27 June 2025
Category: New Drug Approval I Sexual Health I
HIV & Infectious Diseases
Written By: Dewanshee Ingale BPharm
Reviewed By: Pharmacally Editorial Team
In the landmark development, FDA has approved Yeztugo (lenacapavir), an antiretroviral drug representing a novel class of antiretroviral drug called capsid inhibitors, invented by the Gilead Sciences, which is approved as a first, and only biannual injection for pre-exposure prophylaxis (PrEP) to protect the human body from sexually acquired HIV in adults and adolescents especially those who are weighing 35 kg and more. The sanction is considered a historic innovation in HIV prevention, presenting a highly efficient and suitable option that addresses the adherence problems, treatment burden, and disease stigma. Authorities believe that Yeztugo has the potential to significantly enhance pre-exposure prophylaxis (PrEP) initiation and adherence, especially in populations facing difficulties with existing treatments. The invention of Yeztugo (lenacapavir) is a breakthrough to end the HIV epidemic.
About Yeztugo
Yeztugo (lenacapavir) is a completely new class of drug that prevents the HIV-1 infection. Yeztugo is developed by Gilead Sciences and is approved by the FDA as the only injectable that can be administered individually twice a year, with a 6-month interval, for pre-exposure prophylaxis (PrEP). This injection is thought to reduce the risk of acquiring HIV in adults and adolescents who weigh 35 kg or more. This subcutaneous injection should be administered by a healthcare professional. The injectable formulation exhibits a pharmacological activity lasting up to six months, which effectively overcomes the limitations associated with daily oral PrEP regimens, including issues of adherence and pill burden.
FDA approval was supported by evidence from the Phase 3 PURPOSE 1 and PURPOSE 2 clinical trials, which confirmed that over 99.9% of participants remained HIV-negative, providing strong validation of the intervention’s efficacy, which makes it superior to the daily oral PrEP medications. Yeztugo is available as a tablet and an injection dosage form, but the indication of PrEP is only indicated for the injection formulation that is administered twice a year. The development of Yeztugo is a breakthrough in HIV prevention. It is said that it will revolutionize HIV treatment and make it much simpler, lowering the stigma and offering patient acceptance.
Background
Before approval of Yeztugo for PrEP, lenacapavir was marketed under the name of Sunlenca, which was utilized for the treatment of multidrug-resistant HIV-1 infection in heavily treatment-experienced adults. Sunlenca provided a vital therapeutic option for patients with limited treatment choices due to the development of resistance to current treatment or any safety and tolerability issues. Sunlenca was administered as a combination regimen along with previous antiretroviral drugs.
The expansion of lenacapavir’s indications from treatment to prevention states a significant breakthrough in the fight against HIV and gives patients hope and practical solutions.
Mechanism: A novel approach
Lenacapavir is a first-in-class, long-acting capsid inhibitor that targets the HIV-1 capsid protein, a highly conserved structural component essential to multiple stages of the viral lifecycle.
Following viral entry into the host cell, the intact HIV-1 capsid must remain stable as it travels through the cytoplasm to the nuclear pore complex, where uncoating and reverse transcription occur. Lenacapavir stabilizes the capsid structure and prevents its disassembly (uncoating), thereby blocking the nuclear material of the viral genome from incorporating with human DNA. This effectively freezes HIV replication at an early post-entry stage.
In case infection had occurred already, in later stages of the viral replication cycle, lenacapavir disrupts proper capsid assembly during the formation of new virions in infected cells. Interfering with capsid multimerization leads to the production of malformed or immature capsids. The resulting virions are structurally defective and non-infectious, impairing viral maturation and spread.
Through these dual-stage inhibitions, blocking nuclear import in the early stage and preventing correct capsid assembly in the late stage, lenacapavir exerts a potent antiviral effect. Its novel mechanism complements other antiretroviral classes and makes it a valuable option for both treatment and pre-exposure prophylaxis (PrEP), particularly in multidrug-resistant HIV-1 infections.
Clinical trials and approval
The approval of Yeztugo comes from the solid foundation of two phase 3 trials: the Purpose-1 and Purpose-2 trials.
The phase 3 Purpose 1 trial (NCT04994509) was a randomized, double-blind study evaluating the efficacy and safety of lenacapavir for HIV-1 pre-exposure prophylaxis (PrEP) in 5,338 cisgender adolescent girls and young women aged 16–25 years across high-incidence regions of South Africa and Uganda. Participants were randomized in a 2:2:1 ratio to receive twice-yearly subcutaneous lenacapavir injections, daily oral emtricitabine–tenofovir alafenamide (FTC/TAF), or daily oral emtricitabine–tenofovir disoproxil fumarate (FTC/TDF). The primary endpoint was the incidence of HIV-1 infection. Zero HIV infections were observed in the lenacapavir group over 2134 participants compared to 39 infections among 2136 participants in the F/TAF group and 16 infections among 1068 participants in the FTC/TDF group, respectively.
The Purpose 2 trial (NCT04925752) was a Phase 3, randomized, double-blind study assessing the efficacy and safety of twice-yearly subcutaneous lenacapavir for HIV-1 pre-exposure prophylaxis (PrEP) in 3,265 individuals, including cisgender men, transgender women, and gender-diverse individuals aged ≥16 years. Conducted across multiple global regions, including North and South America, Europe, Asia, and Africa, the trial randomized participants in a 2:1 ratio to receive either lenacapavir injections every 26 weeks or daily oral FTC/TDF. The primary endpoint was HIV-1 incidence. Lenacapavir demonstrated a significantly lower HIV incidence rate, 2 cases in total compared to FTC/TDF’s 9 cases overall, yielding an 89% relative risk reduction versus oral PrEP and a 96% reduction versus background incidence.
Safety profile
Yeztugo (lenacapavir) has demonstrated a robust safety and tolerability profile across both the pivotal Phase 3 Purpose 1 and Purpose 2 trials. In Purpose 1, the majority of participants experienced at least one adverse event (AE), with most being mild or moderate in severity. The most commonly reported adverse reactions were injection site reactions (ISRs), such as nodules, pain, and swelling. These ISRs were generally mild to moderate, decreased with subsequent injections, and led to discontinuation in only a small fraction of participants (0.2%). No significant or new safety concerns were identified, and serious adverse events were rare. Importantly, there were no serious ISRs or deaths attributed to lenacapavir throughout the trial.
Impact and future viewpoint
FDA approval of Yeztugo (lenacapavir) as the first and only twice-yearly injectable HIV prevention drug is a milestone in the battle against HIV, with ≥99.9% efficacy in phase 3 clinical trials. Yeztugo provides a game-changing solution, breaking through the decades-long HIV prevention barriers, such as adherence barriers, stigma, resistance, and the burden of a daily pill. Its long-acting injectable will be well-suited to increase PrEP adherence and retention.
The approval of Yezugo has been welcomed and appreciated by global health organizations such as the World Health Organization. WHO has prepared new guidelines to help countries integrate lenacapavir into their HIV protection strategies. The biannual dosing system of the drug allows revolutionizing the public health approaches by simplifying prevention, reducing the cases of missing the dose, and potentially curbing new HIV infections in the population.
Looking ahead, the impact of Yeztugo will depend on equitable and rapid access, especially in low- and middle-income countries where the HIV burden is highest. Efforts are underway to accelerate regulatory approvals worldwide and to facilitate generic manufacturing, which could further expand access. Researchers are also exploring the potential for even longer-acting formulations and combination regimens, raising the prospect of once-yearly PrEP and broader protection.
Reference
Yeztugo® (Lenacapavir) Is Now the First and Only FDA-Approved HIV Prevention Option Offering 6 Months of Protection https://www.gilead.com/news/news-details/2025/yeztugo-lenacapavir-is-now-the-first-and-only-fda-approved-hiv-prevention-option-offering-6-months-of-protection
Yeztugo (lenacapavir) FDA Approval History – Drugs.com https://www.drugs.com/history/yeztugo.html
FDA Approves Yeztugo https://www.drugs.com/newdrugs/fda-approves-yeztugo-lenacapavir-first-only-hiv-prevention-option-offering-6-months-protection-6555.html
Twice-Yearly HIV-1 PrEP Yeztugo Gets FDA Approval https://www.infectiousdiseaseadvisor.com/news/twice-yearly-hiv-1-prep-yeztugo-gets-fda-approval/
U.S. FDA Accepts Gilead’s New Drug Applications for Twice-Yearly Lenacapavir for HIV Prevention Under Priority Review https://www.gilead.com/news/news-details/2025/us-fda-accepts-gileads-new-drug-applications-for-twice-yearly-lenacapavir-for-hiv-prevention-under-priority-review
Pre-Exposure Prophylaxis Study of Lenacapavir and Emtricitabine/Tenofovir Alafenamide in Adolescent Girls and Young Women at Risk of HIV Infection (PURPOSE 1) https://clinicaltrials.gov/study/NCT04994509
Full Efficacy and Safety Results for Gilead Investigational Twice-Yearly Lenacapavir for HIV Prevention Presented at AIDS 2024 https://www.gilead.com/news/news-details/2024/full-efficacy-and-safety-results-for-gilead-investigational-twice-yearly-lenacapavir-for-hiv-prevention-presented-at-aids-2024
Gilead’s Twice-Yearly Lenacapavir Demonstrated 100% Efficacy and Superiority to Daily Truvada® for HIV Prevention https://www.gilead.com/news/news-details/2024/gileads-twice-yearly-lenacapavir-demonstrated-100-efficacy-and-superiority-to-daily-truvada-for-hiv-prevention
Gilead’s twice-yearly shot prevents 100% of HIV cases in trial with women https://www.clinicaltrialsarena.com/news/gileads-twice-yearly-shot-prevents-100-of-hiv-cases-in-trial-with-women/
Long-acting injectable lenacapavir continues to show promising results for HIV prevention https://www.who.int/news/item/26-09-2024-long-acting-injectable-lenacapavir-continues-to-show-promising-results-for-hiv-preventionFDA approval of injectable lenacapavir marks progress for HIV prevention, https://www.who.int/news/item/19-06-2025-fda-approval-of-injectable-lenacapavir-marks-progress-for-hiv-prevention
Bekker LG et al, Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women, N Engl J Med 2024;391:1179-1192, DOI: 10.1056/NEJMoa2407001
Kelley CF et al, Twice-Yearly Lenacapavir for HIV Prevention in Men and Gender-Diverse Persons, N Engl J Med 2025;392:1261-1276, DOI: 10.1056/NEJMoa2411858
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