Randomized, placebo-controlled, single-blind phase 1 studies of the safety, tolerability, and pharmacokinetics of BRII-196 and BRII-198, SARS-CoV-2 spike-targeting monoclonal antibodies with an extended half-life in healthy adults
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Abstract
Background: BRII-196 and BRII-198 are two anti-SARS-CoV-2 monoclonal neutralizing antibodies as a cocktail therapy for treating COVID-19 with a modified Fc region that extends half-life.
Methods: Safety, tolerability, pharmacokinetics, and immunogenicity of BRII-196 and BRII-198 were investigated in first-in-human, placebo-controlled, single ascending dose phase 1 studies in healthy adults. 44 participants received a single intravenous infusion of single BRII-196 or BRII-198 up to 3,000 mg, or BRII-196 and BRII-198 combination up to 1500/1500 mg, or placebo and were followed up for 180 days. Primary endpoints were incidence of adverse events (AEs) and changes from pre-dose baseline in clinical assessments. Secondary endpoints included pharmacokinetics profiles of BRII-196/BRII-198 and detection of anti-drug antibodies (ADAs). Plasma neutralization activities against SARS-CoV-2 Delta live virus in comparison to post-vaccination plasma were evaluated as exploratory endpoints.
Results: All infusions were well-tolerated without systemic or local infusion reactions, dose-limiting AEs, serious AEs, or deaths. Most treatment-emergent AEs were isolated asymptomatic laboratory abnormalities of grade 1-2 in severity. BRII-196 and BRII-198 displayed pharmacokinetics characteristic of Fc-engineered human IgG1 with mean terminal half-lives of 44.6–48.6 days and 72.2–83.0 days, respectively, with no evidence of interaction or significant anti-drug antibody development. Neutralizing activities against the live virus of the SARS-CoV-2 Delta variant were maintained in plasma samples taken on day 180 post-infusion.
Conclusion: BRII-196 and BRII-198 are safe, well-tolerated, and suitable therapeutic or prophylactic options for SARS-CoV-2 infection.
Clinical Trial Registration: ClinicalTrials.gov under identifiers NCT04479631, NCT04479644, and NCT04691180.
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SciScore for 10.1101/2021.07.21.21260964: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Field Sample Permit: These studies were conducted at a single phase 1 unit in China from July 2020 to February 2021 (registered at ClinicalTrials.gov under registration number NCT04479631 and NCT04479644).
IACUC: The study protocol, amendments, and informed-consent forms were reviewed and approved by Ethical Review Committee at the site.
Consent: Participants provided written informed consent before any study-related procedures were performed.Sex as a biological variable Eligible participants were healthy male or female adults aged 18 to 49 years, had a body weight ≤100 kg and a body mass index of 18-24 kg/m2, and were in good health determined by no clinically significant findings from … SciScore for 10.1101/2021.07.21.21260964: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Field Sample Permit: These studies were conducted at a single phase 1 unit in China from July 2020 to February 2021 (registered at ClinicalTrials.gov under registration number NCT04479631 and NCT04479644).
IACUC: The study protocol, amendments, and informed-consent forms were reviewed and approved by Ethical Review Committee at the site.
Consent: Participants provided written informed consent before any study-related procedures were performed.Sex as a biological variable Eligible participants were healthy male or female adults aged 18 to 49 years, had a body weight ≤100 kg and a body mass index of 18-24 kg/m2, and were in good health determined by no clinically significant findings from medical history, physical examination including vital signs, electrocardiogram (ECG), and clinical laboratory assessments. Randomization Study design and participants: BRII-196-001 and BRII-198-001 are two first-in-human phase 1, randomized, single-blind, placebo-controlled, single ascending dose escalation studies in which BRII-196 and BRII-198 were evaluated respectively among healthy adults. Blinding not detected. Power Analysis not detected. Cell Line Authentication Authentication: BRII-196 or BRII-198 serum concentrations were measured using validated enzyme linked immunosorbent assays (ELISA) with the lower limit of quantitation (LLOQ) at 150 ng/mL. Table 2: Resources
Antibodies Sentences Resources Serum samples for anti-drug antibody (ADA) assays were collected at the following time points: pre-dose on day 1 and at days 15, 31, and 181. anti-drugsuggested: NoneSoftware and Algorithms Sentences Resources The PK parameters were estimated by non-compartmental analyses using WinNonlin module in the Phoenix Platform (version 8.3.1.5014, Certara Inc., Princeton, NJ 08540). Phoenix Platformsuggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04479631 Completed Safety, Tolerability, and Pharmacokinetics Study of Human Mo… NCT04479644 Completed Safety, Tolerability, and Pharmacokinetics Study of Human Mo… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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