Background/Purpose: The CD40-CD40L pathway may play a major role in autoimmune disorders like rheumatoid arthritis or SLE. Blocking this pathway may be a promising new treatment for patients suffering from autoimmune diseases. BI 655064 is a novel humanized antagonistic anti-CD40 monoclonal antibody free of agonistic activity and without antibody-dependent cellular- or complement- dependent cytotoxicity. Safety, tolerability, PK and CD40 receptor occupancy (RO) were investigated in a single ascending dose study in Asian male healthy volunteers.

Methods: This was a randomized, double-blind within dose groups, placebo-controlled, two-sites, single rising dose trial evaluating single subcutaneous (SC) doses (80, 120, 180 and 240 mg) of BI 655064. Blood samples were taken for analysis of PK, immunogenicity and CD40 RO throughout the entire trial duration (10 weeks).

Results: Thirty-two Chinese and 32 Japanese subjects, mean age 26.8 years, were treated: 48 received BI 655064 and 16 received placebo. All doses of BI 655064 were well tolerated in both ethnicities. There was no-drug related serious adverse event (AE) or significant AE reported. All AEs were mild, except 1 moderate (Chinese 120 mg; contusion), and all recovered. The percentage of subjects reporting any AE was the same (31.3%) for subjects treated with BI 655064 or placebo. AEs did not show a dose relationship. Nineteen of the 20 subjects that reported at least 1 AE during the treatment phase were Chinese. The most frequently reported AEs were upper respiratory tract infections (reported in 8.3% subjects on BI 655064 vs. 12.5 % on placebo). AEs rated as drug –related by the investigator were only reported in Chinese subjects and did not show a dose relationship. The only drug-related AE that was reported for more than 1 subject was diarrhoea (1 Chinese in each 80 mg and 240 mg treatment). There was no evidence of thromboembolism or bleeding, hypersensitivity reaction, cytokine release and relevant change in safety laboratory tests including coagulation parameters.

Plasma concentrations of BI 655064 increased gradually after a single SC administration of BI 655064, reached a peak at 96 to 144 hours post dose and then declined with the terminal half-life ranging from 105 to 242 hours. The exposure increased more than proportionally with the dose indicating target mediated drug disposition. Single dose of 120 mg SC resulted in >90% CD40-RO and the duration of >90% CD40-RO increased with increasing dose. Anti-drug antibodies were detected in most of the subjects (45 out of 48 subjects) who received BI 655064 with relatively low to moderate titer (mostly ≤ 400, median titer ≤ 80) and median onset time of 41 days.

Conclusion: These data demonstrate that BI 655064 has a favorable clinical safety profile and high potential to block the CD40-CD40L pathway in Chinese and Japanese population. This is in line with results in Caucasians and supports the inclusion of Asian subjects in global clinical trials with BI 655064.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/safety-tolerability-pharmacokinetics-pk-and-pharmacodynamics-of-bi-655064-an-antagonistic-anti-cd40-antibody-following-single-dose-administration-in-chinese-and-japanese-healthy-volunteers/