Safety, Tolerability, and Pharmacokinetics of JNJ-1802, a Pan-serotype Dengue Direct Antiviral Small Molecule, in a Phase 1, Double-Blind, Randomized, Dose-Escalation Study in Healthy Volunteers

Abstract

Background: Dengue is a growing global health threat with no specific antiviral drugs available for treatment or prophylaxis. This first-in-human, double-blind, randomized, placebo-controlled study aimed to examine the safety, tolerability, and pharmacokinetics of increasing single and multiple oral doses of JNJ-1802, a pan-serotype dengue antiviral small molecule. Methods: Eligible healthy participants (18-55 years of age) were randomized to receive oral JNJ-1802 in fasted conditions as (1) single doses (50-1200 mg; n = 29) or placebo (n = 10); or (2) once-daily doses (50-560 mg for 10 consecutive days or 400 mg for 31 days; n = 38) or placebo (n = 9). Safety and tolerability were evaluated throughout the study. Plasma and urine samples were collected at predetermined time points to characterize pharmacokinetics. Results: JNJ-1802 was generally safe and well-tolerated. One grade 3 adverse event (depression) was reported but not considered drug-related by the investigator. Two grade 2 events of rash occurred (multiple-dose part) that were considered very likely related to JNJ-1802 by the investigator and resolved. No clinically relevant changes were observed in laboratory tests, electrocardiograms, or vital signs. JNJ-1802 exposure after single or multiple doses increased dose-proportionally from 50 to 150 mg and less than dose-proportionally for higher doses. The terminal elimination half-life was 6.3-9.2 days and the accumulation factor was 4.3-7.3 after 10 days and 14.6 after 31 days with low amounts of unchanged drug in urine (<0.001% of the 400 mg dose). Conclusions: Pharmacokinetics and safety results of JNJ-1802 support further clinical development for the treatment and prevention of dengue infection.