Written By: Pharmacally Medical News Desk
A groundbreaking phase 2a trial published November 27, 2025, in the New England Journal of Medicine reveals high-dose oral Mosnodenvir cut dengue virus serotype 3 (DENV-3) RNA levels by preventing infection in 60% of participants. Led by Anna P. Durbin at Johns Hopkins Bloomberg School of Public Health, the study tested Janssen’s pan-DENV drug in 31 healthy volunteers deliberately inoculated with mild under attenuated rDEN3Δ30, revealing dose-dependent protection absent in placebo recipients.
Conducted at Johns Hopkins Bloomberg School of Public Health and University of Vermont, the double-blind, randomized, placebo-controlled trial enrolled 31 healthy; DENV/Zika-seronegative adults aged 18-55. Participants received daily oral Mosnodenvir low (40-mg loading/10-mg maintenance), medium (200/50 mg), or high (600/200 mg) doses or placebo for 26 days total, with subcutaneous shot of under attenuated DENV-3 strain rDEN330 on day 1 of maintenance dosing. Primary endpoint focused on log10 DENV-3 RNA area under the curve (AUCD1-29), analyzed via tobit ANOVA comparing high-dose to placebo (P=0.001).
High-dose Mosnodenvir significantly reduced DENV-3 RNA load versus placebo, with 60% (6/10) showing undetectable RNA through day 29—none (0/7) in placebo. Dose-response was clear: 0% infection-free in low-dose (0/6), 17% in medium (1/6); time to RNA detection delayed progressively, and DENV-rash incidence fell to 30% from 100%. No seroconversion or symptoms occurred in infection-free high-dose recipients, validating prophylaxis potential.
Group | N (Efficacy) | No DENV-3 RNA (%) | Rash (%) |
Low Dose | 6 | 0% | 83% |
Medium | 6 | 17% | 50% |
High | 10 | 60% | 30% |
Placebo | 7 | 0% | 100% |
Mosnodenvir (JNJ-64281802) developed by Janssen which targets viral replication of DENV by blocking DENV nonstructural protein 3 (NS3) and NS4B with proven potency in lab and animal models.
All participants, whether on Mosnodenvir or placebo, experienced at least one adverse event during the study period. Most events were mild (grade 1) or moderate (grade 2), occurred at similar frequencies across treatment and placebo groups, and resolved without lasting consequences. Two severe (grade 3) adverse events were observed among Mosnodenvir recipients during follow-up: one medium-dose participant developed markedly elevated lipase and glucose levels, and one high-dose participant developed severe COVID-19. One participant stopped treatment before viral inoculation due to moderate photosensitivity considered related to Mosnodenvir, but this did not progress to a serious event.
Mosnodenvir Future in Limbo
Despite delivering compelling phase 2a proof-of-concept with 60% dengue prevention results Mosnodenvir faces an uncertain future after Johnson & Johnson (Janssen) discontinued its phase 2 field efficacy study (NCT05201794) in October 2024 due to strategic R&D reprioritization away from infectious diseases, unrelated to safety or efficacy concerns. The challenge trial itself was completed earlier through National Institute of Allergy and Infectious Diseases (NIAID)-J&J collaboration at academic sites like Johns Hopkins, with no new sponsor identified to advance development as of late 2025.
Experts like Sophie Yacoub (University of Oxford) report ongoing negotiations for licensing to a new partner, fueled by unreviewed field data and rising global dengue burden, though commercial hurdles in low-profit markets persist, leaving hope that this pan-DENV oral antiviral finds a path forward for outbreaks, travelers, and endemic regions.
References
A.P. Durbin et al, Daily Mosnodenvir as Dengue Prophylaxis in a Controlled Human Infection Model, N Engl J Med 2025;393:2107-18, DOI: 10.1056/NEJMoa2500179
An Evaluation of Repeated Oral Doses of JNJ-64281802 against DENV-3 Challenge, ClinicalTrials.gov ID NCT05048875, https://clinicaltrials.gov/study/NCT05048875
Johnson & Johnson to Discontinue Phase 2 Field Study Evaluating Investigational Antiviral for the Prevention of Dengue, Johnson and Johnson, 04 October 2025, https://www.jnj.com/media-center/press-releases/johnson-johnson-to-discontinue-phase-2-field-study-evaluating-investigational-antiviral-for-the-prevention-of-dengue
Antiviral drug abandoned by pharma shows promise against dengue, Science, 28 November 2025, https://www.science.org/content/article/antiviral-drug-abandoned-pharma-shows-promise-against-dengue
Bouzidi, H.S., Sen, S., Piorkowski, G. et al. Genomic surveillance reveals a dengue 2 virus epidemic lineage with a marked decrease in sensitivity to Mosnodenvir. Nat Commun 15, 8667 (2024). https://doi.org/10.1038/s41467-024-52819-z,