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 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 target in vitro 90% 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.

Xiao-Jian Zhou, Maureen Montrond, Laura Ishak, Keith Pietropaolo, Dayle James, Bruce Belanger, Arantxa Horga, Janet Hammond are employees of and may own stock in Atea Pharmaceuticals, Inc, Boston, MA, USA; Jason Lickliter is an employee of Nucleus Network, Melbourne, Australia, which was contracted by Atea Pharmaceuticals, Inc to help perform this research.

NCT04722627

This study was funded by Atea Pharmaceuticals, Inc. Medical writing support was provided by Samantha Brick, Elements Communications Ltd, UK, and funded by Atea Pharmaceuticals, Inc.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Human Research Ethics Committee of Atea Pharmaceuticals, Inc. gave ethical approval for this work before the trial began, and written informed consent was obtained from each subject before entering the study. This study was conducted according to the principles of the International Council for Harmonisation harmonised tripartite guideline E6(R2): Good Clinical Practice, and the ethical principles from the Declaration of Helsinki.

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All data produced in the present study are available upon reasonable request to the authors