Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a Phase I, open-label, dose-escalating, randomized controlled study

Abstract

Objectives AGILE is a Phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection. Methods We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomized 2:1 in groups of 6 participants to 300, 600 and 800 mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was 25% or greater. Secondary outcomes included safety, clinical progression, pharmacokinetics and virological responses. Results Of 103 participants screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 300, 600 and 800 mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800 mg molnupiravir, respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800 mg was estimated at 0.9%. Conclusions Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.

Molnupiravir in COVID-19: A systematic review of literature

“…All (4/4, 100%) patients receiving 300 and 600 mg, 1/4 (25%) patients receiving 800 mg, and 5/6 patients (83%) receiving SOC were found to have mild adverse events. This finds highest dose of 800 mg twice daily had a 0.9% probability of having 30% excess toxicity over the controls, and therefore molnupiravir was safe and well tolerated with a plasma concentration within the target range [ 15 ].…”

Antiviral activity of Molnupiravir precursor NHC against SARS-CoV-2 Variants of Concern (VOCs) and implications for the therapeutic window and resistance

“…Molnupiravir is an anti-viral pro-drug originally developed against influenza virus currently undergoing clinical trials in humans for the treatment of COVID-19 4, 5 . Interim phase III results suggested the drug reduced the risk of hospitalisation or death by 50% with efficacy unaffected by the timing of symptom onset, underlying risk factors, or variant type (gamma, delta, and mu) 6 .…”

Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients

“…Molnupiravir was evaluated in several phase 1 and 2 trials. 10 , 23 , 24 On the basis of exposure–response analyses from phase 2 trials, an 800-mg dose of molnupiravir was selected for further investigation, 25 including evaluation in phase 3 of the MOVe-OUT trial in at-risk, nonhospitalized adults in whom the onset of signs or symptoms of Covid-19 had occurred not more than 5 days earlier. Here we report efficacy and safety results from the phase 3 component of the MOVe-OUT trial.…”