The FDA has accepted Gilead Sciences' New Drug Application (NDA) for lenacapavir, a twice-yearly injectable HIV-1 capsid inhibitor, for pre-exposure prophylaxis (PrEP). This decision marks a significant step toward potentially introducing the first twice-yearly HIV prevention option. The FDA has granted priority review to the application, setting a Prescription Drug User Fee Act (PDUFA) target action date of June 19, 2025.
Clinical Trial Data
The NDA is based on data from the Phase 3 PURPOSE 1 and PURPOSE 2 trials. The PURPOSE 1 trial (NCT04994509) demonstrated that twice-yearly lenacapavir resulted in zero HIV infections among cisgender women, achieving 100% risk reduction and superiority compared to background HIV incidence (bHIV). The PURPOSE 2 trial (NCT04925752) showed a 96% risk reduction in HIV infections among a broad and geographically diverse range of cisgender men and gender-diverse people, with 99.9% of participants in the lenacapavir group not acquiring HIV infection.
In both trials, lenacapavir also demonstrated superiority in preventing HIV infections compared to once-daily oral Truvada (emtricitabine 200mg and tenofovir disoproxil fumarate 300mg; F/TDF) and was generally well-tolerated, with no significant or new safety concerns identified.
Regulatory Designations and Review
The FDA's acceptance of the NDA follows the receipt of Breakthrough Therapy Designation for lenacapavir for PrEP, granted in October 2024. This designation is intended to expedite the development and regulatory review of investigational treatments for serious or life-threatening conditions that have the potential to substantially improve clinical outcomes compared with available therapy.
Global Access Strategy
Gilead is implementing an access strategy, informed by global health advocates and organizations, that prioritizes speed and enables efficient regulatory review, approval, and access to lenacapavir for PrEP globally. This strategy includes submitting a marketing authorization application (MAA) to the European Commission and an EU-Medicines for All (EU-M4all) application to the European Medicines Agency (EMA) for lenacapavir for PrEP. The EU-M4all application aims to facilitate the availability of lenacapavir for PrEP in low- and lower-middle-income countries.
Expert Commentary
"Today, we are one step closer to introducing the first-ever twice-yearly HIV prevention choice that could, if approved, help transform the landscape for individuals who need or want additional prevention options that better fit into their lives," said Dietmar Berger, MD, PhD, Chief Medical Officer, Gilead Sciences. "We’re excited about the potential of lenacapavir to make a real difference in HIV prevention in the U.S. and around the world, supporting the broader goal of ending the HIV epidemic for everyone, everywhere."
Lenacapavir: Mechanism of Action
Lenacapavir is a first-in-class capsid inhibitor with a multi-stage mechanism of action, distinguishing it from other currently approved classes of antiviral agents. While most antivirals act on just one stage of viral replication, lenacapavir is designed to inhibit HIV at multiple stages of its lifecycle and has no known cross-resistance exhibited in vitro to other existing drug classes.
Ongoing Evaluation
Lenacapavir is being evaluated as a long-acting option in multiple ongoing and planned early and late-stage clinical studies in Gilead’s HIV prevention and treatment research program. It is being developed as a foundation for potential future HIV therapies with the goal of offering both long-acting oral and injectable options with several dosing frequencies, in combination or as a mono agent, that help address individual needs and preferences of people and communities affected by HIV.
The broader landscape
If approved, lenacapavir will join ViiV Healthcare's cabotegravir as long-acting injectable options for PrEP. The current standard of care includes daily oral medications such as Truvada and Descovy, also from Gilead. While effective, adherence to daily regimens can be challenging, making long-acting injectables a welcome addition to the HIV prevention toolkit.
