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 numberNCT01751776

BackgroundBlocking the CD40-CD40L pathway may be a new emergent treatment for patients with RA. BI 655064 is a humanized, purely antagonistic anti-CD40 monoclonal antibody. In healthy volunteers, BI 655064 was well tolerated in doses up to 240 mg q1w s.c. for 4 weeks. Doses ≥120 mg resulted in persistent >90% CD40 receptor occupancy and >90% inhibition of CD40L-induced CD54 upregulation.ObjectivesBI 655064 was investigated in RA patients with prior inadequate response (IR) to a stable dose of MTX at ≥15 mg.MethodsIn this double-blind, randomized trial, RA patients (n=67) were treated with either 120 mg BI 655064 or placebo q1w (2:1, respectively) for 12 weeks as add-on to MTX. Patients were stratified based on region (Eastern Europe vs. Western Europe/New Zealand). 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 week 12.ResultsBaseline variables of the 2 groups were comparable except mean baseline CRP, which was substantially lower in patients treated with BI 655064 (9.8 mg/L) vs. placebo (23.6 mg/L). Treatment was prematurely discontinued by 4 patients (9.1%) in the BI 655064 group and 4 (17.4%) in the placebo group. Adverse events (AE) were reported in 65.9% of BI 655064-treated patients vs. 78.3% of placebo-treated patients. Two SAEs were reported in each group, neither was 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%). There were no relevant changes in safety-related laboratory parameters. Efficacy results of all patients (FAS), including a subgroup of patients with CRP > median (7.5 mg/L; upper limit of normal: 6.0 mg/L), are listed in the table.Table 1BI 655064 (N=44)Placebo (N=22*)ACR20 response %68.245.5ACR50 response %36.418.2Mean change† in DAS28-CRP @wk12−1.65−1.42Subgroup with CRP > medianBI 655064 (N=17)Placebo (N=16)Mean change† in DAS28-CRP @wk12−1.83−1.38CRP change from baseline, mean (SE)−10.45 (3.54)−3.90 (3.65)*1 patient excluded from efficacy analysis due to early use of i.v. steroids. †Adjusted for region, anti-TNF history and baseline CRP.All 6 patients who had previously received anti-TNF therapy were in the BI 655064 group; 4 achieved an ACR20 and 2 achieved an ACR50 response. There was a median decrease in ESR and total rheumatoid factor in the BI 655064-treated group by 16 mm/h and 81.5 IU/mL, respectively, compared with a decrease of 9 mm/h and 0.2 IU/mL in the placebo group.ConclusionsIn this relatively small proof-of-clinical-concept trial, treatment of MTX IR RA patients with BI 655064 did not indicate a relevant safety concern and showed moderate efficacy, which might have been impacted by the relatively high placebo response rate and the imbalance in baseline CRP.Disclosure of InterestS. Daniluk: None declared, R. Ptaszynski: None declared, U. Mueller-Ladner Consultant for: Boehringer Ingelheim, A. Petrikova: None declared, H. Kellner: None declared, E. Dokoupilova: None declared,...