Background GP2013 has been developed as a proposed biosimilar to originator rituximab (RTX), by Sandoz, a Novartis Company. The stepwise development program is comprised of structural and functional characterization with highly sensitive analytical methods followed by nonclinical testing and clinical studies.
Objectives The primary objective of the study was to demonstrate PK bioequivalence of GP2013 and EU-approved rituximab (RTX) in patients with RA, defined as equivalence of AUC(0–inf) up to week 24. Secondary endpoints included other PK and PD parameters and evaluation of safety and efficacy.
Methods In this prospective, randomized, double blind study patients with active RA refractory or intolerant to standard DMARDs and TNF inhibitor(s) were randomized to GP2013 or RTX. Read-out of the primary analysis was performed at week 24. Efficacy and PD data were collected to week 52, while safety follow-up ended 24 weeks after the last infusion of study medication. For anti-drug antibody (ADA) assessment a validated in-house ELISA method for binding ADAs was applied.
Results Of the 325 patients screened, 173 were randomized to either GP2013 or RTX. There were no relevant differences in baseline characteristics between the treatment arms. A similar number of patients received a second treatment course after week 24: 58 (67.4%) patients in the GP2013 and 56 (64.4%) patients in the RTX arm.
The study met its primary objective by demonstrating PK bioequivalence based on AUC0-inf. The ratio of the geometric means (GP2013/RTX) was 1.064, and the 90% confidence interval (CI) was maintained within the standard bioequivalence limits [0.8 to 1.25] (Figure 1).
For maximum serum concentration (Cmax) after the first infusion, the upper limit of the 90% CI of the ratio of the geometric means (1.262) was slightly above the upper bound of the bioequivalence limit (1.25) whereas for Cmax after the second infusion, the CI was fully within the 90% CI. This outcome was attributed to a higher variability in infusion rates and durations during the first infusion. The study met all other secondary PK endpoints.
Equivalence of GP2013 and RTX was also demonstrated in terms of peripheral B cell depletion. The ratio of the geometric means (GP2013/RTX) was 1.019 and the 95% CI was within the equivalence limits [0.8 to 1.25]. Non-inferiority to reference RTX was demonstrated for disease activity score DAS28(CRP) change from baseline at week 24. The LS mean difference between the groups was 0.07 and the 95% confidence interval was below the non-inferiority margin of 0.6. The number of adverse events, serious adverse events and potential infusion related reactions were similar between the treatment arms. Nine (11.0%) patients in the GP2013 vs. 18 (21.4%) patients in the RTX group developed anti-drug antibodies (ADAs).
Conclusions The proposed biosimilar GP2013 met the primary endpoint demonstrating bioequivalence to originator EU-approved RTX. No clinically meaningful differences were found between GP2013 and the reference RTX in PD and safety, as well as efficacy and immunogenicity at week 24.
Disclosure of Interest J. Smolen Grant/research support from: Abbvie, Janssen, Lilly, MSD, Pfizer, Roche, Consultant for: Abbvie, Amgen, Astra-Zeneca, Astro, Celgene, Celtrion, Glaxo, ILTOO, Janssen, Lilly, Medimmune, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB, M. Scheinberg: None declared, H.-P. Tony Consultant for: AbbVie, BMS, Chugai, Janssen, Lilly, MSD, Novartis, Roche, UCB, Speakers bureau: AbbVie, Chugai, Jenssen, Lilly, Roche, P. Zhu Employee of: Sandoz, a Novartis company, T. Shisha Employee of: Sandoz, a Novartis company