PMID- 36697937 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230214 IS - 2193-8229 (Print) IS - 2193-6382 (Electronic) IS - 2193-6382 (Linking) VI - 12 IP - 2 DP - 2023 Feb TI - 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. PG - 663-675 LID - 10.1007/s40121-023-00759-4 [doi] AB - 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 (c)(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. CI - (c) 2023. The Author(s). FAU - Chen, Guiling AU - Chen G AD - Phase I Clinical Trial Unit, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Dongxin Road, 848, Hangzhou, 310000, China. FAU - Li, Nan AU - Li N AD - Phase I Clinical Trial Unit, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Dongxin Road, 848, Hangzhou, 310000, China. FAU - Dai, Xiahong AU - Dai X AD - Phase I Clinical Trial Unit, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Dongxin Road, 848, Hangzhou, 310000, China. FAU - Tu, Shiyan AU - Tu S AD - The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu, China. FAU - Shen, Zhenwei AU - Shen Z AD - Zhejiang Shuren University, Hangzhou, Zhejiang, China. FAU - Wu, Kaiqi AU - Wu K AD - Phase I Clinical Trial Unit, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Dongxin Road, 848, Hangzhou, 310000, China. FAU - Jin, Tinghan AU - Jin T AD - Phase I Clinical Trial Unit, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Dongxin Road, 848, Hangzhou, 310000, China. FAU - Wu, Jiajun AU - Wu J AD - Phase I Clinical Trial Unit, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Dongxin Road, 848, Hangzhou, 310000, China. FAU - Peng, Conggao AU - Peng C AD - Phase I Clinical Trial Unit, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Dongxin Road, 848, Hangzhou, 310000, China. FAU - Sheng, Guoping AU - Sheng G AD - Phase I Clinical Trial Unit, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Dongxin Road, 848, Hangzhou, 310000, China. guoping.sheng@shulan.com. FAU - Zhu, Mengfei AU - Zhu M AD - Phase I Clinical Trial Unit, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Dongxin Road, 848, Hangzhou, 310000, China. mengfei.zhu@shulan.com. FAU - Tang, Lingling AU - Tang L AD - Phase I Clinical Trial Unit, Shulan (Hangzhou) Hospital Affiliated to Zhejiang Shuren University Shulan International Medical College, Dongxin Road, 848, Hangzhou, 310000, China. lingling.tang@shulan.com. FAU - Li, Lanjuan AU - Li L AD - State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, Zhejiang, China. ljli@zju.edu.cn. LA - eng GR - Staidson (Beijing) Biopharmaceuticals/ PT - Journal Article DEP - 20230125 PL - New Zealand TA - Infect Dis Ther JT - Infectious diseases and therapy JID - 101634499 PMC - PMC9876408 OTO - NOTNLM OT - C5a OT - Clinical trial OT - Complement system OT - Phase 1 OT - Severe COVID-19 EDAT- 2023/01/26 06:00 MHDA- 2023/01/26 06:01 PMCR- 2023/01/25 CRDT- 2023/01/25 23:47 PHST- 2022/10/27 00:00 [received] PHST- 2023/01/06 00:00 [accepted] PHST- 2023/01/26 06:00 [pubmed] PHST- 2023/01/26 06:01 [medline] PHST- 2023/01/25 23:47 [entrez] PHST- 2023/01/25 00:00 [pmc-release] AID - 10.1007/s40121-023-00759-4 [pii] AID - 759 [pii] AID - 10.1007/s40121-023-00759-4 [doi] PST - ppublish SO - Infect Dis Ther. 2023 Feb;12(2):663-675. doi: 10.1007/s40121-023-00759-4. Epub 2023 Jan 25.