ABSTRACT
Background: Casirivimab+imdevimab (hereinafter referred to as drug) remains vital in reducing hospitalization/death by 70% when administered early in the course of the infection. Our aim was to illustrate the mechanism of drug action in vivo and determine the magnitude of antiviral efficacy of various dose regimens given to outpatients with COVID-19, evaluating the presence of SARS-CoV-2 sero-antibody and ≥1 high-risk factor for developing severe COVID-19 illness as predictors of viral kinetics. Methods: Analysis data came from 2 clinical studies in SARS-CoV-2 infected outpatients with no or ≥1 risk factor for severe COVID-19 (NCT04425629 and NCT04666441), who received single dose of placebo or drug IV (300mg to 8g) or SC (600mg to 1.2g), had assessed viral load in nasopharyngeal swab and drug concentrations in serum (N=4500). The median number of viral load assessments per patient was 5 (range 1-8) within up to 14 days of follow-up time. Drug concentrations were predicted using the individual pharmacokinetic parameters yielded by a population model. The median patient age was 42 years, with similar proportion of males and females. The median viral load at baseline was 6.79 log10 copies/mL, and the median time of symptom onset was 3 days before study baseline. A standard target cell-limited model was used to estimate the time of infection and reconstruct viral kinetic profiles. Various relationships between exposure and resulting antiviral response were evaluated, where the drug could block de novo infection, increase the elimination rate of infected cells, or reduce viral production from infected cells. Results: The results support that the main mechanism of drug action is blocking de novo infection with an estimated decrease in the infectivity rate of 96.6%, for all dose regimens evaluated herein. High-risk factor for severe COVID-19 and baseline sero-antibody-positive/other status were associated with a 4.71% decrease and a 4.96% increase in the elimination rate of infected cells, respectively. The estimated median and 95th percentile of time to viral clearance (ie, viral count reaches below assay quantification limit) were 1.4 and 3.4 days shorter in drug vs placebo (median 10.6 vs 12.0 days, and 95th percentile 15.2 vs 18.6 days). Conclusion: All IV and SC casirivimab+imdevimab dose regimens evaluated herein showed similar near-maximal antiviral activity by blocking de novo infection;hence, shortening the time to virus clearance.