Viral Dynamic Model-Informed Dose Selection of Mosnodenvir Prophylaxis against DENV-3 in a Controlled Human Infection Model.

Dengue virus (DENV) infection is a significant global health threat. Mosnodenvir (JNJ-64281802) is a pan-serotype small molecule antiviral blocking DENV replication. A Phase IIa study (NCT05048875) evaluated the antiviral activity, safety, and pharmacokinetics of mosnodenvir as prophylaxis against DENV-3 in a controlled human infection model (CHIM). A combined population pharmacokinetic (PopPK) and viral dynamic model (VDM) was developed to estimate the prophylactic effect of mosnodenvir and to inform dose selection. The PopPK model is a two-compartment model based on plasma pharmacokinetic data from three Phase I studies and Cohort 1 of the Phase IIa study. Mosnodenvir exposure metrics were estimated for participants receiving high, medium, or low doses. A VDM with an immune response compartment adequately described DENV-3 RNA profiles for placebo participants and was subsequently extended by including a sigmoid Emax relationship with average mosnodenvir concentration at steady state (Cavg,ss) to capture the antiviral effect on virion production rate. Simulations supported daily and weekly mosnodenvir dosing regimens to further characterize the pharmacokinetic/pharmacodynamic relationship in Cohort 2. Based on the complete Phase IIa study data, the basic reproductive number for DENV-3 in this CHIM was estimated at 21.7, and the typical Cavg,ss required to achieve complete virus eradication was estimated to be 1,410 ng/mL. In conclusion, the combined PopPK and VDM approach effectively informed dose selection and characterized the pharmacokinetic-antiviral activity relationship, supporting the development of mosnodenvir as a prophylactic treatment for dengue infection.