Intramuscular Versus Intravenous SARS-CoV-2 Neutralizing Antibody Sotrovimab for Treatment of COVID-19 (COMET-TAIL): A Randomized Non-inferiority Clinical Trial (preprint)

Background: Convenient administration of coronavirus disease 2019 (COVID-19) treatment in community settings is desirable. Sotrovimab is a pan-sarbecovirus dual-action monoclonal antibody formulated for intravenous (IV) or intramuscular (IM) administration for early treatment of mild/moderate COVID-19. Methods: This phase 3, randomized, multicenter, open-label study tested non-inferiority of IM to IV administration using a 3.5% absolute non-inferiority margin. From June to August 2021, patients aged [≥]12 years with COVID-19, not hospitalized or receiving supplemental oxygen, and at high risk for progression were randomized 1:1:1 to a single 500-mg IV sotrovimab infusion or 500-mg or 250-mg IM sotrovimab injection. The primary composite endpoint was progression to all-cause hospitalization for >24 hours for acute management of illness or all-cause death through day 29. Results: Sotrovimab 500 mg IM was non-inferior to 500 mg IV: 10/376 (2.7%) participants in the sotrovimab 500-mg IM group versus 5/378 (1.3%) in the sotrovimab 500-mg IV group met the primary endpoint (absolute adjusted risk difference: 1.06% [95% confidence interval [CI]: -1.15%, 3.26%]). The CI upper limit was lower than the prespecified non-inferiority margin of 3.5%. 250-mg IM group enrollment was discontinued early because a greater proportion of hospitalizations was seen in that group versus the 500-mg groups. Serious adverse events occurred in <1% to 2% of participants across groups. Four participants experienced serious disease related events and died (500 mg IM: 2/393 [<1%]; 250 mg IM: 2/195 [1%]). Conclusions: Sotrovimab 500-mg IM injection was well tolerated and non-inferior to IV administration. IM administration could expand outpatient treatment access for COVID-19.

REGEN-COV Antibody Cocktail in Outpatients with Covid-19 (preprint)

Background: REGEN-COV (casirivimab and imdevimab) antibody cocktail reduced SARS-CoV-2 viral load in descriptive analyses of the first 275 Covid-19 outpatients in the phase 1/2 portion of an ongoing double-blind, seamless phase 1/2/3 trial. Methods: This final analysis of the phase 1/2 portion includes 799 patients: 275 (group-1) and 524 (group-2). Patients were randomized (1:1:1) to placebo, 2400mg REGEN-COV, or 8000mg REGEN-COV, and characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody-positive/negative). Efficacy was assessed in patients with a positive baseline RT-qPCR result; safety was assessed in all treated patients. Prespecified hierarchical analyses of virologic endpoints in group-2 were performed to confirm previously reported descriptive analyses from group-1. The proportion of patients with [≥]1 Covid-19-related medically-attended visit (MAV) through day 29 was assessed in group-1+2. Results: Time-weighted average reduction in viral load (log10 copies/ml) through day 7 was significantly greater with REGEN-COV (combined 2400mg+8000mg dose groups) versus placebo in patients with baseline viral load >107 copies/ml (prespecified primary endpoint): -0.68 (95% CI, -0.94 to -0.41; P<0.0001). This reduction was -0.73 (P<0.0001) in serum antibody-negative patients and -0.36 (P=0.0003) in the overall population. Proportions of patients with [≥]1 Covid-19-related MAV were 2.8% (12/434) with REGEN-COV versus 6.5% (15/231) with placebo (P=0.024; relative risk reduction=57%), with greater relative risk reductions in MAVs in patients with [≥]1 risk factor for hospitalization (71%). Adverse events were similar across groups. Conclusions: REGEN-COV treatment of outpatients significantly reduced SARS-CoV-2 viral load and Covid-19-related medically-attended visits. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.)