Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Anti-C5a Antibody BDB-001 for Severe COVID-19: A Randomized, Double-Blind, Placebo-Controlled Phase 1 Clinical Trial in Healthy Chinese Adults

Abstract

Introduction Severe Coronavirus Disease 2019 (COVID-19) progresses with inflammation and coagulation, due to an overactive complement system. Complement component 5a (C5a) plays a key role in the complement system to trigger a powerful “cytokine and chemokine storm” in viral infection. BDB-001, a recombinant human immunoglobulin G4 (IgG4) that specially binds to C5a, has the potential to inhibit the C5a-triggered cytokine storm in treating COVID-19 patients and other inflammation diseases. Here, we have explored its safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy adults. This trial is registered with http://www.chinadrugtrials.org.cn/(CTR20200429 ). Methods Thirty-two enrolled participants were randomized into three single-dose cohorts (2, 4, and 8 mg/kg) and 1 multi-dose cohort (4 mg/kg), and received either BDB-001 or placebo (3:1) double-blindly. The safety and tolerability after administration were evaluated for 21 days for single-dose cohorts and 28 days for the multi-dose cohort. The pharmacokinetics of BDB-001 in plasma and pharmacodynamics as free C5a in plasma were analyzed. Results The incidence of drug-related adverse events (AEs) was low, and all AEs were mild or moderate: neither AEs ≥ 3 (NCI-Common Terminology Criteria For Adverse Events, CTCAE 5.0) nor serious adverse events (SAEs) were found. The area under the concentration–time curve from time zero to 480 h (AUC 0-480h ), that from time zero to infinity (AUC inf ), and peak plasma concentration © max ) increased dose-dependently from 2 to 8 mg/kg in the single-dose cohorts and were characterized by a nonlinear pharmacokinetics of target-mediated drug disposal (TMDD). The accumulation index by AUC 0-tau after five administrations (4 mg/kg) from the multi-dose cohort was 6.42, suggesting an accumulation effect. Furthermore, inhibition of C5a at the plasma level was observed. Conclusion The results of this phase I study supported that BDB-001 is a potent anti-C5a inhibitor with safety, tolerability, and no immunogenicity. Trial Registration Number CTR20200429. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-023-00759-4.

Rational design of antibody‐like peptides for targeting the human complement fragment protein C5a

“…[21][22][23][24] However, it is evidenced that among all classes of molecules, antibodies targeting C5a have seen relatively more clinical success as therapeutics than other low-molecular-weight therapeutics. So far, IFX-1, 25 TNX-558, 26 BDB-001, 27 MEDI7814, 28 and ALXN-1007 29 are the few promising antibodies that have been designed against C5a, and among them, vilobelimab (IFX-1) has recently received an EUA from the FDA for COVID-19. Despite the success stories, pharmacological impediments generally reported against antibodies have created a renewed avenue for small molecular entities as drugs.…”