Drug Database: Lenacapavir (HIV prevention)

Pharmacology

Pharmacology

Mechanism of Action

Capsid inhibitor. Lenacapavir is a long-acting, potent inhibitor of the HIV capsid protein with in vitro activity against viral strains resistant to other ARV classes. By targeting HIV capsid, lenacapavir interferes with multiple early- to late-stage processes of the viral life cycle: nuclear transport, virus assembly and release, and capsid assembly.⁵

Lenacapavir binds directly to HIV capsid in a pocket between capsid protein subunits in hexamers. In early stages of the virus life cycle, lenacapavir interferes with capsid-mediated nuclear import of HIV-1 proviral DNA, as it targets the same capsid binding site utilized by host factors that aid in viral nuclear import and integration. In late stages of the HIV life cycle, lenacapavir interferes with the functioning of Gag/Gag-Pol and reduces capsid protein subunit production. Additionally, lenacapavir increases the rate of HIV capsid assembly, resulting in abnormalities in capsid structure.^5–8

Half-life (T_½)

The elimination half-life of lenacapavir is 10 to 12 days (oral formulation) and 8 to 12 weeks (subcutaneous [SC] formulation).⁶

Metabolism/Elimination

Lenacapavir undergoes minor metabolism via CYP3A and UGT1A1. Following a single intravenous (IV) dose of radiolabeled lenacapavir administered to participants without HIV, unchanged drug was the predominant compound in plasma and accounted for 69% of the total radioactive dose. Less than 1% of the administered dose was excreted in urine and 76% was excreted in feces (33% as unchanged drug).⁶

Resistance

Treatment-emergent resistance to lenacapavir has been reported in the Phase 2/3 CAPELLA trial evaluating lenacapavir for HIV treatment. Information on HIV resistance mutations associated with lenacapavir is described in the FDA-approved Full Prescribing Information for Sunlenca.⁶

Select Clinical Trials

Select Clinical Trials

Lenacapavir for HIV prevention

Study Identifiers: PURPOSE 1; GS-US-412-5624; NCT04994509

Sponsor: Gilead Sciences
Phase: 3
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this study is to evaluate the safety and efficacy of twice-yearly SC lenacapavir and daily oral emtricitabine/tenofovir alafenamide (Descovy) for PrEP in adolescent girls and young women who are at risk of acquiring HIV infection.
Study Population:

• Participants are cisgender adolescent girls and young women, 16 years to 25 years of age.
• Incidence Phase: Participants are not using PrEP, have unknown HIV status at screening, and had no prior HIV testing within the last 3 months. Participants are sexually active with cisgender male individuals.
• Randomized Phase: Participants are confirmed HIV-negative and at risk of acquiring HIV.^2,9

Selected Study Results: Results presented at AIDS 2024 and published in the N Engl J Med (2024) showed that none of the women who received twice-yearly lenacapavir injections acquired HIV. HIV incidence with lenacapavir was significantly lower compared to background HIV incidence and HIV incidence with the active control, emtricitabine/tenofovir DF (Truvada). HIV incidence with Descovy was not significantly different than background HIV incidence. Notably, researchers found that adherence to lenacapavir injections was high but adherence to oral Truvada and Descovy was low.^9,10

Study Identifiers: PURPOSE 2; GS-US-528-9023; NCT04925752

Sponsor: Gilead Sciences
Phase: 3
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this study is to evaluate the safety and efficacy of twice-yearly SC lenacapavir and daily oral emtricitabine/tenofovir DF (Truvada) for PrEP in cisgender men, transgender women, transgender men, and gender nonbinary people who have sex with partners assigned male at birth and are at risk of acquiring HIV infection.
Study Population:

• Participants are cisgender men, transgender women, transgender men, and gender nonbinary people, 16 years of age or older.
• Incidence Phase: Participants have unknown HIV status at screening and no prior HIV testing in the last 3 months. Participants have condomless receptive anal sex with partners who are assigned male at birth and are at risk for acquiring HIV infection.
• Randomized Phase: Participants are confirmed HIV-negative and at risk of acquiring HIV.³

Selected Study Results: Results presented at HIVR4P 2024 showed that among the participants who received twice-yearly lenacapavir injections, 99.9% of participants did not acquire HIV and only two participants acquired HIV. Lenacapavir reduced HIV incidence by 96% compared with background HIV incidence. Also, when compared to the active control (Truvada), lenacapavir was shown to be more effective in preventing HIV.¹¹

Study Identifiers: PURPOSE 3; HPTN-102; GS-US-528-6020; NCT06101329

Sponsor: Gilead Sciences
Phase: 2
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate the pharmacokinetics of twice-yearly SC lenacapavir and to assess the safety and acceptability of twice-yearly SC lenacapavir and daily oral Truvada for PrEP in cisgender women in the United States.
Study Population:

• Participants are cisgender women who are disproportionately affected by HIV.
• Participants are HIV- and HBV-negative.
• Participants have had at least one episode of condomless vaginal or anal sex with a cisgender man in the 12 months before enrollment.¹²

Study Identifiers: PURPOSE 4; HPTN-103; GS-US-528-6363; NCT06101342

Sponsor: Gilead Sciences
Phase: 2
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate the pharmacokinetics of twice-yearly SC lenacapavir and to assess the safety of twice-yearly SC lenacapavir and daily oral Truvada for PrEP in people who inject drugs in the United States.
Study Population:

• Participants are adults with a positive urine drug screen test and evidence of recent injection. Participants must also self-report sharing of injection paraphernalia in the past 30 days.
• Participants are HIV- and HBV-negative.¹³

Study Identifiers: PURPOSE 5; GS-US-528-6727; NCT06513312

Sponsor: Gilead Sciences
Phase: 2
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate the persistence, safety, acceptability, and pharmacokinetics of twice-yearly SC lenacapavir for PrEP in people who would benefit from PrEP.
Study Population:

• Participants are cisgender men who have sex with men, transgender women, transgender men, cisgender women, and nonbinary people.
• Participants have an increased likelihood of HIV acquisition.
• At screening, participants have confirmed HIV-negative testing.¹⁴

Adverse Events

Adverse Events

PURPOSE 1 (NCT04994509)

In the Phase 3 PURPOSE 1 trial evaluating twice-yearly SC lenacapavir and Descovy for PrEP, no safety concerns were seen. Adverse events (AEs) associated with lenacapavir, Descovy, and Truvada (active control) were comparable to what has been observed in previous studies of these drugs. Serious adverse events (SAEs) occurred in a similar percentage of participants across study groups (2.8% lenacapavir; 4.0% Descovy; 3.3% Truvada).^9,10

Injection-site reactions (ISRs) occurred more frequently in participants receiving lenacapavir injections (68.8%) than in participants receiving placebo injections (34.9%). The incidence of ISRs associated with lenacapavir decreased with subsequent injections. Four participants in the lenacapavir arm (0.2%) discontinued treatment because of ISRs.^9,10

PURPOSE 2 (NCT04925752)

In the Phase 3 PURPOSE 2 trial evaluating twice-yearly SC lenacapavir and Truvada for PrEP, the safety profile of both study drugs was consistent with what has been seen in previous studies. Serious AEs occurred in a similar percentage of participants in both study groups (3% lenacapavir; 4% Truvada). Two participants receiving Truvada discontinued treatment because of decreased creatinine clearance.¹¹

The most common ISRs were nodules, injection-site pain, and erythema, the majority of which were mild or moderate in severity. Nodules occurred more frequently with lenacapavir than with placebo (63.4% lenacapavir; 39.2% placebo). Seven participants receiving lenacapavir had Grade 3 ISRs (n = 4 pain; n = 3 erythema), and one participant receiving placebo had Grade 3 pain. The incidence of ISRs, including nodules, decreased over time. Twenty-six participants receiving lenacapavir and three participants receiving placebo discontinued treatment because of ISRs.¹¹

Additional AEs known to be associated with lenacapavir treatment are described in the FDA-approved Full Prescribing Information for Sunlenca.⁶

Drug Interactions

Drug Interactions

Lenacapavir is a substrate of CYP3A, P-gp, and UGT1A1.⁶

Drugs that are strong or moderate CYP3A inducers may significantly decrease plasma concentrations of lenacapavir and coadministration of strong CYP3A inducers with lenacapavir is contraindicated. The concomitant use of moderate CYP3A inducers with lenacapavir is not recommended. Coadministration of lenacapavir with combined P-gp, UGT1A1, and strong CYP3A inhibitors is not recommended, as they may significantly increase plasma concentrations of lenacapavir.⁶

Lenacapavir moderately inhibits CYP3A activity. Given the long half-life of lenacapavir following SC administration, lenacapavir may increase the exposure of drugs primarily metabolized by CYP3A that are initiated within 9 months after the last SC dose of lenacapavir.⁶

Additionally, clinical studies indicate that lenacapavir is an inhibitor of the P-gp drug transporter and BCRP protein.⁶

Specific drug-drug interactions associated with lenacapavir are described in the FDA-approved Full Prescribing Information for Sunlenca.⁶

References

References

1. National Center for Biotechnology Information. PubChem compound summary for CID 153435888, lenacapavir sodium. Accessed November 14, 2024
2. Gilead Sciences. A Phase 3, double-blinded, multicenter, randomized study to evaluate safety and efficacy of twice yearly long-acting subcutaneous lenacapavir, and daily oral emtricitabine/tenofovir alafenamide for pre-exposure prophylaxis in adolescent girls and young women at risk of HIV infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on August 2, 2021. NLM Identifier: NCT04994509. Accessed November 14, 2024
3. Gilead Sciences. A Phase 3, double-blind, multicenter, randomized study to evaluate the efficacy and safety of subcutaneous twice yearly long-acting lenacapavir for HIV pre-exposure prophylaxis in cisgender men, transgender women, transgender men, and gender non-binary people ≥ 16 years of age who have sex with partners and are at risk for HIV infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 28, 2021. NLM Identifier: NCT04925752. Accessed November 14, 2024
4. Gilead Sciences: Press release, dated December 22, 2022. Sunlenca® (lenacapavir) receives FDA approval as a first-in-class, twice-yearly treatment option for people living with multi-drug resistant HIV. Accessed November 14, 2024
5. Ogbuagu O, Segal-Maurer S, Brinson C, et al. Long-acting lenacapavir in people with multidrug resistant HIV-1: Week 52 results. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 12-16, 2022; Virtual. Accessed November 14, 2024
6. Gilead Sciences, Inc. Sunlenca: full prescribing information, July, 30 2024. DailyMed. Accessed November 14, 2024
7. Link JO, Rhee MS, Tse WC, et al. Clinical targeting of HIV capsid protein with a long-acting small molecule. Nature. 2020;584(7822):614-618. doi:10.1038/s41586-020-2443-1. Accessed November 14, 2024
8. Bester SM, Wei G, Zhao H, et al. Structural and mechanistic bases for a potent HIV-1 capsid inhibitor. Science. 2020;370(6514):360-364. doi:10.1126/science.abb4808. Accessed November 14, 2024
9. Bekker L-G. Twice-yearly lenacapavir or daily emtricitabine/tenofovir alafenamide for HIV prevention in cisgender women: interim analysis results from the PURPOSE 1 study. Presented at: International AIDS Conference; July 22-26, 2024; Munich, Germany and Virtual. Accessed November 14, 2024
10. Bekker LG, Das M, Abdool Karim Q, et al. Twice-yearly lenacapavir or daily F/TAF for HIV prevention in cisgender women. N Engl J Med. Published online July 24, 2024. doi:10.1056/NEJMoa2407001. Accessed November 14, 2024
11. Kelley CF. Twice-yearly lenacapavir for HIV prevention in cisgender, gay, bisexual, and other men, transgender women, transgender men, and gender-nonbinary people who have sex with partners assigned male at birth: interim analysis results from the PURPOSE 2 study. Slides presented at: HIV Research for Prevention (HIVR4P); October 6-10, 2024; Lima, Peru. Accessed November 14, 2024
12. Gilead Sciences. A Phase 2, open-label, multicenter, randomized study to evaluate the pharmacokinetics, safety, and acceptability of twice yearly long-acting subcutaneous lenacapavir for pre-exposure prophylaxis in cisgender women in the United States. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 20, 2023. NLM Identifier: NCT06101329. Accessed November 14, 2024
13. Gilead Sciences. A Phase 2, open-label, multicenter, randomized study to evaluate the pharmacokinetics and safety of twice yearly long-acting subcutaneous lenacapavir for pre-exposure prophylaxis in people who inject drugs. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 20, 2023. NLM Identifier: NCT06101342. Accessed November 14, 2024
14. Gilead Sciences. A Phase 2, open-label, multicenter, randomized study to evaluate the persistence, safety, acceptability, and pharmacokinetics of twice yearly long-acting subcutaneous lenacapavir for HIV pre-exposure prophylaxis (PrEP) in people who would benefit from PrEP. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on July 16, 2024. NLM Identifier: NCT06513312. Accessed November 14, 2024

Last Reviewed: November 14, 2024