New Phase III Data Show Twice-Yearly Lenacapavir Reduces HIV Infections by 96% in Gender-Diverse Populations, Cisgender Men

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Additional data released from the Phase III PURPOSE 2 trial (NCT04925752) demonstrated that twice-yearly lenacapavir significantly lowered HIV infections by 96% among gender-diverse individuals and cisgender men.^1,2 These latest results follow interim data released last month showing that lenacapavir lowered HIV infections by 96% compared to background HIV incidence, while also showing superiority to daily Truvada (emtricitabine/tenofovir disoproxil).³

“These data reinforce that twice-yearly lenacapavir could be a highly effective and potentially game-changing HIV prevention choice that we have long hoped for in our efforts to end the HIV epidemic,” PURPOSE 2 principal investigator Colleen Kelley, MD, MPH, professor of Medicine at Emory University, said in a press release. “PURPOSE 2 was intentionally designed to reflect the lives and locations of many people who are disproportionately affected by HIV around the world by focusing on gender, racial, ethnic, and geographic diversity.”¹

Lenacapavir is a potential first-in-class, long-acting HIV-1 capsid inhibitor. The multi-stage mechanism of action for lenacapavir is distinguishable from currently approved antiviral drug classes and is intended to provide a new pathway for the development of long-acting treatments for individuals 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 and has no known cross resistance to other existing drug classes, according to Gilead.⁴

PURPOSE 2 is a double-blind, multicenter, randomized trial comparing the safety and efficacy of twice-yearly subcutaneous (SC) lenacapavir for pre-exposure prophylaxis (PrEP) vs. once-daily oral Truvada and bHIV. The trial included more than 3,200 cisgender men, transgender men, transgender women, and gender non-binary patients over 16 years of age who are sexually active with people assigned male gender at birth. The trial included 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.

The latest data show the significant efficacy of lenacapavir in lowering the rate of HIV infections, as 99.9% of individuals in the lenacapavir cohort did not acquire HIV, with two incident cases among 2,179 participants (0.10/100 person-years, 95% CI, 0.012 to 0.373). Twice-yearly lenacapavir also showed superiority over bHIV (2.37/100 person-years, 95% CI, 1.649 to 3.417; primary endpoint), with a 96% relative risk reduction (IRR 0.04, 95% CI, p<0.0001), vs. nine incident cases among 1,086 patients assigned to the Truvada cohort (0.93/100 person-years, 95% CI, 0.426 to 1.768; secondary endpoint). Gilead noted that twice-yearly lenacapavir was 89% more effective than once-daily Truvada (IRR 0.11, 95% CI, p=0.00245).

In terms of safety, the profile of lenacapavir in the PURPOSE 2 trial did not identify any significant or new safety concerns, with the drug being generally well-tolerated. The most common adverse event (AEs) among patients in the trial was injection site reactions. The most common of these were SC nodules (lenacapavir: 63.4%; placebo: 39.2%), injection site pain (lenacapavir: 56.4%; placebo: 53.4%), and erythema (lenacapavir: 17.3%; placebo: 19.4%), with 29 patients (<1%) across cohorts discontinuing treatment due to an injection site reaction.

The other most frequently reported AEs were rectal chlamydia infection (lenacapavir: 13.2%; Truvada: 11.8%), oropharyngeal gonococcal infection (lenacapavir: 13.0%; Truvada: 10.9%), and rectal gonococcal infection (lenacapavir: 10.7%; Truvada: 9.1%). Further, 3.3% of patients in the lenacapavir cohort reported serious AEs compared to 4.0% of patients in the Truvada cohort.

Gilead stated that it will release more detailed data from PURPOSE 2 at a future conference and in a future publication. The company added that it will begin regulatory filings for lenacapavir for PrEP by the end of 2024.

“The PURPOSE clinical trial program continues to set new standards for innovative science, trial design, community input and intentional recruitment, all coming together to yield stellar results,” Jared Baeten, MD, PhD, senior vice president, Clinical Development and Virology Therapeutic Area Head, Gilead Sciences, said in a press release. “Gilead is committed to employing the same kind of rigorous, thoughtful and collaborative approach to ensure that lenacapavir for PrEP has the most transformative impact possible if approved.”¹

References

1. Gilead Presents Additional Efficacy, Safety and Demographic Data From PURPOSE 2 Trial at 5th HIV Research for Prevention Conference. News release. Gilead. October 7, 2024. Accessed October 8, 2024. https://www.gilead.com/news/news-details/2024/gilead-presents-additional-efficacy-safety-and-demographic-data-from-purpose-2-trial-at-5th-hiv-research-for-prevention-conference

2. Study of Lenacapavir for HIV Pre-Exposure Prophylaxis in People Who Are at Risk for HIV Infection (PURPOSE 2). ClinicalTrials.gov. Updated July 12, 2024. Accessed October 8, 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 October 8, 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 October 8, 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