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Full results from the Phase III PURPOSE 2 trial (NCT04925752) further demonstrate the efficacy of twice-yearly lenacapavir injections in significantly lowering the rate of HIV infections, with high adherence rates and no new safety signals.1,2 The full results follow previously released interim data showing that lenacapavir lowered HIV infections by 96% compared to background HIV incidence (bHIV), while also showing superiority to daily pre-exposure prophylaxis (PrEP) medication Truvada (emtricitabine/tenofovir disoproxil).3
“We’re at a crossroads in the HIV epidemic, and a twice-yearly choice for HIV prevention, if approved, could be transformative as we work toward achieving the UNAIDS 2030 targets around the world,” PURPOSE 2 principal investigator Onyema Ogbuagu, MBBCh, FACP, FIDSA, associate professor of Medicine and Pharmacology at Yale School of Medicine and director of the Yale Antivirals and Vaccines Research Program, said in a press release. “Lenacapavir for PrEP could provide an important alternative to existing preventative medications that require more frequent dosing, and could help transform the HIV prevention landscape by addressing a range of unmet needs for individuals who need or want PrEP globally.”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 lenacapavir Breakthrough Therapy Designation in May 2019 to treat 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 double-blind, multicenter, randomized PURPOSE 2 trial analyzed the safety and efficacy of twice-yearly subcutaneous lenacapavir for PrEP compared with once-daily oral Truvada and bHIV. Investigators enrolled more than 3,200 cisgender men, transgender men, transgender women, and gender non-binary patients aged 16 years and above who are sexually active with people assigned male gender at birth.
The trial was conducted at 88 sites across Argentina, Brazil, Mexico, Peru, South Africa, Thailand, and the United States. Patients were randomly assigned in a 2:1 ratio to receive either lenacapavir or Truvada, with a primary endpoint of superiority.
Investigators found that 99.9% of participants did not become infected with HIV in the lenacapavir cohort. Lenacapavir was found to be 89% more effective at lowering HIV infections than once-daily Truvada (IRR 0.11; 95% CI, 0.02 to 0.51; p=0.00245). Twice-yearly lenacapavir also showed superiority to bHIV (2.37/100 person-years, 95% CI, 1.65 to 3.42; primary endpoint), with 96% a relative risk reduction (IRR 0.04; 95% CI, 0.01 to 0.18; p<0.0001).
Investigators reported nine incident HIV cases among 1,086 participants in the Truvada cohort (0.93/100 person-years; 95% CI, 0.43 to 1.77). These individuals had low or no adherence to Truvada or discontinued the drug more than 10 days before being diagnosed with HIV, according to the investigators.
Lenacapavir also showed a high rate of adherence, with 91.0% and 92.8% of all trial participants receiving on-time injections at week 26 and at one year, respectively. The rates of on-time injections were similar between the lenacapavir and placebo cohorts, according to investigators.
Data from the PURPOSE trial program will be submitted to support multiple global regulatory filings for lenacapavir for PrEP by the end of 2024.
“Gilead recognizes the importance of prevention in ending the HIV epidemic and is deeply committed to ensuring broad, sustainable global access to lenacapavir for PrEP, if approved,” Jared Baeten, MD, PhD, senior vice president, Clinical Development and Virology Therapeutic Area head, Gilead Sciences, said in the release.1
References
1. 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 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
2. Study of Lenacapavir for HIV Pre-Exposure Prophylaxis in People Who Are at Risk for HIV Infection (PURPOSE 2). ClinicalTrials.gov. October 24, 2024. Accessed November 13, 2024. https://clinicaltrials.gov/study/NCT04925752?cond=HIV&term=purpose%202&rank=1
3. Gilead’s Twice-Yearly Lenacapavir for HIV Prevention Reduced HIV Infections by 96% and Demonstrated Superiority to Daily Truvada® in Second Pivotal Phase 3 Trial. Gilead. September 12, 2024. Accessed November 13, 2024. https://www.gilead.com/news-and-press/press-room/press-releases/2024/9/gileads-twiceyearly-lenacapavir-for-hiv-prevention-reduced-hiv-infections-by-96-and-demonstrated-superiority-to-daily-truvada-in-second-pivotal-ph
4. FDA Lifts Clinical Hold on Investigational Lenacapavir for the Treatment and Prevention of HIV. Gilead Sciences. News release. May 16, 2022. Accessed November 13, 2024. https://www.gilead.com/news-and-press/press-room/press-releases/2022/5/fda-lifts-clinical-hold-on-investigational-lenacapavir-for-the-treatment-and-prevention-of-hiv