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

• DOI: 10.1128/aac.01615-23
• Publication Date: 2024-03-25T12:45:39Z
• Authors: Xiao-Jian Zhou; Jason Lickliter; Maureen Montrond; Laura Ishak; Keith Pietropaolo; Dayle James; Bruce Belanger; Arantxa Horga; Janet Hammond
• Keywords: Male; Adult; 0301 basic medicine; Dengue Virus; Middle Aged; Antiviral Agents; Guanine Nucleotides; Dengue; Young Adult; 03 medical and health sciences; Double-Blind Method; Humans; Prodrugs; Female; Half-Life

ABSTRACT AT-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 safety, tolerability, and pharmacokinetics ascending single multiple oral doses in healthy subjects. was well tolerated when administered as dose up to 1,500 mg or 750 three times daily (TID). No serious adverse events occurred, majority treatment-emergent were mild severity resolved by end study. In those receiving AT-752, no pharmacokinetic sensitivity observed Asian subjects, food effect observed. Plasma exposure nucleoside metabolite AT-273, surrogate active triphosphate drug, increased increasing levels exhibited long half-life approximately 15–25 h. Administration TID led rapid increase plasma AT-273 exceeding target vitro 90% effective concentration (EC 90 ) 0.64 µM inhibiting DENV replication, maintained this level over treatment period. The favorable safety results support evaluation an for future clinical studies. Registered at ClinicalTrials.gov ( NCT04722627 ).