Gilead Sciences' lenacapavir is showing significant promise in both HIV prevention and treatment, according to recent trial data. The drug, administered as a twice-yearly injection, demonstrated a 96% reduction in HIV infections compared to background HIV incidence in a Phase 3 trial. This news sets the stage for potential regulatory approvals and a new option for individuals seeking HIV prevention.
Lenacapavir for PrEP: A Game Changer?
The PURPOSE 2 trial (NCT04925752) evaluated lenacapavir for pre-exposure prophylaxis (PrEP) in a diverse population of 3,273 participants, including cisgender men, transgender men, transgender women, and gender non-binary individuals who have sex with partners assigned male at birth. The study, conducted across 88 sites in Argentina, Brazil, Mexico, Peru, South Africa, Thailand, and the United States, compared twice-yearly subcutaneous injections of lenacapavir to daily oral Truvada (emtricitabine/tenofovir disoproxil fumarate).
The results, announced in September 2024, revealed that 99.9% of participants in the lenacapavir group did not acquire HIV, with only two incident cases among 2,180 individuals. This translated to a 96% relative risk reduction compared to background HIV incidence (p<0.0001). Furthermore, lenacapavir was 89% more effective than once-daily Truvada (p=0.00245), with nine incident cases observed in the Truvada group (n=1,087).
"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.
Safety and Tolerability
Lenacapavir was generally well-tolerated in the PURPOSE 2 trial. Serious adverse events (AEs) were reported in 3.3% of participants in the lenacapavir group, compared to 4.0% in the Truvada group. The most common 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%). Injection site reactions (ISRs) were also common, with subcutaneous nodules reported in 63.4% of lenacapavir recipients and injection site pain in 56.4%. However, discontinuations due to ISRs were rare, occurring in less than 1% of participants.
Regulatory Pathway and Access
Gilead plans to begin global regulatory filings for lenacapavir for PrEP by the end of 2024, with a potential launch in 2025. The company is prioritizing access in high-incidence, resource-limited countries, which are primarily low- and lower-middle-income countries. To that end, Gilead has signed non-exclusive, royalty-free voluntary licensing agreements with six generic pharmaceutical companies to manufacture and supply low-cost versions of lenacapavir in 120 countries.
Once-Weekly Oral Combination Therapy
In addition to its potential as a long-acting PrEP option, lenacapavir is also being investigated as part of a once-weekly oral combination therapy for HIV treatment. A Phase 2 trial (NCT05052996) evaluating the combination of islatravir (Merck) and lenacapavir in virologically suppressed adults (n=104) on Biktarvy demonstrated sustained viral suppression at 48 weeks. Participants were randomized to either switch to once-weekly oral islatravir 2 mg and lenacapavir 300 mg or continue daily oral Biktarvy. At Week 48, 94.2% of participants in the islatravir/lenacapavir group and 92.3% in the Biktarvy group maintained HIV-1 RNA levels below 50 copies/mL. No participants in either group had a viral load of ≥ 50 copies/mL at Week 48.
Based on these results, Gilead and Merck are advancing the islatravir/lenacapavir combination into Phase 3 trials, potentially offering a more convenient treatment option for people living with HIV.
"Novel HIV treatment options that allow for less frequent oral dosing have the potential to help support adherence and address stigma faced by some individuals taking daily oral therapy," said Dr. Elizabeth Rhee, Vice President, Global Clinical Development, Merck Research Laboratories.
