Phase I Trial Supports Development of Once-Yearly Lenacapavir as Long-Acting HIV PrEP Option

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Results from an ongoing Phase I trial have shown the potential of once-yearly intramuscular administration of lenacapavir as a long-acting pre-exposure prophylaxis (PrEP) for HIV prevention.¹ These results follow data from the Phase III PURPOSE 1 (NCT04994509) and PURPOSE 2 (NCT04925752) trials that demonstrated the efficacy of twice-yearly lenacapavir injections in significantly lowering the rate of HIV infections, with high adherence rates and no new safety signals.^2,3

“Gilead is continuing to innovate in our work to develop additional person-centered long-acting injectable and oral options to help people find an HIV prevention choice that is right for them,” Jared Baeten, MD, PhD, senior vice president, Virology Therapeutic Area Head, Gilead Sciences, said in a press release. “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.”¹

Lenacapavir is a potential first-in-class, long-acting HIV-1 capsid inhibitor. Its multi-stage mechanism of action is distinguishable from currently approved antiviral drug classes and is intended to provide a new pathway develop long-acting treatments for patients infected with or at risk for HIV-1, according to Gilead. The FDA granted Breakthrough Therapy Designation to lenacapavir in May 2019 for HIV infection in heavily treatment-experienced patients with multi-drug resistance in combination with other antiretroviral drugs. Although most antiretroviral agents act on a single stage of viral replication, lenacapavir targets multiple stages of the HIV-1 lifecycle with no known cross resistance to other existing medication classes, according to Gilead.⁴

The Phase I study analyzed the pharmacokinetics, safety, and tolerability of two intramuscular single-dose 5000 mg lenacapavir free acid formulations in 40 healthy adults. Formulation one was administered at 5% w/w ethano (n = 20) and formulation two at 10% w/w ethanol (n = 20).

Participants were between 18 and 55 years of age with a low risk of acquiring HIV and a body mass index less than or equal to 35.0 kg/m². Results published by The Lancet show that plasma concentrations of lenacapavir stayed above the 95% efficacy concentration for at least 56 weeks with both formulations.⁵

Median trough concentrations with both formulations of once-yearly lenacapavir at one year—57.0 ng/mL and 65.6 ng/mL, respectively—were higher than the concentrations reported with twice-yearly lenacapavir in the PURPOSE 1 and PURPOSE 2 trials at week 26, which was 23.4 ng/mL.

“In this phase 1 study of two intramuscular formulations of lenacapavir, we found pharmacokinetics to be adequate for once-yearly dosing, and intramuscular administration to be safe and well tolerated,” the study authors wrote in The Lancet. “Median plasma lenacapavir concentrations after intramuscular administration remained above median twice-yearly subcutaneous lenacapavir concentrations up to 56 weeks, indicating that similarly high efficacy can be expected.”⁵

In terms of safety, the most frequently reported adverse event with both intramuscular formulations of lenacapavir was injection site pain, which was reported by 80% of participants administered formulation one and by 75% administered formulation two. The injection site pain was primarily mild in severity and resolved within a week.

The study authors noted that the small patient population lacked the necessary demographic diversity to fully analyze the efficacy of once-yearly lenacapavir in HIV PrEP. As such, a larger trial is planned to include a more diverse patient population.

“The oral loading regimen for a once-yearly intramuscular lenacapavir to achieve similar pharmacokinetics to twice-yearly subcutaneous lenacapavir will be established with population pharmacokinetic modelling and simulation,” the study authors wrote. “Selection of the final formulation for future development and the dosing window for delayed administration of the intramuscular injection would also be informed by these population pharmacokinetic simulations.”⁵

References

1. First Clinical Data for Gilead’s Investigational Once-Yearly Lenacapavir for HIV Prevention Presented at CROI 2025 and Published in The Lancet. News release. Gilead. March 11, 2025. Accessed March 13, 2025. https://www.gilead.com/news/news-details/2025/first-clinical-data-for-gileads-investigational-once-yearly-lenacapavir-for-hiv-prevention-presented-at-croi-2025-and-published-in-the-lancet

2. Pre-Exposure Prophylaxis Study of Lenacapavir and Emtricitabine/​Tenofovir Alafenamide in Adolescent Girls and Young Women at Risk of HIV Infection (PURPOSE 1). ClinicalTrials.gov. Updated February 24, 2025. Accessed March 13, 2025. https://clinicaltrials.gov/study/NCT04994509

3. Study of Lenacapavir for HIV Pre-Exposure Prophylaxis in People Who Are at Risk for HIV Infection (PURPOSE 2). ClinicalTrials.gov. Updated December 20, 2024. Accessed March 13, 2025. https://clinicaltrials.gov/study/NCT04925752?cond=HIV&term=purpose%202&rank=1

4. Gilead Presents Full PURPOSE 2 Data Results for Twice-Yearly Lenacapavir for HIV Prevention at HIV Glasgow. News release. Gilead Sciences. November 13, 2024. Accessed March 13, 2025. 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

5. Pharmacokinetics and safety of once-yearly lenacapavir: a phase 1, open-label study. Jogiraju, Vamshi et al. The Lancet, Volume 0, Issue 0.