Daily Mosnodenvir as Dengue Prophylaxis in a Controlled Human Infection Model

Approximately half the worldwide population is at risk for dengue. No antiviral prophylaxis or treatment options are available.

In a phase 2a, double-blind, randomized trial, we assigned healthy adults to receive oral mosnodenvir once daily as a low dose (40-mg loading dose followed by 10-mg maintenance dose), medium dose (200 mg followed by 50 mg), or high dose (600 mg followed by 200 mg) or matched placebo. Loading doses were given for 5 days and maintenance doses for 21 days. In a controlled human infection model, participants received subcutaneous inoculation of an underattenuated dengue virus serotype 3 (DENV-3) strain (rDEN3Δ30) on the day of the first maintenance dose (day 1). The primary efficacy end point was the DENV-3 RNA load, assessed as the log₁₀ area under the concentration-time curve from day 1 (immediately before inoculation) through day 29 (AUC_D1-29). The high-dose and placebo groups were compared in the primary end-point analysis. Safety, pharmacokinetic features, and virologic and serologic features were evaluated through day 85.

The percentage of participants without signs of DENV-3 infection was 0% (0 of 6 participants) with the low dose of mosnodenvir, 17% (1 of 6) with the medium dose, and 60% (6 of 10) with the high dose, as compared with 0% (0 of 7) with placebo. High-dose mosnodenvir led to a significantly lower DENV-3 RNA load, assessed as the log₁₀ AUC_D1-29, than placebo (two-sided P<0.001 by tobit analysis of variance). In this small trial, mosnodenvir did not result in any serious adverse events. Plasma concentrations of mosnodenvir increased from day -5 to day 1 and were maintained through day 21. Among participants with available NS4B sequencing data, emerging amino acid variations in the NS4B region of the rDEN3Δ30 genome were detected in 14 of 14 mosnodenvir recipients and none of 7 placebo recipients.

In a controlled human infection model, a high daily dose of oral mosnodenvir led to a significantly lower DENV-3 RNA load than placebo. Mosnodenvir did not result in any serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases and Johnson & Johnson; ClinicalTrials.gov number, NCT05048875.).