The investigational oral pre-exposure prophylaxis (PrEP) agent MK-8527 showed a similar, well-tolerated safety profile to placebo, with dose-proportional pharmacokinetics, among adults with a low likelihood of HIV-1 exposure, a phase II study suggested.
The overall rate of adverse events was 61.4%, 68.3%, and 66.7% for those receiving MK-8527 at doses of 3 mg, 6 mg, and 12 mg compared with 63.3% for those receiving placebo, and the proportion of drug-related adverse events was also similar (14.9%, 15.8%, and 20.2% vs 18.4%), reported Kenneth Mayer, MD, of Harvard Medical School and Beth Israel Deaconess Medical Center in Boston, at the International AIDS Society Conference on HIV Science in Kigali, Rwanda.
MK-8527 is a novel oral nucleoside reverse transcriptase translocation inhibitor whose pharmacokinetics allow for dosing once a month.
“We all know that we’re still seeing too many new HIV infections despite many PrEP modalities,” Mayer told attendees. “The efficacy of oral PrEP, FTC [emtricitabine]/TDF [tenofovir disoproxil fumarate] or FTC/TAF [tenofovir alafenamide], is great when people are highly adherent,” but daily oral medication can be a challenge for people, and some do not want to get the injections that provide long-acting PrEP options, he noted.
In a survey his group conducted with men who have sex with men in Alabama, “we found that oral monthly PrEP was actually a preferred modality among the respondents when compared to everything that’s currently available,” Mayer said.
Onyema Ogbuagu, MBBCh, director of the Yale School of Medicine’s Antivirals and Vaccines Research Program in New Haven, Connecticut, was more circumspect about a once-monthly oral PrEP option.
“While a monthly dosed oral pill seems appealing to clients, based on prior qualitative studies and care providers, it’s not clear to me that a less frequently dosed oral can overcome challenges with pill taking and that it can compete with the now-approved two injectable agents for PrEP with regards to efficacy or adherence,” Ogbuagu told MedPage Today. “However, I can see it as an option for those who are averse to injections of any kind.”
Though he has heard that a head-to-head trial will soon compare MK-8527 to oral FTC/TDF, he noted that this does not address how MK-8527’s performance compares with injectable PrEP.
“Frankly, FTC/TDF is concerning to me as the only offered comparator as we have evidence that injectables have superior efficacy compared to FTC/TDF and should be the standard of care everywhere, access issues notwithstanding, from an ethical standpoint,” Ogbuagu said. “Other things I would love to hear about MK-8527 are its barrier to resistance and the impact of emergence of resistance on future HIV treatment options, specifically those containing NRTIs [nucleoside reverse transcriptase inhibitors].”
This study tested the safety, tolerability, and pharmacokinetics of once-monthly MK-8527 in 350 adults who were at low risk of HIV-1 exposure, not pregnant or breastfeeding, and had not previously used islatravir or MK-8527. The participants, from Israel, South Africa, and the U.S., were a median 28 years old, 58% were women, 51% were white, 41% were Black, and 16% were Hispanic/Latino.
The four groups included 49 participants receiving placebo, 101 receiving 3-mg MK-8527, 101 receiving 6-mg MK-8527, and 99 receiving 12-mg MK-8527 monthly for up to 6 consecutive months, followed by an 8-week follow-up.
HIV testing was conducted every 4 weeks, and no HIV seroconversions occurred during the study. Pharmacokinetics were assessed with plasma samples at days 1 and 2, at the last dose, and on the first follow-up day. The researchers also measured peripheral blood mononuclear cells of MK-8527-triphosphate in approximately 20 participants at each study visit.
The most common drug-related adverse events were headache (3.7% of participants receiving MK-8527 and 2% receiving placebo) and nausea (2.9% and 2%, respectively). Fatigue was reported in 1.7% of participants receiving MK-8527 and 2% receiving placebo. Grade 3 or 4 adverse events occurred in 5% of the 3-mg group, 2% of the 6-mg group, 4% of the 12-mg group, and 8.2% of the placebo group.
One miscarriage at 6 weeks’ gestation, in a participant with a history of pregnancy complications, was considered related to MK-8527.
Two participants discontinued the study drug due to drug-related adverse events, one for a grade 1 CD4/lymphocyte count decrease and one for grade 2 hypoesthesia.
No meaningful changes occurred in total lymphocyte count or CD4 count in those receiving MK-8527 at any dose. The concentration of MK-8527 in plasma was proportional based on dose over time, and it did not appear to accumulate.
Disclosures
The research was funded by Merck Sharp & Dohme.
Mayer reported research grants from and advisory board service at Merck, ViiV Healthcare, and Gilead Sciences.
Ogbuagu serves on advisory boards for Gilead and ViiV/GSK.
Primary Source
International AIDS Society Conference on HIV Science
Source Reference: Mayer K, et al “Safety and pharmacokinetics of once-monthly MK-8527: a phase 2 study in adults at low risk of HIV-1 exposure” IAS 2025.
