FKB327, an adalimumab biosimilar, versus the reference product: results of a randomized, Phase III, double-blind study, and its open-label extension

Abstract

Objective: To compare the efficacy, serum drug concentrations, immunogenicity, and safety of FKB327 with the adalimumab reference product (RP) in combination with methotrexate in patients with moderate-to-severe, active rheumatoid arthritis (RA).

Methods: Patients were randomized 1:1 in a double-blind study (NCT02260791), received 40 mg of FKB327 or RP by subcutaneous injection every other week for 24 weeks (Period I), then re-randomized 2:1, remaining on the same study drug or switching to the other up to week 54 in an open-label extension (Period II, NCT02405780). Efficacy was evaluated using American College of Rheumatology (ACR20) response rate difference at week 24 with equivalence margins of ± 13% and - 12% to + 15% using 95% and 90% confidence intervals (CIs), respectively. Efficacy, serum drug concentrations, immunogenicity, and safety were compared at week 54.

Results: A total of 730 patients were randomized in Period I (n = 367 FKB327, n = 363 RP), and 645 transitioned to Period II (n = 216 FKB327-FKB327, n = 108 FKB327-RP, n = 108 RP-FKB327, n = 213 RP-RP). At week 24, ACR20 response rates were 74.1% with FKB327 versus 75.7% with RP. 95% and 90% CI of the response rate difference were - 7.9 to 4.7% and - 7.3 to 3.6%, respectively, meeting predefined equivalence margins. The ACR20 response rate remained over 70% of patients to week 54 with all treatment sequences. In Period I, mean trough serum drug concentrations were slightly higher for patients receiving FKB327 than those receiving RP. Mean concentrations were stable over time and reflected steady state in Period II. The proportions of patients with samples positive for neutralizing antidrug antibodies (ADAs) were comparable (57.7% with FKB327 vs. 55.5% with RP) at week 24, and no consistent difference in ADA were seen between continuous and switched treatments in Period II. Efficacy was slightly reduced in the small proportion of patients with high ADA titers in all treatment groups. No clinically significant differences were observed in the incidence of commonly reported treatment-emergent adverse events between the treatments across Periods I and II.

Conclusion: FKB327 was equivalent to RP in clinical efficacy and demonstrated comparable safety and immunogenicity in patients with moderate-to-severe RA. No effect of switching between FKB327 and RP was observed.

Trial registration: ClinicalTrials.gov, NCT02260791, Registered 29 July 2014. ClinicalTrials.gov, NCT02405780, Registered 17 July 2015.

Keywords: Adalimumab; Biosimilar; Comparative clinical trials; Efficacy; FKB327; Immunogenicity; Pharmacokinetics; Rheumatoid arthritis; Safety.

Fig. 1

Patient disposition in Periods I and II (encompassing the double-blind and extension study). AE adverse event, DB double-blind, OLE open-label extension, RP reference product. *Including two patients treated with FKB327 and one patient treated with RP who discontinued study treatment due to lack of efficacy

Fig. 2

Efficacy results from Period I (double-blind study) from weeks 0 to 24 for a ACR20 response rate, b ACR50 response rate, c ACR70 response rate, d ACR20, ACR50, and ACR70 response rates at week 24, e mean DAS28-CRP (95% CI) from weeks 0 to 24. ACR American College of Rheumatology, CI confidence interval, DAS28-CRP disease activity score 28 based on C-reactive protein, RP reference product

Fig. 3

Long-term efficacy results from weeks 0 to 54 of treatment (to the end of Period II); a ACR20 response rate, b ACR50 response rate, c ACR70 response rate, d mean DAS28-CRP (95% CI). ACR American College of Rheumatology, CI confidence interval, DAS28-CRP disease activity score 28 based on C-reactive protein, RP reference product

Fig. 4

Effect of maximum ADA titer results on ACR20 response rate and mean DAS28-CRP at week 24 (end of Period I) and week 54 (Period II); a ACR20 response rate, b mean DAS28-CRP, c change in mean DAS28-CRP. ACR American College of Rheumatology, ADA, antidrug antibody, DAS28-CRP disease activity score 28 based on C-reactive protein, F FKB327, RP reference product. Low ADA titer was defined as ≤ the lower quartile, high ADA titer as ≥ the upper quartile, with mid titer between the lower and upper quartiles (both not included)