Antiviral Activity and Safety of Molnupiravir in Healthy Participants Inoculated With Influenza Virus: A Phase 2a, Randomized, Human Challenge Trial

Influenza viruses cause substantial global morbidity and mortality. Molnupiravir, an orally administered prodrug of β‐D‐N4‐hydroxycytidine, has broad activity against RNA viruses, including influenza. A phase 2a, randomized, two‐part human challenge trial in healthy adults (NCT05818124) was conducted to evaluate molnupiravir for influenza infection. In Part 1, 20 participants were inoculated with 10 6.26 TCID 50 of A/France/759/21 (H1N1) to establish infectivity, pathogenicity, and safety. After assessment of Part 1, a 10‐fold lower virus dose was selected for Part 2 to delay time to peak viral load (PVL). In Part 2, 141 participants were randomized 1:1:1:1 to receive molnupiravir (5 days, 800 mg twice daily) postexposure prophylaxis (PEP; initiated 12 hours after inoculation), molnupiravir treatment (initiated 48 hours after inoculation), oseltamivir treatment (5 days, 75 mg twice daily, initiated 48 hours after inoculation), or placebo. Primary endpoints, assessed by quantitative viral culture, were PVL in all participants for PEP and viral load area under the curve (VL‐AUC) in participants with confirmed infection for treatment. Lowering the viral inoculum delayed PVL by ~12 hours, although infection rates in the Part 2 placebo arm (40%) were lower than in Part 1 (75%). Molnupiravir PEP did not significantly reduce PVL compared with placebo but was associated with lower viral burden (difference in mean log 10 VL‐AUC –2.21 day*log 10 TCID 50 /mL; P = 0.03). No significant antiviral effect was observed with molnupiravir or oseltamivir treatment compared with placebo. Molnupiravir was well tolerated, with an adverse event profile similar to placebo. Although primary endpoints were not met, early administration of molnupiravir showed antiviral activity.