Antiretroviral Activity, Pharmacokinetics, and Safety of MK-8527, an Oral Nucleoside Reverse Transcriptase Translocation Inhibitor, in Adults Living With HIV-1 Who Had Not Previously Taken Antiretroviral Agents: Results From Two Open-Label, Phase 1 Studies

Abstract Background MK-8527 is a novel oral nucleoside reverse transcriptase translocation inhibitor under clinical development as HIV-1 prevention. Two Phase 1 single-dose monotherapy studies were conducted to evaluate antiretroviral activity, pharmacokinetics (PK), and safety of MK-8527 in adults living with HIV-1 who had not previously taken antiretroviral agents. Methods In two Phase 1 studies, participants received a single oral dose of MK-8527 (0.25, 0.5, 1, 3, or 10 mg). Reduction in viral load (measured as log10 plasma HIV-1 RNA copies/mL at 7 days post-dose), PK of plasma MK-8527 through 7 days, intracellular MK-8527-triphosphate (TP, the active form of MK-8527) through 28 days, exposure-response relationship, and safety through 28 days were assessed. Adverse events were descriptively summarized. Results In total, 37 participants completed the studies. After single doses of MK-8527 0.5 to 10 mg, the mean decrease in HIV-1 RNA at 7 days-post dose was ≥1.0 log10 copies/mL. The inhibitory quotient (defined as the ratio of MK-8527-TP concentration at 168 hours post-dose C168 to the mean intracellular concentration of MK-8527-TP at the half-maximal inhibitory concentration IC50) exceeded 3 at single doses of ≥0.5 mg. MK-8527 at all dose levels was well tolerated, with a limited number of mild or moderate adverse events that were determined by investigators to be unrelated to the study treatment. Conclusions In adults living with HIV-1 who had not previously taken antiretroviral agents, single doses of MK-8527 as low as 0.5 mg achieved ≥1.0 log10 decreases in HIV-1 RNA at 7 days post-dose administration. Clinical trial registration www.clinicaltrials.gov NCT03615183, NCT05494736