Lenacapavir Looks Promising for Once-Yearly PrEP

Highly anticipated twice-yearly pre-exposure prophylaxis (PrEP) is expected to launch this summer, but researchers at Gilead Sciences aren’t resting on their laurels and are aiming for annual injections for HIV prevention.

The company revealed in December that it is working on longer-acting formulations of lenacapavir that could potentially be administered just once a year. The first Phase 1 data were reported this month at the Conference on Retroviruses and Opportunistic Infections (CROI 2025) and in The Lancet. Gilead considers the results promising enough to skip directly to Phase 3 trials.

“Once-yearly lenacapavir, if approved, could become an important new HIV prevention option that could help address PrEP adherence and persistence challenges for individuals who need or want PrEP around the world,” said Jared Baeten, MD, PhD, Gilead’s senior vice president for clinical development and virology therapeutic area head.

Daily oral PrEP using Truvada (tenofovir disoproxil fumarate/emtricitabine) or Descovy (tenofovir alafenamide/emtricitabine) is highly effective when taken consistently, but other options are still needed. Some people may have trouble remembering to take a daily pill, may not want to think about HIV every day, or may be hesitant to have pill bottles that could be lost or stolen.

Lenacapavir (brand name Sunlenca), the first HIV capsid inhibitor, was approved in 2022 as part of a combination treatment regimen for people with multidrug-resistant virus, but it is not yet authorized for HIV prevention. Lenacapavir is an antiretroviral drug that blocks HIV replication, not a vaccine that trains the immune system to fight the virus. But all traditional HIV vaccine candidates tested in large trials have failed, so long-acting PrEP is the next best thing.

A pair of Phase 3 trials presented last year showed that twice-yearly lenacapavir is highly effective for HIV prevention. Results from the PURPOSE 1 trial found that lenacapavir PrEP was 100% effective for young cisgender women in Africa—significantly more so than daily Truvada pills. Findings from the PURPOSE 2 study showed that lenacapavir injections every six months reduced the risk of HIV acquisition by 96% relative to background incidence and by 89% compared to Truvada for gay and bisexual men and gender-diverse people in the United States and six other countries.

Once-yearly lenacapavir could potentially also be used for HIV treatment, but it would need to be combined with other medications to maintain viral suppression, and no potential partners with such long duration are on the horizon.

Given the impressive efficacy of twice-yearly lenacapavir for PrEP, Renu Singh, PhD, Gilead’s senior director clinical pharmacology, and colleagues evaluated the pharmacokinetics, safety, and tolerability of two different once-yearly formulations.

This Phase 1 trial enrolled healthy adults with a low likelihood of HIV acquisition. About two thirds were men, 80% were white, 20% were Black and most were of Latino ethnicity. The median age was approximately 35 years.

The participants received a single 5,000 milligram dose of lenacapavir given as two 5 milliliter intramuscular injections in the buttocks at the same time. In contrast, twice-yearly lenacapavir is administered as a single subcutaneous injection into the fat layer beneath the skin of the abdomen. Half received a formulation containing 5% ethanol, which reduces the thickness of the injection, while the other received a 10% ethanol formulation.

Lenacapavir levels were even higher than those seen with twice-yearly dosing, Singh reported. Blood plasma levels remained above the 95% effective concentration for at least 56 weeks with both new formulations.

Lenacapavir injections form a “depot” under the skin that releases the drug over time. Drug levels rose rapidly after administration, reaching a maximum concentration at 10 to 12 weeks, and then slowly declined. The highest median concentrations of once-yearly lenacapavir remained well above the median peak concentration of twice-yearly lenacapavir, and the median trough (lowest) concentrations at week 52 exceeded that of twice-yearly dosing in PURPOSE 1 and PURPOSE 2.

“As a clinical pharmacologist, it gives me great pleasure to see a small molecule last this long—it has never been done before,” Singh told reporters at a CROI media briefing. “Overall, these results indicate that once-yearly lenacapavir has the potential to provide similarly high efficacy as twice-yearly subcutaneous lenacapavir, which is huge.”

Once-yearly lenacapavir was safe and generally well tolerated, and adverse events were mostly mild to moderate with both formulations, according to Singh. The most common side effect was injection site pain, reported by 75% to 80% of study participants. This was generally mild, resolved within a week and could be reduced by applying an ice pack before the shots. Nodules under the skin where the drug depot forms are a common side effect of subcutaneous injections, but they were not reported with the intramuscular formulations.

Commenting on the results at the briefing, HIV researcher Joseph Eron, MD, of the University of North Carolina at Chapel Hill, noted that 5 milliliters is about a teaspoon and he was “surprised people tolerate it that well, but it’s great that they did.” Given that the observed drug concentrations were so high, Singh suggested that the final dose would probably end up being less than 5 milliliters.

Gilead plans to start a Phase 3 trial of once-yearly lenacapavir PrEP in the second half of this year, bypassing intermediate Phase 2 trials. Phase 3 studies provide the data needed for Food and Drug Administration approval, and the company suggested that these data might be ready for review in 2027.

While long-acting PrEP could help end the HIV epidemic, researchers, advocates and global health officials stress that its promise can only be realized if it is widely available and affordable to everyone who needs it. Gilead announced last year that it will work with pharmaceutical manufacturers to provide generic lenacapavir for PrEP in more than 100 resource-limited countries. Access is a growing concern, however, given recent cuts to U.S. foreign aid programs, including PEPFAR (the President’s Emergency Plan for AIDS Relief), which is the main distributor of PrEP worldwide.