Gilead Sciences, Inc.announced additional data from its pivotal Phase III PURPOSE 2 trial providing an overview of the efficacy and safety of twice-yearly lenacapavir,

The new data are being presented during an oral abstract session on October 8 at the 5 ^th HIV Research for Prevention Conference (HIVR4P) in Lima, Peru and follow the unblinding of the trial at interim analysis in September, which showed that twice-yearly lenacapavir reduced HIV infections by 96% compared to background HIV incidence (bHIV) and demonstrated superiority to once-daily Truvada (emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg; F/TDF) for HIV prevention as pre-exposure prophylaxis (PrEP).

“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,” said Colleen Kelley, MD, MPH, Professor of Medicine at Emory University and a PURPOSE 2 Principal Investigator. “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.”

Lenacapavir was highly effective in PURPOSE 2, reducing HIV infections by 96% with two incident cases among 2,179 participants receiving lenacapavir Lenacapavir was highly effective at reducing infections among trial participants: 99.9% of participants did not acquire HIV in the lenacapavir group, with 2 incident cases among 2,179 participants (0.10/100 person-years, 95% CI, 0.012 to 0.373). The results demonstrated superiority of twice-yearly lenacapavir over bHIV (2.37/100 person-years, 95% CI, 1.649 to 3.417; primary endpoint), with 96% relative risk reduction (IRR 0.04, 95% CI, p<0.0001), compared with 9 incident cases among 1,086 individuals in the Truvada group (0.93/100 person-years, 95% CI, 0.426 to 1.768; secondary endpoint). Additionally, twice-yearly lenacapavir was 89% more effective than once-daily Truvada (IRR 0.11, 95% CI, p=0.00245).

PURPOSE 2 is a Phase III, double-blind, multicenter, randomized study evaluating the safety and efficacy of twice-yearly subcutaneous lenacapavir for PrEP versus bHIV and once-daily oral Truvada in 3,273 cisgender gay, bisexual, and other men, transgender women, transgender men, and gender nonbinary individuals aged 16 years or older who have sex with partners assigned male at birth. The trial spanned 88 sites in Argentina, Brazil, Mexico, Peru, South Africa, Thailand and the United States and participants were randomized in a 2:1 ratio to lenacapavir and Truvada, respectively. Because effective PrEP options already exist, there is broad consensus in the PrEP field that a placebo group would be unethical; thus, the trial used bHIV as the primary comparator and Truvada as a secondary comparator.

This is the second pivotal Phase III trial to demonstrate superior efficacy for twice-yearly lenacapavir for the investigational use of HIV prevention as PrEP, and to be unblinded early because it met its key efficacy endpoints. In June 2024, the PURPOSE 1 trial (NCT04994509), studying lenacapavir for PrEP among cisgender women in sub-Saharan Africa, was also unblinded early because it met its key efficacy endpoints.

Lenacapavir was well-tolerated among trial participants with few serious adverse events; Safety and tolerability findings from PURPOSE 2 demonstrated no significant or new safety concerns identified, and lenacapavir was generally well-tolerated. Aside from injection site reactions (ISRs), the most common adverse events (AEs) observed 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%). Serious AEs were reported in 3.3% of participants in the lenacapavir group, compared to 4.0% in the Truvada group. Frequency of AEs was consistent between study groups.

Few discontinuations due to injection site reactions; Lenacapavir is injected into the subcutaneous layer of fat in the abdomen to form a drug depot, which should get smaller and resolve, or reduce in size substantially, prior to the next lenacapavir injection. The drug depot may be palpable as a bump or nodule but is usually not visible. A total of 15,239 lenacapavir and placebo injections were administered during the trial. The most commonly reported ISRs were subcutaneous nodules (lenacapavir: 63.4%; placebo: 39.2%), injection site pain (lenacapavir: 56.4%; placebo: 53.4%) and erythema (lenacapavir: 17.3%; placebo: 19.4%). Twenty-nine people (<1%) across both groups discontinued due to ISRs. ISR incidence, including nodules, decreased with subsequent injections.

High level of diversity among trial participants and geographic regions

The importance of studying HIV prevention across diverse global communities and populations, including gender-diverse populations, was one of the key recommendations from the PURPOSE 2 Global Community Advisory Group (G-CAG) and other community members. As a result, the study enrolled participants from seven countries across four continents and was the first Phase 3 HIV prevention trial to intentionally include transgender men and non-binary individuals.

Among trial participants, 67% were non-White, including 38% Black participants, and 63% were of Hispanic/Latine ethnicity. More than 20% were gender-diverse: 15% were transgender women, 1% were transgender men and 6% were gender non-binary.

Community advocates also stressed the importance of including adolescents and young people in PURPOSE 2, which, along with PURPOSE 1, is the first Phase 3 HIV prevention trial to intentionally include adolescents. About one-third of PURPOSE 2 trial participants were aged 25 years or younger, and the median age of participants was 29.

More detailed data from PURPOSE 2 will be presented at a future conference and in a future publication.

Gilead to begin regulatory filings for lenacapavir for PrEP by the end of 2024 and recently announced voluntary licensing partners to increase access in high-incidence, resource-limited countries

To ensure the results from PURPOSE 1 and PURPOSE 2 help translate into decreased HIV incidence globally if lenacapavir for PrEP is approved, Gilead is executing an access strategy, informed by more than 100 global health advocates and organizations, that prioritizes speed and enables the most efficient paths for the regulatory review and approval of lenacapavir for PrEP in regions around the world. Data from both trials will support a series of global regulatory filings for lenacapavir for PrEP that will begin by the end of 2024.

On October 2, Gilead announced that it had signed non-exclusive, royalty-free voluntary licensing agreements with six pharmaceutical companies to manufacture and supply high-quality, low-cost versions of lenacapavir for 120 primarily low- and lower-middle income countries. These agreements are just one component of Gilead’s overall global strategy to enable broad, sustainable access to lenacapavir for PrEP, if approved. Gilead is actively working on additional ways to support access in upper-middle and high-income countries to establish fast, efficient pathways to help reach people who need or want PrEP, including timely regulatory filings, engagement with partners and governments, and manufacturing planning. This includes the countries with PURPOSE 2 trial sites, including Argentina, Brazil, Mexico, Peru and the United States, where trial participants have been offered and will be able to stay on open-label lenacapavir until it is available in their country.