Meeting UNAIDS’ “95/95/95” targets for 2025—95% of people with HIV knowing their status, 95% of those who know their status on treatment, and 95% of people on treatment having a suppressed viral load—will be critical to ending AIDS as a public health threat by 2030. Reducing new infections through effective pre-exposure prophylaxis (PrEP) is just as essential. While daily oral PrEP is highly effective, adherence challenges, including HIV-related stigma and the limitations of injectable options, leave prevention gaps.
A new approach may change that. In their paper, “MK-8527 is a novel inhibitor of HIV-1 reverse transcriptase translocation with potential for extended-duration dosing,” published in PLOS Biology, Merck scientists describe the discovery and optimization of MK-8527, a novel nucleoside reverse transcriptase translocation inhibitor (NRTTI) designed as a once-monthly oral PrEP pill.
Preclinical studies showed that MK-8527 potently inhibits HIV replication in multiple models, with activity across HIV-1 subtypes and against HIV-2. It works by blocking reverse transcriptase translocation and can induce both immediate and delayed chain termination of reverse transcription. Pharmacokinetic studies in primates demonstrated good oral absorption and an intracellular half-life of approximately 48 hours in peripheral blood mononuclear cells (PBMCs)—supporting potential for long-acting oral dosing.
The researchers noted that these findings, together with Phase I data, supported initiation of a Phase II clinical trial evaluating monthly oral dosing in participants at low risk of HIV exposure. Today, MK-8527 has advanced further:
“A once-monthly oral PrEP option could play a role in global efforts to reduce HIV incidence by addressing some of the persistent HIV prevention implementation challenges like access to healthcare and the stigma associated with daily HIV pills,” Rebeca Plank, MD, distinguished scientist, clinical research, Merck Research Laboratories, tells GEN. “MK-8527, taken by mouth monthly, could provide a user-friendly, healthcare system-friendly prevention option with the potential to be available in a variety of settings that allow for more flexibility and privacy.”
Built on medicinal chemistry campaigns leveraging islatravir (ISL) as a starting point, MK-8527 showed robust antiviral potency and a favorable safety profile in preclinical testing. Phase II data presented at IAS 2025 confirmed this. “In this study, MK-8527 was generally safe and well-tolerated, with a safety profile similar to that of placebo. Further, the pharmacokinetic results demonstrated the feasibility of once-monthly doses of 11 mg,” added Plank.
“Specifically, MK-8527 inhibits HIV reverse transcriptase through multiple mechanisms of action, including inhibition of translocation and delayed chain termination,” Plank explained. “Its pharmacokinetic profile—how the body absorbs, distributes, and eliminates the drug—supports sustained drug levels that can be maintained for a month after a single dose, representing a potential innovation over current daily oral PrEP options.”
The candidate is now entering two large Phase III trials involving about 9,000 participants worldwide, according to Plank:
- EXPrESSIVE-11 (NCT07044297) will evaluate MK-8527’s safety and efficacy in people with a greater likelihood of HIV exposure across 16 countries.
- EXPrESSIVE-10 (NCT07071623), in collaboration with the Gates Foundation, will evaluate the safety and efficacy of MK-8527 in young women and adolescent girls in sub-Saharan Africa.
Along with the Gates Foundation, they will collaborate with the International Clinical Research Center (ICRC) within the University of Washington Department of Global Health on the EXPrESSIVE-10 trial. “These partnerships are essential to ensure the research reaches diverse populations most affected by HIV and to support the complex clinical trials needed to evaluate safety and effectiveness,” Plank said. “Until now, long-acting PrEP has been synonymous with injectable formulations, and an oral prevention option like MK-8527 could represent a paradigm shift.”
If successful, MK-8527 could expand prevention choices beyond daily pills and injectables—offering adherence, privacy, and accessibility benefits. Plank tells GEN, “The development of MK-8527 underscores Merck’s commitment to expanding HIV prevention options with a focus on person-centric solutions that address real-world challenges such as adherence and stigma.” As part of the global push toward 95/95/95, MK-8527 may represent a transformative step forward in the fight against HIV.
