Lencacapvir is in Phase 2/3 development for HIV treatment.
(Compound details obtained from NIAID Therapeutics Database1 and ClinicalTrials.gov2)
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: capsid disassembly and nuclear transport, virus production, and capsid assembly.3,4
Lenacapavir binds directly to HIV capsid in a pocket between two adjacent capsid monomers. In early stages of the virus life cycle, lenacapavir stabilizes the capsid shell and inhibits disassembly of the shell, a step which is essential for viral replication. Additionally, lenacapavir interferes with the transport of viral complexes across the nuclear pore, as it targets the same capsid binding site utilized by host factors (Nup153 and CPSF6) that aid in viral nuclear import and integration.4–7 In late stages of the HIV life cycle, lenacapavir distorts the capsid lattice, resulting in abnormalities in virus structure and inhibition of virus maturation.4
Lenacapavir is currently in Phase 2/3 development for HIV treatment.2 Clinical trials evaluating its use as injectable PrEP are planned.8
Half-life (T½): In a Phase 1 single ascending-dose study, participants without HIV were randomized to receive subcutaneous (SC) lenacapavir (300 mg, given as one 1.0 mL dose and 900 mg, given as either three 1.0 mL doses or two 1.5 mL doses). The median half-life of SC lenacapavir ranged from 49.6 days (900 mg, three 1.0 mL doses) to 64.6 days (900 mg, two 1.5 mL doses) to 175 days (300 mg, one 1.0 mL dose).9 In a separate study, the half-life of oral lenacapavir (300 mg) was determined to be approximately 12 days.3
Metabolism/Elimination: Lenacapavir appears to be metabolized via glucuronidation by UGT1A1, and to a lesser extent, CYP3A.10
Resistance: In the ongoing Phase 2/3 CAPELLA trial (NCT04150068), lenacapavir was evaluated in heavily treatment-experienced participants with multidrug-resistant HIV who were failing their current ARV regimen. Resistance analysis through at least Week 16 of the study found that among 72 total participants who received SC lenacapavir, two participants developed treatment-emergent capsid mutations – M66I and N74D in one participant and M66I in another participant. Both participants had viral rebound above detectable levels and both resuppressed while on lenacapavir, one with a change in their optimized background regimen (OBR) and one with no change in their OBR. Notably, the M66I capsid mutation was found to significantly reduce HIV replication capacity.11
Select Clinical TrialsStudy Identifiers: CALIBRATE; GS-US-200-4334; NCT04143594
Sponsor: Gilead Sciences
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate the safety and efficacy of lenacapavir in combination with other ARV agents in treatment-naive adults.
- Participants are treatment-naive adults with HIV who have not used any ARVs within one month of screening.
- Participants have HIV RNA ≥200 copies/mL and CD4 counts ≥200 cells/mm3 at screening.12
Study Identifiers: CAPELLA; GS-US-200-4625; NCT04150068
Sponsor: Gilead Sciences
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this study is to evaluate the safety and efficacy of lenacapavir administered as functional monotherapy in participants with multi-drug resistant HIV. After the functional monotherapy period, the efficacy of lenacapavir in combination with OBR will be assessed.
- Participants are treatment-experienced children (12 years and older) and adults with multi-drug resistant HIV and who are failing their current ARV regimen.
- Participants have two or fewer fully active ARV agents available to effectively form a viable regimen.
- Participants have HIV RNA ≥400 copies/mL at screening.2
A Phase 1b trial (NCT03739866) evaluating the safety, pharmacokinetics and antiviral activity of SC lenacapavir in adults with HIV was completed.13
In the ongoing Phase 2/3 CAPELLA trial, a safety analysis through at least Week 16 of the study found that among a total of 72 randomized and nonrandomized participants who received lenacapavir, there were no drug-related serious adverse events (SAEs) and no adverse events (AEs) resulting in discontinuation of lenacapavir. Excluding injection site reactions (ISRs), common AEs occurring in at least 5% of participants included headache, nausea, cough, diarrhea, back pain, pyrexia, rash, and urinary tract infection.11
Forty-six percent of participants reported at least one ISR related to SC lenacapavir. ISRs included swelling, erythema, nodule, and pain. The majority of ISRs were Grade 1 and resolved within days; however, nodules (all of which were mild) persisted for a few months. One participant experienced Grade 3 swelling and erythema. There were no Grade 4 ISRs and no discontinuations due to ISRs.11
Among the 72 participants who received lenacapavir, 21% had a Grade 3 or 4 laboratory abnormality, including low creatinine clearance/eGFR, hyperglycemia, high creatinine, and glycosuria; however, these abnormalities were reported to be transient or unconfirmed. Some cases of hyperglycemia and glycosuria were related to underlying diabetes.11
A Phase 1 drug-drug interaction (DDI) study evaluating oral lenacapavir coadministered with probe drugs confirms that lenacapavir is a substrate of CYP3A and P-gp; data also indicate lenacapavir is primarily metabolized by UGT1A1.10
Lenacapavir coadministered with strong CYP3A and P-gp inhibitors, such as darunavir/cobicistat, resulted in increased lenacapavir area under the curve (AUC). These interactions, however, are not considered clinically significant, and lenacapavir can be coadministered with potent CYP3A and P-gp inhibitors without dose modification.10
Until further data is available, coadministration of lenacapavir with strong UGT1A1 inhibitors is currently not recommended. Additionally, potent inducers of CYP3A/P-gp/UGT, such as rifampin, should not be concomitantly administered with lenacapavir.10
Gastric acid-reducing agents (H2 receptor antagonists and proton pump inhibitors) can be given with lenacapavir.10
Lenacapavir is a moderate inhibitor of CYP3A and a weak inhibitor of the drug transporters P-gp and BCRP. It does not affect OATP. Investigators recommend caution when coadministering lenacapavir with sensitive CYP3A substrates.10
- National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed March 16, 2021
- Gilead Sciences. A Phase 2/3 study to evaluate the safety and efficacy of long acting capsid inhibitor GS-6207 in combination with an optimized background regimen in heavily treatment experienced people living with HIV-1 infection with multidrug resistance. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 28, 2019. NLM Identifier: NCT04150068. https://clinicaltrials.gov/ct2/show/NCT04150068. Accessed March 16, 2021
- Rhee, M. Lenacapavir (GS-6207): a first-in-class long acting HIV capsid inhibitor. HIV DART; December 10, 2020; Virtual Meeting. National AIDS Treatment Advocacy Project (NATAP): HIV Articles; 2020. https://www.natap.org/2020/HIV/121520_02.htm. Accessed March 16, 2021
- Dick A, Cocklin S. Recent Advances in HIV-1 Gag Inhibitor Design and Development. Molecules. 2020;25(7). doi:10.3390/molecules25071687
- 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
- Engelman AN. HIV Capsid and Integration Targeting. Viruses. 2021;13(1). doi:10.3390/v13010125
- Rossi E, Meuser ME, Cunanan CJ, Cocklin S. Structure, Function, and Interactions of the HIV-1 Capsid Protein. Life (Basel). 2021;11(2). doi:10.3390/life11020100
- Gilead Sciences: Press Release, dated March 9, 2021. Gilead’s investigational lenacapavir demonstrates sustained long-acting efficacy through Week 26 in data presented at CROI. https://www.gilead.com/news-and-press/press-room/press-releases/2021/3/gileads-investigational-lenacapavir-demonstrates-sustained-long-acting-efficacy-through-week-26-in-data-presented-at-croi. Accessed March 16, 2021
- Begley R, Lutz J, Rhee M, et al. Lenacapavir sustained delivery formulation supports 6-month dosing interval. Poster presented at: International AIDS Conference; July 6-10, 2020; Virtual. Poster PEB0625. https://programme.aids2020.org/PAGMaterial/PPT/3400_3610/Begley AIDS2020.pptx. Accessed March 16, 2021
- Begley R, Lutz J, Dvory-Sobol H, et al. Clinical evaluation of drug interactions with oral lenacapavir and probe drugs. Conference on Retroviruses and Opportunistic Infections (CROI); March 6-10, 2021; Virtual. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2021. https://www.natap.org/2021/CROI/croi_26.htm. Accessed March 16, 2021
- Segal-Maurer S , Castagna A , Berhe M, et al. Potent antiviral activity of lenacapavir in Phase 2/3 in heavily ART-experienced PWH. Conference on Retroviruses and Opportunistic Infections (CROI); March 6-10, 2021; Virtual. Levin: Conference Reports for National AIDS Treatment Advocacy Project (NATAP); 2021. https://www.natap.org/2021/CROI/croi_47.htm. Accessed March 16, 2021
- Gilead Sciences. A Phase 2 randomized, open label, active controlled study evaluating the safety and efficacy of long-acting capsid inhibitor GS-6207 in combination with other antiretroviral agents in people living with HIV. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on October 28, 2019. NLM Identifier: NCT04143594. https://clinicaltrials.gov/ct2/show/NCT04143594. Accessed March 16, 2021
- Gilead Sciences. A Phase 1b randomized, double-blinded, placebo controlled, multi-cohort study of the safety, pharmacokinetics, and antiviral activity of GS-6207 administered subcutaneously in HIV-1 infected subjects. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on November 2, 2018. NLM Identifier: NCT03739866. https://clinicaltrials.gov/ct2/show/NCT03739866. Accessed March 16, 2021
Last Reviewed: March 16, 2021