Effects of BI 655064, an antagonistic anti-CD40 antibody, on clinical and biomarker variables in patients with active rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase IIa study
Sudha Visvanathan, Stefan Daniluk, Rafał Ptaszyński, Ulf Müller-Ladner, Meera Ramanujam, Bernd Rosenstock, Anastasia G Eleftheraki, Richard Vinisko, Alena Petříková, Herbert Kellner, Eva Dokoupilova, Brygida Kwiatkowska, Rieke Alten, Christian Schwabe, Patrick Baum, David Joseph, Jay S Fine, Steven J Padula, Jürgen Steffgen, Sudha Visvanathan, Stefan Daniluk, Rafał Ptaszyński, Ulf Müller-Ladner, Meera Ramanujam, Bernd Rosenstock, Anastasia G Eleftheraki, Richard Vinisko, Alena Petříková, Herbert Kellner, Eva Dokoupilova, Brygida Kwiatkowska, Rieke Alten, Christian Schwabe, Patrick Baum, David Joseph, Jay S Fine, Steven J Padula, Jürgen Steffgen
Abstract
Objective: To evaluate the safety, efficacy and therapeutic mechanism of BI 655064, an antagonistic anti-CD40 monoclonal antibody, in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX-IR).
Methods: In total, 67 patients were randomised to receive weekly subcutaneous doses of 120 mg BI 655064 (n=44) or placebo (n=23) for 12 weeks. The primary endpoint was the proportion of patients who achieved 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Safety was assessed in patients who received at least one dose of study drug.
Results: At week 12, the primary endpoint was not met, with 68.2% of patients treated with BI 655064 achieving an ACR20 vs 45.5% with placebo (p=0.064); using Bayesian analysis, the posterior probability of seeing a difference greater than 35% was 42.9%. BI 655064 was associated with greater changes in CD40-CD40L pathway-related markers, including reductions in inflammatory and bone resorption markers (interleukin-6, matrix metalloproteinase-3, receptor activator of nuclear factor-κB ligand), concentration of autoantibodies (immunoglobulin [Ig]G rheumatoid factor [RF], IgM RF, IgA RF) and CD95+ activated B-cell subsets. No serious adverse events (AEs) related to BI 655064 treatment or thromboembolic events occurred; reported AEs were mainly of mild intensity.
Conclusion: Although blockade of the CD40-CD40L pathway with BI 655064 in MTX-IR patients with RA resulted in marked changes in clinical and biological parameters, including reductions in activated B-cells, autoantibody production and inflammatory and bone resorption markers, with a favourable safety profile, clinical efficacy was not demonstrated in this small phase IIa study.
Trial registration number: NCT01751776.
Keywords: B-cells; autoantibodies; rheumatoid arthritis.
Conflict of interest statement
Competing interests: SD, RP, AP, HK, ED and BK report no disclosures; UM-L reports being an advisor for Boehringer Ingelheim; RA and CS report having received research/grant support from Boehringer Ingelheim; SV, MR, BR, AGE, RV, PB, DJ, JSF, SJP and JS report being employed by Boehringer Ingelheim.
© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
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