Background and Objectives <p>New coronavirus disease 2019 (COVID-19) therapeutics, including intramuscular (IM) formulations, may increase patient access. In COMET-TAIL, sotrovimab 500&#xa0;mg IM was non-inferior to 500&#xa0;mg intravenous (IV) in reducing the risk of COVID-19 progression; however, 250&#xa0;mg IM was associated with more hospitalizations, despite similar viral load (VL) reductions to 500&#xa0;mg IM.</p> Methods <p>COMET-PEAK was a randomized, three-part study to assess safety, tolerability, and viral pharmacodynamics of sotrovimab in adults with early, mild-to-moderate COVID-19. Parts B/C evaluated sotrovimab 500-mg IV infusion versus 500-mg or 250-mg IM injection. The primary objective was to compare virologic response of sotrovimab IM versus IV (mean area under the curve from day 1 to day 8 [AUC_D1–8] of severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] VL); 90% confidence interval (CI) limits of 0.5–2.0 indicated equivalence.</p> Results <p>Parts B/C included 167 and 157 participants, respectively. Median age range was 42–47 years, and approximately 50% of participants had one or more risk factor for severe disease. The primary objective was met: the ratio of geometric mean VL AUC_D1–8 of sotrovimab IM versus IV was 1.04 (90% CI 0.98–1.09; Part B) and 1.02&#xa0;(90% CI 0.94–1.11; Part C). No new safety signals emerged for sotrovimab; IM administration was well tolerated, with few injection-site reactions.</p> Conclusions <p>Both sotrovimab IM doses were equivalent to 500&#xa0;mg IV with respect to SARS-CoV-2 VL change. IM administration was safe and well tolerated. The validity of VL as a biomarker for COVID-19 progression warrants further study.</p> Clinical Trial Registration <p>NCT04779879 (date of first registration: March 3, 2021), <a href="https://classic.clinicaltrials.gov/ct2/show/NCT04779879">https://classic.clinicaltrials.gov/ct2/show/NCT04779879</a>.</p>