Nele Goeyvaerts1, Xavier Woot de Trixhe1, Martine Neyens1, Thomas Kakuda2, Liesbeth Van Wesenbeeck1, Annemie Buelens1, Freya Rasschaert1, Anna Durbin3, Oliver Ackaert1
1Johnson & Johnson, 2Johnson & Johnson, 3John Hopkins Bloomberg School of Public Health
Introduction: Dengue virus (DENV) infection is transmitted to humans through the bite of infected mosquitoes and caused by any of the four virus serotypes (DENV-1 to DENV-4). About half of the world’s population is at risk of dengue with an estimated 100-400 million infections occurring each year [1]. While many dengue infections are asymptomatic, a small fraction can progress to severe disease or even be fatal. Currently, there is no DENV-specific treatment available. Mosnodenvir (JNJ-64281802) is a pan-serotype dengue antiviral small molecule in clinical development that blocks viral replication by inhibiting de novo interactions between DENV nonstructural (NS) proteins NS3 and NS4B [2]. A Phase 2a study (NCT05048875) evaluated the antiviral activity, safety, and pharmacokinetics (PK) of repeated oral doses of mosnodenvir as prophylaxis against DENV-3 infection in a controlled human infection model (CHIM). Objectives: To estimate the prophylactic effect of mosnodenvir against DENV-3 in a CHIM using a combined population PK (PopPK) and viral kinetic model (VKM), and to inform dose selection for a subsequent cohort of the same study using model-based simulations. Methods: A PopPK model for mosnodenvir was developed based on plasma PK data from three Phase 1 studies and the Phase 2a study, including single- and multiple-doses administered daily or (twice) weekly. Based on the PopPK model, individual mosnodenvir exposure metrics were estimated for the healthy participants in the CHIM receiving mosnodenvir high dose (600 mg loading dose (LD)/200 mg maintenance dose (MD) daily), medium dose (200 mg LD/50 mg MD daily) or low dose (40 mg LD/10 mg MD daily). The target cell-limited model [3] and the immune response model [4] were considered as VKMs to describe the observed DENV-3 RNA levels in the CHIM. A stepwise approach was used by first building a VKM for participants on placebo and subsequently extending the VKM with the PopPK model to capture the antiviral effect of mosnodenvir. Based on the final PK-VKM, 500 study replicates were simulated for different dosing regimens. Simulated mosnodenvir exposure metrics and antiviral activity metrics were compared to guide dose selection for the subsequent cohort. PopPK models were fitted using FOCE-I, VKMs were fitted using the Laplace method, and PK-VKM simulations were conducted in NONMEM version 7.4. PopPK model simulations were conducted in R version 3.6.2 or higher. Results: The PopPK model for mosnodenvir was developed based on 8,352 plasma PK samples from 246 healthy participants. Mosnodenvir PK was adequately described by a two-compartment disposition model with a food-, dose-, and formulation-dependent delayed absorption and linear clearance. A covariate effect of BMI was included on the relative bioavailability, first-order absorption rate constant and apparent clearance. The PK-VKM was developed on 602 serum samples from 29 participants in the CHIM, receiving placebo or one of the three mosnodenvir dosing regimens. The DENV-3 RNA course was adequately described by an immune response model with mosnodenvir antiviral effect on the virion production rate, assuming a sigmoid Emax relationship with the average mosnodenvir concentration at steady state (Cavg,SS). The basic reproductive number, ie, the average number of secondary infections caused by a single infected cell over its lifespan within the host, was estimated as 28.7 cells. The reproduction minimum inhibitory concentration (RMIC, [5]) for mosnodenvir was estimated as Cavg,SS of 2,180 ng/mL. PK-VKM based simulations were used to support one daily dose regimen and two weekly dose regimens for the subsequent cohort of the study, with the aim to further characterize the PK/PD relationship of mosnodenvir. Conclusions: A semi-mechanistic exposure-response VKM adequately described observed DENV-3 RNA profiles under placebo and different mosnodenvir dosing regimens in a CHIM and proved useful to estimate the prophylactic drug effect and inform dose selection in this Phase 2a study.
[1] WHO dengue fact sheet: https://www.who.int/news-room/fact-sheets/detail/dengue-and-severe-dengue [2] Goethals O, Kaptein SJF, Kesteleyn B, et al. Blocking NS3-NS4B interaction inhibits dengue virus in non-human primates. Nature 2023;615(7953):678-686. [3] Baccam P, Beauchemin C, Macken CA, Hayden FG, Perelson AS. Kinetics of influenza A virus infection in humans. J Virol. 2006 Aug;80(15):7590-9. [4] Clapham HE, Tricou V, Van Vinh Chau N, Simmons CP, Ferguson NM. Within-host viral dynamics of dengue serotype 1 infection. J R Soc Interface. 2014;11(96):20140094. [5] Jacqmin P, McFadyen L, Wade JR. Basic PK/PD principles of drug effects in circular/proliferative systems for disease modelling. J Pharmacokinet Pharmacodyn. 2010 Apr;37(2):157-77.
Reference: PAGE 33 (2025) Abstr 11447 [www.page-meeting.org/?abstract=11447]
Poster: Drug/Disease Modelling - Infection