement Sonya Lehto and Monica Ramchandani for medical writing. Study investigators and patients Disclosure of Interests Mark C. Genovese Grant/research support from: Sanofi/Genzyme, Genentech/Roche, RPharm, Consultant for: Sanofi/Genzyme, Genentech/Roche, RPharm, Juan Sanchez-Burson Speakers bureau: Lilly, Janssen, Pfizer, MyungShin Oh Shareholder of: Amgen, Employee of: Amgen, éva Balázs Grant/research support from: Celltrion, Inc., Consultant for: Merck and Amgen, Jeffrey Neal Consultant for: Investigator Amgen, Gary Fanjiang Shareholder of: Amgen, Employee of: Amgen, Stanley Cohen Grant/research support from: AbbVie, Amgen Inc., AstraZeneca, Biogen-IDEC, Bristol Meyer Squibb, Genentech, Janssen, Eli Lilly, Novartis, Pfizer, Merck, and Roche, Consultant for: Abbvie, Amgen, AstraZeneca, Biogen-IDEC, Bristol Meyer Squibb, Genentech, Janssen, Lilly, Novartis Pfizer, Merck and Roche