Phase 2 dose-ranging study of the virologic efficacy and safety of the combination COVID-19 antibodies casirivimab and imdevimab in the outpatient setting
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Abstract
Background
The monoclonal antibody combination casirivimab and imdevimab (REGEN-COV ® ) reduced viral load, hospitalisation, or death when administered 1:1 as an intravenous (IV) dose ≥1200 mg in a phase 3 COVID-19 outpatient study. Availability of subcutaneous (SC) and/or lower IV doses should increase accessibility and/or drug supplies for patients.
Methods
This is a double-blind, placebo-controlled study of SARS-CoV-2-infected outpatients who were asymptomatic, or symptomatic but without risk factors for severe COVID-19. Patients were randomised to single IV dose (517 patients) of REGEN-COV 300, 600, 1200 or 2400 mg or placebo; or a single SC dose (286 patients) of REGEN-COV 600 or 1200 mg or placebo. The primary endpoint was time-weighted average daily change from baseline (TWACB) in viral load from day 1 (baseline) through day 7 in patients seronegative to SARS-CoV-2 at baseline.
Findings
All REGEN-COV treatments showed significant (p<0·001 versus pooled placebo) virologic reduction through day 7. Least-squares mean differences in TWACB viral load for the treatments versus placebo ranged from –0·56 to –0·71 log 10 copies/mL. Each REGEN-COV treatment showed significant (p<0·001 versus pooled placebo) and similar virologic reduction through day 7. There were no safety concerns, dose-related safety findings, grade ≥2 infusion related/hypersensitivity reactions, grade ≥3 injection-site reactions, nor fatalities. Two serious adverse events not related to COVID-19 or the study drug were reported.
Interpretation
In asymptomatic and low-risk symptomatic SARS-CoV-2-infected outpatients seronegative for antibodies against SARS-CoV-2 at baseline, REGEN-COV significantly and comparably reduced viral load at all IV and SC doses.
Funding
Regeneron Pharmaceuticals, Inc. and Hoffman-La Roche
RESEARCH IN CONTEXT
Evidence before this study
Early phase 1/2 data in coronavirus disease 2019 (COVID-19) outpatients ( NCT04425629 ) found that the REGEN-COV ® antibody combination, casirivimab and imdevimab, administered 1:1 as a single intravenous (IV) dose of 2400 mg or 8000 mg significantly reduced viral load over the first week compared to placebo. Enhanced viral clearance was more pronounced in patients who were seronegative for antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or who had high viral load at baseline. The phase 3 portion of this outpatient treatment study subsequently evaluated 1200 mg IV and 2400 mg IV doses, demonstrating consistent virologic efficacy, further demonstrating that REGEN-COV treatment reduced risk of COVID-19-related hospitalisation or all-cause death, and shortened time to symptom resolution. Virologic clearance was similar among those treated with any of the three doses (8000 mg, 2400 mg, or 1200 mg); therefore, maximal virologic efficacy may have been achieved at the 1200 mg dose in this treatment setting. These results warranted investigation of lower dose regimens.
Added value of this study
The present dose-ranging study evaluated whether a lower dose regimen could demonstrate virologic efficacy similar to that observed with 1200 mg IV and 2400 mg IV doses in outpatient treatment study. Exploration of a wider dose range will provide further characterisation of the clinical effects of REGEN-COV. Moreover, identifying a lower efficacious dose could bolster the ability to provide an adequate therapeutic supply of REGEN-COV in the setting of a global pandemic. A 1200 mg subcutaneous (SC) dose of REGEN-COV also prevented COVID-19 in household contacts of SARS-CoV-2-infected individuals ( NCT04452318 ). The availability of a SC regimen could improve access for patients who have confirmed SARS-CoV-2 infection but for who IV infusion is not feasible.
Implications of all the available evidence
Despite the growing number of therapeutics with authorisation or approval for the treatment and/or prevention of COVID-19, there remains a significant global need for effective COVID-19 therapies. Additional therapeutics and dosing regimens will be required to meet demand and to meet the needs of specific patient populations. Lower IV doses of REGEN-COV, and the option of SC administration, should increase accessibility for patients. This increased availability needs to be weighed against several unanswered questions, including 1) whether the correlation between decreased viral load in the nasopharynx and improvement in clinical outcome holds at lower doses of REGEN-COV, and 2) whether the reduced drug exposure margins are sufficient to prevent viral escape and emergence of variants of concern.
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SciScore for 10.1101/2021.11.09.21265912: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization Trial design: This phase 2, randomised, double-blind, placebo-controlled, parallel-group, dose-ranging study (NCT04666441) was conducted at 47 sites across the USA (see appendix 1 for a full list of the study sites and investigators and appendix 2 for the Regeneron study team). Blinding Healthcare providers, patients and their caregivers were blinded to placebo and the doses of REGEN-COV drug but not to the route of administration. Power Analysis Statistical analysis: It was estimated that a sample size of 57 patients per treatment group would provide 98% power to detect a difference of –0·73 log10 copies/mL (assuming a … SciScore for 10.1101/2021.11.09.21265912: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization Trial design: This phase 2, randomised, double-blind, placebo-controlled, parallel-group, dose-ranging study (NCT04666441) was conducted at 47 sites across the USA (see appendix 1 for a full list of the study sites and investigators and appendix 2 for the Regeneron study team). Blinding Healthcare providers, patients and their caregivers were blinded to placebo and the doses of REGEN-COV drug but not to the route of administration. Power Analysis Statistical analysis: It was estimated that a sample size of 57 patients per treatment group would provide 98% power to detect a difference of –0·73 log10 copies/mL (assuming a standard deviation [SD] of 0·948) between any active treatment group and pooled placebo (IV and SC). Table 2: Resources
No key resources detected.
Results 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 NCT04425629 Recruiting Safety, Tolerability, and Efficacy of Anti-Spike (S) SARS-Co… NCT04452318 Completed COVID-19 Study Assessing the Efficacy and Safety of Anti-Spi… NCT04666441 Completed COVID-19 Study Assessing the Virologic Efficacy of REGN10933… 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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