The Food and Drug Administration (FDA) has accepted an application for a once-weekly oral version of lenacapavir, sold as Yeztugo, for HIV prevention, Gilead Sciences announced this week, adding a potential future alternative to long-acting injections.

Gilead has not completed separate clinical trials of oral lenacapavir for pre-exposure prophylaxis (PrEP) but rather is basing its request on the established effectiveness of twice-yearly injectable lenacapavir in two large Phase III studies.

“Once-weekly oral lenacapavir is a new and distinct use for Yeztugo, which is being evaluated as a stand-alone dosing approach,” a Gilead spokesperson told POZ. “Lenacapavir’s efficacy and safety profile for HIV prevention has already been established in the large, randomized clinical trials PURPOSE 1 and PURPOSE 2, which demonstrated high efficacy across diverse global populations, including cisgender women, cisgender men and gender-diverse people.”

Lenacapavir pills are already approved as part of an initial loading dose when used for HIV treatment (branded as Sunlenca) or prevention and as a “bridge” when administration of the twice-yearly injections are delayed, the spokesperson noted. 

Twice-yearly injectable lenacapavir has been hailed as a breakthrough in HIV prevention. In PURPOSE 1, subcutaneous injections administered every six months were 100% effective at preventing HIV among young cisgender women in Africa. In PURPOSE 2, the shots reduced the risk of HIV acquisition by 96% compared with background incidence for gay and bisexual men and gender-diverse people in the United States and six other countries. What’s more, studies to date show that once-yearly lenacapavir shots look promising.

Some people would rather avoid shots, however, and setting up appointments to administer injections every six months can be cumbersome. Though generally well tolerated, recipients may experience injection site reactions, and injectable lenacapavir forms a depot under the skin that can sometimes be felt as a hard nodule. 

The first approved PrEP pill—Gilead’s tenofovir disoproxil fumarate/emtricitabine (Truvada and generic equivalents)—may be used “on demand” before and after sex rather than every day. A weekly pill would offer yet another alternative, and having more options means more people can find a prevention method that works for them.

“This filing reflects Gilead’s continued commitment to advancing new HIV prevention options,” Gilead chief medical officer Dietmar Berger, MD, PhD, said in the news release. “Nearly one year after the approval of twice-yearly Yeztugo, we are building on the established clinical profile of lenacapavir to potentially extend the impact of our long‑acting innovation into new formulations to meaningfully broaden how HIV prevention is delivered as PrEP. HIV prevention is not one-size-fits-all, and if approved, once-weekly oral Yeztugo would provide more choice for people who need or want PrEP.”

The FDA is expected to decide on approval of weekly lenacapavir PrEP pills by February 2, 2027, which could make it the first longer-acting oral PrEP option.

Further back in the pipeline, Merck is working on a once-monthly oral PrEP candidate dubbed MK-8527, a novel nucleoside reverse transcriptase translocation inhibitor. MK-8527 is a successor to islatravir that does not share the same safety concerns at high doses. A combination pill containing low-dose islatravir and doravirine was approved for HIV treatment in April.

In early studies, MK-8527 reached protective levels in HIV-negative volunteers with no notable safety signals. As reported at the 2025 International AIDS Society Conference on HIV Science, MK-8527 was well tolerated with no meaningful changes in white blood cell counts. At this year’s Conference on Retroviruses and Opportunistic Infections, Merck researchers reported on dose selection for Phase III trials.

The EXPrESSIVE-10 (NCT07071623) study aims to enroll nearly 4,600 sexually active young women and adolescent girls in Kenya, South Africa and Uganda. EXPrESSIVE-11 (NCT07044297) will enroll about 4,400 sexually active people who could benefit from PrEP—including gay men, transgender women and men and nonbinary people—in 16 countries. In both trials, participants will be randomly assigned to receive once-monthly oral MK-8527 or standard daily PrEP pills (tenofovir disoproxil fumarate/emtricitabine).

These studies are expected to be completed in mid- to late-2027. Gilead’s weekly lenacapavir PrEP pill will have a substantial head start if it gets the FDA nod in February, but Merck’s monthly pill could offer another attractive oral option if approved in 2028.

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