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

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 E_max relationship with average mosnodenvir concentration at steady state (C_avg,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 C_avg,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.