High lung levels of active triphosphate predicted with oral at-527 in COVID patients

ABSTRACT

Background: AT-527 is a guanosine nucleotide prodrug with potent in vitro antiviral activity against flaviviruses and coronaviruses including SARS-CoV-2 (EC90=0.5 μM), the virus responsible for COVID-19. AT-527 exhibits a unique mechanism of action predominantly targeting the NiRAN function of the SARS-CoV-2 polymerase. The clinical safety to date and in vitro potency of AT-527 prompted evaluation of this drug candidate in patients with COVID-19. The purpose of this study was to assess the safety and pharmacokinetics (PK) of AT-527 dosed 550 mg twice a day (BID) in healthy subjects and to predict human lung exposure of the active triphosphate metabolite AT-9010. Methods: Twenty healthy subjects were randomized 11 to receive orally AT-527 550 mg BID or matching placebo for 5 days. Safety assessments included adverse events (AEs), vital signs, electrocardiograms (ECGs) and standard safety laboratory tests. Intensive PK sampling was performed after the first and last two doses and assayed for plasma AT-511, the free base form, and metabolites including AT-273, the guanosine nucleoside metabolite, a surrogate for intracellular AT-9010. Results: AT-527 was well tolerated with no discontinuations, serious AEs, clinically significant changes in vital signs or ECGs based on still blinded safety data. AT-511 was rapidly absorbed followed by fast and extensive metabolic conversion to an L-alanyl intermediate metabolite AT-551 and ultimately intracellular AT-9010, reflected by plasma AT-273. Steady state levels were quickly achieved by the third dose of AT-527. Plasma levels of AT-273 were used to predict lung concentrations of AT-9010 using a scaling factor of 1.2X previously determined from in vivo tissue distribution of the triphosphate metabolite in cynomolgus monkeys. As early as 3 hours after the first dose and maintained from the second dose throughout 5 days of dosing, the predicted lung AT-9010 levels were consistently above the EC90 of the drug candidate in inhibiting SARS-CoV-2 replication in vitro. Conclusion: AT-527 orally administered with a regimen of 550 mg BID for 5 days was well-tolerated in healthy subjects. A favorable PK profile was demonstrated rapid attainment of steady state with a fast build-up of trough levels of AT-273, which were reflective of efficacious active triphosphate metabolite levels in the lungs. AT-527, with a 550 mg BID dosing regimen, is currently being evaluated in Phase 2 clinical studies as an early treatment option for COVID-19.