tetano
Editor, Senior Moderator
Infect Dis Ther
. 2023 Jan 25.
doi: 10.1007/s40121-023-00759-4. Online ahead of print.
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
Guiling Chen[SUP] #[/SUP][SUP] 1 [/SUP], Nan Li[SUP] #[/SUP][SUP] 1 [/SUP], Xiahong Dai[SUP] #[/SUP][SUP] 1 [/SUP], Shiyan Tu[SUP] 2 [/SUP], Zhenwei Shen[SUP] 3 [/SUP], Kaiqi Wu[SUP] 1 [/SUP], Tinghan Jin[SUP] 1 [/SUP], Jiajun Wu[SUP] 1 [/SUP], Conggao Peng[SUP] 1 [/SUP], Guoping Sheng[SUP] 4 [/SUP], Mengfei Zhu[SUP] 5 [/SUP], Lingling Tang[SUP] 6 [/SUP], Lanjuan Li[SUP] 7 [/SUP]
Affiliations
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[SUB]0-480h[/SUB]), that from time zero to infinity (AUC[SUB]inf[/SUB]), and peak plasma concentration ©[SUB]max[/SUB]) 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[SUB]0-tau[/SUB] 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.
Keywords: C5a; Clinical trial; Complement system; Phase 1; Severe COVID-19.
. 2023 Jan 25.
doi: 10.1007/s40121-023-00759-4. Online ahead of print.
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
Guiling Chen[SUP] #[/SUP][SUP] 1 [/SUP], Nan Li[SUP] #[/SUP][SUP] 1 [/SUP], Xiahong Dai[SUP] #[/SUP][SUP] 1 [/SUP], Shiyan Tu[SUP] 2 [/SUP], Zhenwei Shen[SUP] 3 [/SUP], Kaiqi Wu[SUP] 1 [/SUP], Tinghan Jin[SUP] 1 [/SUP], Jiajun Wu[SUP] 1 [/SUP], Conggao Peng[SUP] 1 [/SUP], Guoping Sheng[SUP] 4 [/SUP], Mengfei Zhu[SUP] 5 [/SUP], Lingling Tang[SUP] 6 [/SUP], Lanjuan Li[SUP] 7 [/SUP]
Affiliations
- PMID: 36697937
- DOI: 10.1007/s40121-023-00759-4
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[SUB]0-480h[/SUB]), that from time zero to infinity (AUC[SUB]inf[/SUB]), and peak plasma concentration ©[SUB]max[/SUB]) 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[SUB]0-tau[/SUB] 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.
Keywords: C5a; Clinical trial; Complement system; Phase 1; Severe COVID-19.