First-in-human trial evaluating safety and pharmacokinetics of AT-752, a novel nucleotide prodrug with pan-serotype activity against dengue virus

Abstract

ABSTRACTAT-752 is a novel guanosine nucleotide prodrug inhibitor of the dengue virus (DENV) polymerase with sub-micromolar, pan-serotype antiviral activity. This Phase 1, double-blind, placebo-controlled, first-in-human study evaluated the safety, tolerability, and pharmacokinetics of ascending single and multiple oral doses of AT-752 in healthy subjects. AT-752 was well tolerated when administered as a single dose up to 1500 mg, or when administered as multiple doses up to 750 mg three times daily (TID). No serious adverse events occurred, and the majority of treatment-emergent adverse events were mild in severity and resolved by the end of the study. In those receiving single ascending doses of AT-752, no pharmacokinetic ethnic sensitivity was observed in Asian subjects and no food effect was observed. Plasma exposure of the guanosine nucleoside metabolite AT-273, the surrogate of the active triphosphate metabolite of the drug, increased with increasing dose levels of AT-752 and exhibited a long half-life of approximately 15–25 h. Administration of AT-752 750 mg TID led to a rapid increase in plasma levels of AT-273 exceeding the targetin vitro90% effective concentration (EC90) of 0.64 μM in inhibiting DENV replication, and maintained this level over the treatment period. The favorable safety and pharmacokinetic results support evaluation of AT-752 as an antiviral for the treatment of dengue in future clinical studies.