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A Single Monotherapy Dose of MK-8591, a Novel NRTI, Suppresses HIV for 10 Days
Evan Friedman1; Dirk Schuermann2; Deanne J. Rudd3; Sabrina Fox-Bosetti3; Sandra Zhang3; Martine Robberechts3; Andreas Hueser4; Daria J. Hazuda5; Marian Iwamoto3; Jay Grobler5; for the HIV Early Development Team
1Merck & Co, Rahway, NJ, USA;2Charité Rsr Organisation GmbH, Berlin, Germany;3Merck & Co, Kenilworth, NJ, USA;4Charité Universitätsmedizin Berlin, Berlin, Germany;5Merck & Co, West Point, PA, USA
MK-8591 is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) in early clinical development. MK-8591-triphosphate (TP), the active phosphorylated anabolite of MK-8591, exhibited protracted intracellular persistence in human and monkey peripheral blood mononuclear cells (PMBCs) in vitro. In preclinical experiments, MK-8591 administered once-weekly in an SIV rhesus macaque model demonstrated potent antiviral efficacy. Clinically, MK-8591-TP exhibited a half-life of ~150-160 hrs in human PBMCs with C168hr exceeding projected efficacious concentrations at doses of >10 mg. A Phase 1b monotherapy proof-of-concept efficacy study is currently underway to assess the potential for once weekly oral dosing in the clinic. The antiviral potency, human pharmacokinetics (PK), and physical properties of MK-8591 have the potential to open new paradigms for extended duration HIV treatment and prophylaxis approaches.
In an open label study in HIV-1 infected subjects naïve to antiretroviral treatment (ART), subjects are being administered a single dose of MK-8591 across a range of doses. Doses were chosen based on PK/PD simulations. Blood samples are being collected for viral load (VL), MK-8591 PK, and MK-8591-TP PK at prespecified time points up to 10 days postdose. Following completion of Day 10 procedures, subjects are being offered standard of care ART. Safety, PK, and VL data from the 10-mg dose (N=6) are available.
A single 10 mg dose of MK-8591 was associated with a rapid and robust reduction in VL. At 168 hours postdose, a mean (95% CI) placebo adjusted VL reduction of 1.67 log10 (1.47, 1.87) was observed. Mean VL continued to decline through Day 10 with a mean reduction of 1.78 log10 (1.59, -1.98) and no evidence of recrudescence. The 10-mg dose was generally well tolerated with a limited number of mild/moderate adverse experiences reported. MK-8591 plasma and MK-8591-TP PBMC PK were similar to previously reported data in healthy subjects.
MK-8591 suppressed HIV replication for at least ten days when administered as a single 10 mg dose. The low dose and potent antiviral effect of MK8591 provides a platform for extended duration oral and parenteral formulations.