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

• Published in: Annals of the rheumatic diseases Vol. 78; no. 6; pp. 754 - 760
• Main Authors: Visvanathan, Sudha, Daniluk, Stefan, Ptaszyński, Rafał, Müller-Ladner, Ulf, Ramanujam, Meera, Rosenstock, Bernd, Eleftheraki, Anastasia G, Vinisko, Richard, Petříková, Alena, Kellner, Herbert, Dokoupilova, Eva, Kwiatkowska, Brygida, Alten, Rieke, Schwabe, Christian, Baum, Patrick, Joseph, David, Fine, Jay S, Padula, Steven J, Steffgen, Jürgen
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.06.2019; BMJ Publishing Group
• Subjects: Adult; Aged; Antibodies, Monoclonal, Humanized - adverse effects; Antibodies, Monoclonal, Humanized - therapeutic use; Antirheumatic Agents - adverse effects; Antirheumatic Agents - therapeutic use; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - physiopathology; Autoantibodies; Autoantibodies - blood; Autoimmune diseases; B-Lymphocyte Subsets - drug effects; Bayesian analysis; Biomarkers - blood; Bone matrix; Bone Remodeling - drug effects; Bone resorption; CD40 antigen; CD40 Ligand - antagonists & inhibitors; CD40L protein; CD95 antigen; Clinical trials; Dendritic cells; Disease; Double-Blind Method; Double-blind studies; Female; Fibroblasts; Health risk assessment; Humans; Immunoglobulin A; Immunoglobulin M; Immunoglobulins; Inflammation; Inflammation Mediators - metabolism; Injections, Subcutaneous; Interleukin 6; Kinases; Ligands; Lupus; Lymphocytes B; Male; Matrix metalloproteinase; Metalloproteinase; Methotrexate; Methotrexate - therapeutic use; Middle Aged; Monoclonal antibodies; Pathogenesis; Patients; Rheumatoid Arthritis; Rheumatoid factor; Rheumatology; Safety; Severity of Illness Index; Thromboembolism; Tumor necrosis factor-TNF; Young Adult; New Zealand; B-cells; autoantibodies; rheumatoid arthritis
• ISSN: 0003-4967; 1468-2060
• DOI: 10.1136/annrheumdis-2018-214729

ObjectiveTo 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).MethodsIn 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.ResultsAt 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.ConclusionAlthough 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