Background/Purpose: Costimulation through the CD40–CD40L axis is implicated in the pathogenesis of RA including T cell-mediated responses, B cell-driven autoantibodies, adhesion molecule expression, synovial hyperplasia and pannus formation, in addition to secretion of proinflammatory cytokines and MMPs. Circulating sCD40L levels are elevated in RA patients versus healthy controls. Studies have shown a significant association between the CD40 rs4810485 T allele and RA. BI 655064 is a humanized antagonistic anti-CD40 monoclonal antibody that blocks the CD40–CD40L interaction in in vitro CD40L-induced B cell and APC activation assays with IC50 of <1 nM. In healthy volunteers, BI 655064 was well tolerated in doses up to 240 mg q1w s.c. for 4 wks. Doses ≥120 mg resulted in persistent >90% CD40 receptor occupancy and >90% inhibition of CD40L-induced CD54 upregulation.

Methods:  In this double-blind randomized trial (NCT01751776), RA patients (n=67) received either 120 mg BI 655064 or placebo q1w for 12 wks as add-on to MTX. Inclusion criteria were ≥6 swollen and ≥6 tender joints, CRP ≥8 mg/L or ESR ≥28 mm/1h. The primary efficacy endpoint was ACR20 response at wk 12. Select biomarkers were assessed in whole blood and serum pre- and post-treatment with BI 655064. Rs4810485 was genotyped in a subset of patients (25 BI 655064, 18 placebo) by an allelic discrimination assay based on TaqMan PCR. For statistical analysis, patients were grouped into T allele carriers (TT/GT) and non-T allele carriers (GG).

Results:  Higher ACR20/50 response rates were observed with BI 655064 (68.2%, 36.4%) vs placebo (45.5%, 18.2%) at wk 12. Baseline variables for the two groups were comparable except mean CRP (BI 655064 9.8 mg/L, placebo 23.6 mg/L; p<0.02). BI 655064 had minimal effects on the median %CD19+ B cell population but larger median decreases in select %CD95+ activated B cell subsets, specifically class switched (CD19+IgD-CD27+CD95+), pre-switched (CD19+IgD+CD27+CD95+) and double-negative (CD19+IgD-CD27-CD95+) cells (p=0.0097) at wk 12. Reductions in median IgG and IgA rheumatoid factor (RF, p=0.0018, p=0.005) and total IgG and IgM levels (p=0.0082, p=0.0002) were observed with BI 655064 vs placebo at 12 wks. Median decreases in IL-6 levels (B cell and monocyte differentiation) and select bone resorption biomarkers (MMP-3 and RANKL p=0.0041) were also observed with BI 655064 vs placebo at 12 wks. In patients who carried at least one T allele, a trend towards better ACR20 responses [72% (TT/GT) vs 50% (GG)] was observed with BI 655064 but not placebo. Two SAEs were reported in each group, but were not considered drug related. The most frequently reported AEs were nasopharyngitis (BI 655064 13.6%, placebo 21.7%) and headache (BI 655064 6.8%, placebo 13.0%).

Conclusion:  Treatment of MTX-IR RA patients with BI 655064 resulted in moderate efficacy, which was potentially impacted by the relatively high placebo response rate and the imbalance in baseline CRP, and did not indicate any safety concerns. Treatment with BI 655064 decreased selected activated B cell subsets, inhibited RF production, and reduced levels of select circulating inflammatory and bone resorption biomarkers through 12 wks in RA patients.

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/treatment-with-bi-655064-antagonistic-anti-cd40-antibody-modulates-clinical-and-biomarker-parameters-associated-with-rheumatoid-arthritis-ra/