Drug information

Audio
Download files:
Pronounce:
Other Names
LEN, GS-6207, GS-CA2
Drug Class
Capsid Inhibitors
Molecular Formula

C39 H32 Cl F10 N7 O5 S2

Registry Number
2189684-44-2 (CAS)
Chemical Name

1H-Cyclopropa[3,4]cyclopenta[1,2-c]pyrazole, N-[(1S)-1-[3-[4-chloro-3-[(methylsulfonyl)amino]-1-(2,2,2-trifluoroethyl)- 1H-indazol-7-yl]-6-[3-methyl-3-(methylsulfonyl)-1-butyn-1-yl]-2-pyridinyl]- 2-(3,5-difluorophenyl)ethyl]-5,5-difluoro-3b,4,4a,5-tetrahydro-3- (trifluoromethyl)-, (3bS,4aR)-

Organization
Gilead Sciences, Inc.
Phase of Development

Lenacapavir is in Phase 3 development for HIV prevention.

FDA-Approved Products for HIV Treatment: Lenacapavir (brand name: Sunlenca), in combination with other antiretrovirals, is approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV in heavily treatment-experienced adults with multidrug-resistant HIV.

(Compound details obtained from NIAID Therapeutics Database,1 American Medical Association website,2 ClinicalTrials.gov,3,4 and Gilead press release5)

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.6

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.6–9

Half-life (T½)

The elimination half-life of lenacapavir is 10 to 12 days (oral formulation) and 8 to 12 weeks (subcutaneous [SC] formulation).7

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).7

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.7

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 currently recruiting participants.
Study Purpose: The purpose of this study is to evaluate the efficacy of twice yearly SC lenacapavir and daily oral Descovy for PrEP in adolescent girls and young women who are at risk of acquiring HIV infection.
Study Population:

  • Participants are adolescent girls and young women, 16 years to 25 years of age.
  • Incidence Phase: Participants have unknown HIV status at screening and 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.3

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

Sponsor: Gilead Sciences
Phase: 3
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this study is to evaluate the efficacy of twice yearly SC lenacapavir 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.4

Adverse Events

Adverse Events

Study results for the Phase 3 prevention trials (PURPOSE 1; NCT04994509 and PURPOSE 2; NCT04925752) evaluating lenacapavir for HIV PrEP are not yet available.


Adverse events (AEs) known to be associated with lenacapavir treatment are described in the FDA-approved Full Prescribing Information for Sunlenca.7

Drug Interactions

Drug Interactions

Lenacapavir is a substrate of CYP3A, P-gp, and UGT1A1.7

Drugs that are strong or moderate CYP3A inducers may significantly decrease plasma concentrations of lenacapavir and coadministration of these drugs with lenacapavir is contraindicated. Coadministration of lenacapavir with combined P-gp, UGT1A1, and strong CYP3A inhibitors is not recommended, as they may significantly increase plasma concentrations of lenacapavir.7

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.7

Additionally, clinical studies indicate that lenacapavir is an inhibitor of the P-gp drug transporter and BCRP protein.7

Specific drug-drug interactions associated with lenacapavir are described in the FDA-approved Full Prescribing Information for Sunlenca.7

References

References

  1. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. Accessed April 19, 2023
  2. American Medical Association (AMA) website. Statement on a nonproprietary name adopted by the USAN council: lenacapavir. Accessed January April 19, 2023
  3. 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 April 19, 2023
  4. 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 assigned male at birth 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 April 19, 2023
  5. 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 April 19, 2023
  6. 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 April 19, 2023
  7. Gilead Sciences, Inc. Sunlenca: full prescribing information, December 21, 2022. DailyMed. Accessed April 19, 2023
  8. 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 April 19, 2023
  9. 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 April 19, 2023

Last Reviewed: April 19, 2023