The emergence of SARS-CoV-2 viral variants threatens current anti-viral and preventative strategies, including monoclonal antibodies and vaccines. Critically, the limited supply of vaccines and the complex logistics surrounding the delivery of infusion-based therapies herald the need for an easily produced, distributed, and specific direct-acting antiviral for COVID-19 that limits progression of illness and ideally prevents transmission.
The efficacy of molnupiravir was evaluated in a double-blind, randomized, placebo-controlled, Phase 2 dose-range finding study using realtime polymerase chain reaction (RT-PCR) and virus isolation was conducted at 11 study sites in the U.S. Participants were randomized if they had signs or symptoms of COVID-19 within 7 days, and a positive SARS-CoV-2 RT-PCR within 4 days of enrollment. Initially, participants were randomized in a 1:1 ratio to receive 200 mg molnupiravir or placebo twice daily for 5 days. Subsequently, in the dose-range finding portion of the study, participants were randomized in a 3:1 ratio to receive 200, 400, or 800 mg molnupiravir or placebo twice daily for 5 days. Nasopharyngeal swabs were analyzed from 175 subjects at enrollment, Day 3, and Day 5 for SARS-CoV-2 infectivity. Samples were stored at 4°C for up to 72 hours, shipped refrigerated, aliquoted, and stored at -80°C until testing. Vero E6 cell monolayers were infected with the sample for 1 hour. Culture medium was analyzed for viral load at 2 and 5 days post-infection by RT-PCR.
Seventy-eight (45%) participants, median 4.62 days (min. 1.40, max. 7.54) from symptom onset, had a positive SARS-CoV-2 culture at enrollment (52 on active and 26 on placebo). The percentage of participants with a positive viral culture at enrollment who were positive on Day 3 was 20.4% on active and 28% on placebo (p = 0.56). At day 5, 24% of placebo participants were culture-positive compared to none treated with molnupiravir (p = 0.001). Between treatment, comparisons were performed using Fisher’s exact test.
This is the first demonstration of reduced infectiousness by antiviral therapy in people with SARS-2 infection. This simple, short-course oral therapy may benefit individuals and public health and is unlikely to be impacted by spike-protein variants.