Virologic Outcomes with Molnupiravir in Non-hospitalized Adult Patients with COVID-19 from the Randomized, Placebo-Controlled MOVe-OUT Trial.

ABSTRACT

INTRODUCTION: The randomized, placebo-controlled, double-blind MOVe-OUT trial demonstrated molnupiravir (800 mg every 12 h for 5 days) as safe and effective for outpatient treatment of mild-to-moderate COVID-19, significantly reducing the risk of hospitalization/death in high-risk adults. At the time of that report, virologic assessments from the trial were partially incomplete as a result of their time-intensive nature. Here we present final results from all prespecified virology endpoints in MOVe-OUT based on the full trial dataset. METHODS: Nasopharyngeal swabs were collected at baseline (day 1, prior to first dose) and days 3, 5 (end-of-treatment visit), 10, 15, and 29. From these samples, change from baseline in SARS-CoV-2 RNA titers (determined by quantitative PCR), detection of infectious SARS-CoV-2 (by plaque assay), and SARS-CoV-2 viral error induction (determined by whole genome next-generation sequencing) were assessed as exploratory endpoints. RESULTS: Molnupiravir was associated with greater mean reductions from baseline in SARS-CoV-2 RNA than placebo (including 50% relative reduction at end-of-treatment) through day 10. Among participants with infectious virus detected at baseline (n = 96 molnupiravir, n = 97 placebo) and evaluable post-baseline samples, no molnupiravir-treated participant had infectious SARS-CoV-2 by day 3, whereas infectious virus was recovered from 21% of placebo-arm participants on day 3 and 2% at end-of-treatment. Consistent with molnupiravir's mechanism of action, sequence analysis demonstrated that molnupiravir was associated with an increased number of low-frequency transition errors randomly distributed across the SARS-CoV-2 RNA genome compared with placebo (median 143.5 molnupiravir, 15 placebo), while transversion errors were infrequent overall (median 2 in both arms). Outcomes were consistent regardless of baseline SARS-CoV-2 clade, presence of SARS-CoV-2-specific immune response, or viral load. CONCLUSIONS: A 5-day course of orally administered molnupiravir demonstrated a consistently greater virologic effect than placebo, including rapidly eliminating infectious SARS-CoV-2, in high-risk outpatients with mild-to-moderate COVID-19. TRIAL REGISTRATION ClinicalTrials.gov, NCT04575597.