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Background MK-8507 is a novel HIV-1 non-nucleoside reverse transcriptase inhibitor being developed for treatment of HIV-1 infection. MK-8507 has high antiviral potency in vitro and pharmacokinetic (PK) properties that support once-weekly dosing. Setting A phase 1, open-label, proof-of-concept study was conducted in treatment-naive adults with HIV-1 infection to assess monotherapy antiviral activity. Methods In 3 sequential panels, participants aged 18-60 years with baseline plasma HIV-1 RNA ≥10,000 copies/mL and CD4+ T-cell count >200/mm3 received a single oral dose of 40, 80, or 600 mg MK-8507 in the fasted state. Participants were assessed for HIV-1 RNA for at least 7 days, PK for 14 days, and safety and tolerability for 21 days post dose. Results A total of 18 participants were enrolled (6 per panel). The mean 7-day post-dose HIV-1 RNA reduction ranged from ∼1.2 to ∼1.5 log10 copies/mL across the doses assessed. One patient had a viral rebound associated with emergence of a F227C reverse transcriptase variant (per chain-termination method sequencing) 14 days post dose; this variant was found in a second participant by ultra-deep sequencing as an emerging minority variant. MK-8507 PK were generally dose-proportional and similar to observations in participants without HIV-1 infection in prior studies; mean MK-8507 half-life was 56-69 hours in this study. MK-8507 was generally well tolerated at all doses. Conclusions The robust antiviral activity, PK, and tolerability of MK-8507 support its continued development as part of a complete once-weekly oral regimen for HIV-1 treatment; combination therapy could mitigate the emergence of resistance-associated variants.

MK-8507 is a novel HIV-1 non-nucleoside reverse transcriptase inhibitor in clinical development with potential for once-weekly oral administration for the treatment of HIV-1 infection. Two randomized, double-blind, placebo-controlled phase 1 studies in adults without HIV-1 evaluated the safety, tolerability, and pharmacokinetics of single and multiple doses of MK-8507; drug interaction with midazolam (a cytochrome P450 3A4 substrate) and food effect were also assessed. In Study 1, 16 participants received oral ascending single doses of MK-8507 (2-400 mg) or placebo in an alternating fashion. In Study 2, 24 participants received ascending single doses of MK-8507 (400-1200 mg) or placebo and multiple doses (once weekly for 3 weeks) of MK-8507 (100-400 mg) or placebo. MK-8507 pharmacokinetics were approximately dose proportional at 2-1200 mg. MK-8507 had a time to maximum concentration of 2-7 hours and a mean terminal half-life of ∼58-84 hours. MK-8507 doses ≥100 mg achieved a plasma concentration at 168 hours post-dose (7 days) associated with antiviral efficacy. A high-fat meal had no clinically meaningful effect on MK-8507 pharmacokinetics, and MK-8507 400 mg once weekly had no clinically meaningful effect on midazolam pharmacokinetics. Single and multiple doses of MK-8507 were generally well tolerated. No trends with dose and no clinically meaningful changes were observed in vital signs, electrocardiograms, and laboratory safety tests. The pharmacokinetics and safety data are supportive of once-weekly oral administration and support further clinical investigation of MK-8507 for the treatment of HIV-1 infection. Over the last 3 decades, substantial improvements have been made in oral HIV antiretroviral therapies (ART), which now offer people living with HIV (PLWH) the potential for a near-normal life expectancy (1, 2). To achieve this, individuals must maintain life-long viral suppression, which requires daily administration of efficacious medication (3). Issues surrounding tolerability, complicated regimens, and treatment fatigue from daily dosing can lead to poor adherence and suboptimal viral suppression (3-6). Regimens can become complex when there is the need to take multiple pills, requirement to take a medication fasted or with food, or the potential for interactions with other medications, including those required to treat HIV-related comorbidities (3, 78). New treatment options that are not only highly effective but also offer excellent tolerability, a high barrier to resistance, favorable drug interaction profiles, and the potential for less frequent dosing remain the focus of much clinical research (7, 9). While 1 pill once a day meets the needs of many PLWH, for others daily administration poses challenges, including treatment fatigue and daily reminders and/or stigma associated with ART (10, 11). While treatment regimens that can be taken less often than daily are attractive to many PLWH, the long-acting injectable combination of cabotegravir/rilpivirine is currently the only treatment option available without daily dosing; however, administration requires injection by a health care professional (12), potentially posing other challenges.