Mosnodenvir provides Dose-Dependent Protection Against Dengue infection: NEJM

A new study published in The New England Journal of Medicine showed that when compared to a placebo, a high daily dose of oral mosnodenvir resulted in a considerably reduced DENV-3 RNA burden.

Dengue poses a threat to around half of the world's population. There are no choices for antiviral prophylaxis or therapy. This study presents the preliminary findings of a phase 2a trial that evaluated the pharmacokinetic profile, safety, and prophylactic antiviral activity of various daily doses of mosnodenvir in healthy participants following challenge with an underattenuated DENV-3 strain in a regulated human infection model.

Healthy people were randomized to receive oral mosnodenvir once daily as a low dosage (40 mg loading dose followed by 10 mg maintenance dose), medium dose (200 mg followed by 50 mg), high dose (600 mg followed by 200 mg), or matched placebo in this study. For five days, loading doses were administered, and for 21 days, maintenance doses. On the day of the first maintenance dosage (day 1), participants in a controlled human infection model were subcutaneously injected with an underattenuated dengue virus serotype 3 (DENV-3) strain (rDEN3Δ30).

The DENV-3 RNA load, measured as the log10 area under the concentration–time curve from day 1 (just before inoculation) to day 29 (AUCD1–29), was the main efficacy end goal. The major end-point analysis contrasted the high-dose and placebo groups. Through day 85, safety, pharmacokinetic characteristics, and virologic and serologic characteristics were assessed.

When compared to 0% (0 of 7) with a placebo, the percentage of subjects who did not exhibit symptoms of DENV-3 infection was 0% (0 of 6) with the low dose of mosnodenvir, 17% (1 of 6) with the medium dose, and 60% (6 of 10) with the high dose. The high-dose mosnodenvir dramatically reduced the DENV-3 RNA load, measured as the log10 AUCD1–29 (two-sided P<0.001 using tobit analysis of variance) when compared to a placebo.

Mosnodenvir did not cause any significant side effects in this tiny experiment. Mosnodenvir plasma concentrations rose from day −5 to day 1 and remained steady until day 21. Emerging amino acid changes in the NS4B region of the rDEN3Δ30 genome were found in 14 of 14 mosnodenvir recipients and none of the 7 placebo recipients among persons with accessible NS4B sequencing data.

Overall, in a regulated human infection model, mosnodenvir can prevent DENV-3 infection and related symptoms in a dose-dependent manner. These evaluations' findings will supplement information from the phase 2 clinical field investigation on mosnodenvir prophylaxis.

Reference:

Durbin, A. P., Van Wesenbeeck, L., Pierce, K. K., Herrera-Taracena, G., Ebone, L., Buelens, A., Lutton, P., Sabundayo, B. P., Van Eygen, V., De Clerck, K., Fetter, I., Voge, N. V., Fang, X., Goeyvaerts, N., Vandendijck, Y., Mayfield, J., Lenz, O., De Meyer, S., Kakuda, T. N., … Rasschaert, F. (2025). Daily mosnodenvir as dengue prophylaxis in a controlled human infection model. The New England Journal of Medicine, 393(21), 2107–2118. https://doi.org/10.1056/NEJMoa2500179