Background
MK-8527 is a novel nucleoside reverse transcriptase translocation inhibitor (NRTTI) under clinical development as an oral monthly antiretroviral agent for prevention of HIV‑1 infection. MK‑8527 is phosphorylated intracellularly to the pharmacologically active triphosphate form, MK-8527-TP. Clinical and nonhuman primate data were incorporated into an assessment of the pharmacokinetic/pharmacodynamic (PK/PD) relationship for MK-8527-TP to inform Phase 2 dose selection.
Methods
A rhesus macaque preexposure prophylaxis (PrEP) model evaluating weekly oral doses of MK-8527 (ranging from 0.1 to 6.0 mg/kg) followed by weekly simian/human immunodeficiency virus (SHIV) intrarectal challenge was used to define a PK/PD threshold. In two Phase 1b studies, treatment naive participants with HIV-1 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) and PK of MK-8527-TP in peripheral blood mononuclear cells (PBMCs) were used to establish an exposure-response relationship. A preliminary population PK model was used to simulate exposures across the Phase 1 studies to support dose selection in Phase 2.
Results
Doses of MK-8527 ≥0.1 mg/kg provided protection against intrarectal acquisition of SHIV in rhesus macaques. In Phase 1b studies, the mean decrease in HIV-1 RNA at Day 7 post-dose was ≥1.0 log10 copies/mL following single doses of MK-8527 ≥0.5 mg. The totality of data from the rhesus macaque study and Phase 1b trials suggests that efficacy for HIV‑1 prevention is achieved with an approximate inhibitory quotient ranging from 1 to 3. A PrEP PK/PD threshold for MK-8527-TP was set at 0.03 pmol/million PBMCs for HIV-1 prevention which is ~3‑fold above the in vitro half-maximal inhibitory concentration (0.00972 pmol/million PBMCs) of MK-8527-TP against wild type HIV-1. Based on this PK/PD threshold, and a preliminary population PK model, a ≥6-mg once-monthly oral dose of MK‑8527 would maintain MK-8527-TP levels above the PK/PD threshold in >90% of the population. Three oral dose levels of MK-8527 (3, 6, and 12 mg, administered monthly) were selected for the Phase 2 study.
Conclusions
PK/PD results incorporating clinical and nonclinical data support efficacy and further development of MK-8527 doses up to 12 mg for monthly oral PrEP.