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

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.

Figures

Figure 1

Patient disposition. Disposition of the study patients treated with subcutaneous 120 mg BI 655064 or placebo administered once weekly for 12 weeks. Discontinuations due to AEs unrelated to RA were a fatal cerebral haemorrhage and one case of iron deficiency in the BI 655064 group and one case of pleural effusion, one case of elevated ALT and AST and one case of nasopharyngitis in the placebo group.*One patient excluded from full analysis set due to insufficient efficacy data; all 67 patients treated were included in the safety analysis set.AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; RA, rheumatoid arthritis.

Figure 2

Treatment response at week 12. Responses were defined according to (A) ACR20/50/70 improvement criteria (FAS, non-responder imputation) and (B) EULAR response (DAS28-CRP; FAS, observed). The primary endpoint (ACR20 at week 12) was evaluated with a Bayesian approach. ACR20/50/70, American College of Rheumatology 20/50/70% improvement criteria; DAS28-CRP, Disease Activity score in 28 joints based on C-reactive protein; EULAR, European League Against Rheumatism; FAS, full analysis set.

Figure 3

Median per cent change from baseline to week 12 in autoantibody levels. Median per cent change from baseline to week 12 in levels of total IgG, IgM and IgG ACPA. FAS, observed. *p≤0.05; **p≤0.01; ***p≤0.001; ****p≤0.0001. ACPA, anticyclic citrullinated protein antibody; FAS, full analysis set; Ig, immunoglobulin.

Figure 4

Median per cent change from baseline to week 12 in levels of CD95+ activated CD19+ B-cell subsets. Median per cent change from baseline to week 12 in B-cell subsets CD19+IgD−CD27−CD95+, CD19+IgD−CD27+CD95+ and CD19+IgD+CD27+CD95+. FAS, observed. *p≤0.01. FAS, full analysis set.