Safety, Pharmacokinetics, and Activity of AT-752, a Novel Nucleotide Prodrug with Pan-Serotype Activity against Dengue Virus: A Phase 2, Randomized, Double-Blind Study

AT-752 is a novel guanosine nucleotide prodrug inhibitor with pan-serotype antiviral activity against dengue virus. In this phase 2, randomized, double-blind, placebo-controlled study, we evaluated the activity, safety, and pharmacokinetics of oral AT-752 (750 mg thrice daily for 5 days) compared with a placebo in 21 adults with confirmed dengue infection. The primary endpoint was the change from baseline in viral load via reverse transcription quantitative polymerase chain reaction testing, with assessments performed daily on Days 1-8, 14, and 28. The primary endpoint was nonevaluable because many patients presented late during the course of disease, with low baseline viremia levels precluding accurate quantification at subsequent timepoints. In the as-treated population (patients with assessment at baseline and at each post-baseline timepoint), the numerical mean reduction (versus baseline) in viral load on Day 4 was greater in the AT-752 group than the placebo group (P = 0.0022). The median time to a sustained resolution of fever (the major clinical sign of dengue) was 4 days in the AT-752 group compared with >5 days in the placebo group; the reduction in oral temperature at the Day 4 timepoint was greater in the AT-752 group (treatment difference: 0.84°C; P = 0.0322). There was a trend toward faster platelet recovery in the AT-752 group compared with the placebo group, and proportionally fewer patients in the AT-752 group underwent hospitalization for disease progression (one patient in each group). AT-752 exhibited favorable safety and tolerability; the majority of adverse events were mild or moderate, and Grade 3 or 4 adverse events occurred at similar rates in both groups. These data support the further evaluation of AT-752 in treating dengue in future clinical trials.