Lenacapavir Approved for Twice-Yearly Injection for HIV Prevention, a Landmark FDA Decision

The FDA has approved lenacapavir (Yeztugo) as pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV in adult and adolescent patients weighing at least 35 kg, Gilead Sciences announced in a news release.¹ The decision makes the therapy the first and only twice-yearly option available in the United States for PrEP.

Lenacapavir’s approval was based on data from the phase 3 PURPOSE 1 (NCT04994509) and PURPOSE 2 (NCT04925752) trials, in which the therapy met the primary endpoints in both studies of superiority to background HIV incidence and once-daily oral emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg (Truvada), also developed by Gilead and approved by the FDA in 2012.

“Yeztugo could be the transformative PrEP option we’ve been waiting for—offering the potential to boost PrEP uptake and persistence and adding a powerful new tool in our mission to end the HIV epidemic,” Carlos del Rio, MD, distinguished professor of medicine in the division of infectious diseases at Emory University School of Medicine, said in the release.¹ “A twice-yearly injection could greatly address key barriers like adherence and stigma, which individuals on more frequent PrEP dosing regimens, especially daily oral PrEP, can face.”

PURPOSE 1 was a double-blind, active-controlled, multicenter, randomized phase 3 trial evaluating the safety and efficacy of twice-yearly, subcutaneous lenacapavir for PrEP, and once-daily oral emtricitabine 200 mg/tenofovir alafenamide 25 mg (Descovy; Gilead) or once-daily oral emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg (Truvada) for the investigational use of HIV prevention in women.²

The study cohort included 5338 HIV-negative adolescent girls and young women between the ages of 16 and 25 years who were sexually active with men. Key exclusion criteria included prior receipt of an HIV vaccine, prior use of long-acting systemic PrEP therapy, or prior use of HIV postexposure prophylaxis therapy. Of the participants, 2134 received lenacapavir, 2136 received Descovy, and 1068 received Truvada.²

Investigators found that there were 0 incident HIV infections in the lenacapavir-treated group, 39 in the Descovy-treated group, and 16 in the group that received Truvada. Compared to a background HIV incidence of 2.41 per 100 person-years in the screened population of 8094, the incidence with lenacapavir was found to be significantly lower. Lenacapavir also had a high adherence rate: 91.5% of all trial participants received on-time injections at week 26, and 92.8% received on-time injections at one year.²

PURPOSE 2 is a double-blind, multicenter, randomized phase 3 study evaluating the safety and efficacy of twice-yearly subcutaneous lenacapavir for PrEP compared to background HIV incidence and once-daily oral emtricitabine and tenofovir disoproxil fumarate (Truvada) in cisgender men, transgender men, transgender women and gender non-binary individuals aged 16 years or older. The study cohort included 3295 participants from 88 sites across the world, including the US, Argentina, Thailand, Brazil, Mexico, Peru, and South Africa.³

Despite high levels of reported sexual behavior, chemsex and sexually transmitted infections among participants, the study showed that 99.9% in the lenacapavir group did not acquire HIV, with 2 incident cases among the 2180 participants. There was a 96% risk reduction associated with lenacapavir treatment when compared to background HIV incidence. In the Truvada group, there were 9 incident cases among 1087 individuals, demonstrating that lenacapavir was 89% more effective.³

“This is a historic day in the decades-long fight against HIV. Yeztugo is one of the most important scientific breakthroughs of our time and offers a very real opportunity to help end the HIV epidemic,” Daniel O’Day, chairman and CEO of Gilead, said in the press release.¹ “This is a medicine that only needs to be given twice a year and has shown remarkable outcomes in clinical studies, which means it could transform HIV prevention. Gilead scientists have made it their life’s work to end HIV and now, with the FDA approval of Yeztugo and in collaboration with our many partners, we can help to make that goal a reality.”¹

References

1. Yeztugo® (lenacapavir) is now the first and only FDA-approved HIV prevention option offering 6 months of protection. News Release. Gilead. June 18, 2025. Accessed June 18, 2025. https://investors.gilead.com/news/news-details/2025/Yeztugo-Lenacapavir-Is-Now-the-First-and-Only-FDA-Approved-HIV-Prevention-Option-Offering-6-Months-of-Protection/default.aspx
2. 2. Full efficacy and safety results for Gilead investigational twice-yearly lenacapavir for HIV prevention presented at AIDS 2024. News Release. Gilead Sciences. July 24, 2024. Accessed July 24, 2024. https://www.gilead.com/news-and-press/press-room/press-releases/2024/7/full-efficacy-and-safety-results-for-gilead-investigational-twice-yearly-lenacapavir-for-hiv-prevention-presented-at-aids-2024
3. 3. Gilead presents full PURPOSE 2 data results for twice-yearly lenacapavir for HIV prevention at HIV Glasgow. News Release. Gilead. November 13, 2024. Accessed November 13, 2024. https://www.gilead.com/news/news-details/2024/gilead-presents-full-purpose-2-data-results-for-twice-yearly-lenacapavir-for-hiv-prevention-at-hiv-glasgow