Background Blocking 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.
Objectives BI 655064 was investigated in RA patients with prior inadequate response (IR) to a stable dose of MTX at ≥15 mg.
Methods In 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.
Results Baseline 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.
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.
Conclusions In 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 Interest S. 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, B. Kwiatkowska: None declared, R. Alten Grant/research support from: Boehringer Ingelheim, C. Schwabe Grant/research support from: Boehringer Ingelheim, B. Rosenstock Employee of: Boehringer Ingelheim, T. Doan Employee of: Boehringer Ingelheim, R. Thiedmann Employee of: Boehringer Ingelheim, F. Fleischer Employee of: Boehringer Ingelheim, J. Hilbert Employee of: Boehringer Ingelheim, S. Visvanathan Employee of: Boehringer Ingelheim, S. Padula Employee of: Boehringer Ingelheim, J. Steffgen Employee of: Boehringer-Ingelheim