Background:
MK-8527 is a novel oral nucleoside reverse transcriptase translocation inhibitor (NRTTI) under clinical development as an antiretroviral for HIV-1 infection. Based on previous preclinical and phase 1 clinical studies, the pharmacokinetic properties of MK-8527 support extended once-weekly or longer dosing. Two phase 1 single dose monotherapy studies were conducted to evaluate the antiretroviral activity of MK-8527 in treatment-naive participants with HIV-1.
Methods:
Eligible participants were treatment-naive adults 18–60 years of age with HIV-1. In two phase 1 studies (NCT03615183 and NCT05494736), participants received a single oral dose of MK-8527 (0.5, 1, 3, or 10 mg). Reduction in viral load (measured as log10 plasma HIV-1 RNA copies/mL), safety, tolerability, and intracellular pharmacokinetics of MK-8527-triphosphate (TP, the active form of MK-8527) in peripheral blood mononuclear cells were assessed. Data were analyzed and presented per dosing panel; data for the 1-mg dose group were pooled from both studies. Incidence of adverse events were descriptively summarized.
Results:
A total of 31 participants have been enrolled and completed dosing. Following single doses of 0.5 to 10 mg, the mean decrease in HIV-1 RNA at Day 7 following dose administration was ≥1.0 log10 copies/mL (Table). The inhibitory quotient (defined as the ratio of geometric mean of MK-8527-TP C168 and IC50) exceeded 3 at all doses assessed. MK-8527 at all dose levels was generally well tolerated, with a limited number of mild to moderate adverse events determined by investigators to be unrelated to the study treatment; there were no serious adverse events, events of clinical interest, or deaths.
Conclusions:
In treatment-naive persons with HIV-1, single doses of MK-8527 as low as 0.5 mg achieved ≥1 log10 decreases in HIV-1 RNA at Day 7 following dose administration.
