1. 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.
- Author
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Visvanathan S, Daniluk S, Ptaszyński R, Müller-Ladner U, Ramanujam M, Rosenstock B, Eleftheraki AG, Vinisko R, Petříková A, Kellner H, Dokoupilova E, Kwiatkowska B, Alten R, Schwabe C, Baum P, Joseph D, Fine JS, Padula SJ, and Steffgen J
- Subjects
- Adult, Aged, Antibodies, Monoclonal, Humanized adverse effects, Antirheumatic Agents adverse effects, Arthritis, Rheumatoid immunology, Arthritis, Rheumatoid physiopathology, Autoantibodies blood, B-Lymphocyte Subsets drug effects, Biomarkers blood, Bone Remodeling drug effects, CD40 Ligand antagonists & inhibitors, Double-Blind Method, Female, Humans, Inflammation Mediators metabolism, Injections, Subcutaneous, Male, Methotrexate therapeutic use, Middle Aged, Severity of Illness Index, Young Adult, Antibodies, Monoclonal, Humanized therapeutic use, Antirheumatic Agents therapeutic use, Arthritis, Rheumatoid drug therapy
- 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., Competing Interests: 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.)
- Published
- 2019
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