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

Lencacapvir is in Phase 2/3 development for HIV treatment and Phase 3 development for HIV prevention.


A new drug application (NDA) for lenacapavir to treat HIV infection in heavily treatment-experienced people with multidrug-resistant HIV was resubmitted to the U.S. Food and Drug Administration (FDA) in June 2022. The NDA was accepted by FDA on July 27, 2022 and is currently under review.

(Compound details obtained from NIAID Therapeutics Database,1 American Medical Association website,2 ClinicalTrials.gov,3-5 and Gilead press release6)

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: capsid disassembly and nuclear transport, virus production, and capsid assembly.7,8

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.8-11 In late stages of the HIV life cycle, lenacapavir distorts the capsid lattice, resulting in abnormalities in virus structure and inhibition of virus maturation.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).12 In a separate study, the half-life of oral lenacapavir (300 mg) was determined to be approximately 12 days.7

Metabolism/Elimination: Lenacapavir appears to be metabolized via glucuronidation by UGT1A1, and to a lesser extent, CYP3A.13

Resistance: In the ongoing Phase 2 CALIBRATE trial (NCT04143594), SC and oral lenacapavir in combination with other ARVs was evaluated in treatment-naive adults with HIV. Week 54 data showed that out 157 participants who received lenacapavir, two participants developed treatment-emergent resistance. One participant developed Q67H and K70R capsid mutations at Week 10, which was preceded by the M184M/I reverse transcriptase mutation; the other participant developed the Q67H capsid mutation at Week 54. Both participants had evidence of incomplete or nonadherence to emtricitabine/tenofovir alafenamide (Descovy), and both resuppressed on a regimen containing an INSTI plus two NRTIs.14,15

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 Week 52 found that among 72 total participants who received SC lenacapavir, eight participants developed treatment-emergent capsid mutations, including M66I, Q67H/K/N, K70H/N/R/S, N74D/H/S, A105S/T, and T107A/C/N. All participants with emergent lenacapavir resistance either had no fully active drugs in their optimized background regimen (OBR) or had poor adherence to OBR. Three participants resuppressed while on lenacapavir, one without a change in OBR and two with OBR changes.3,16

Select Clinical Trials

Select Clinical Trials

Lenacapavir for HIV treatment

Study Identifiers: CALIBRATE; GS-US-200-4334; NCT04143594
Sponsor: Gilead Sciences
Phase: 2
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The purpose of this open-label study is to evaluate the efficacy of SC and oral lenacapavir in combination with other ARV agents in treatment-naive adults.
Study Population:
  • 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.15

Selected Study Results: Week 54 results presented at CROI 2022 showed that SC lenacapavir administered every 6 months, initially in combination with Descovy and later in combination with tenofovir alafenamide or bictegravir, achieved high rates of viral suppression, comparable to oral daily bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy). Similar efficacy results were seen with oral lenacapavir in combination with Descovy.14


Study Identifiers: CAPELLA; GS-US-200-4625; NCT04150068
Sponsor: Gilead Sciences
Phase: 2/3
Status: This study is ongoing, but not recruiting participants.
Study Purpose: The primary purpose of this study is to evaluate the efficacy of oral lenacapavir administered as functional monotherapy over 14 days in participants with multidrug-resistant HIV. After the functional monotherapy period, the efficacy of SC lenacapavir in combination with OBR will be assessed.
Study Population:

  • Participants are treatment-experienced individuals with multidrug-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.3

Selected Study Results: Results presented at CROI 2021 showed that a significantly higher proportion of participants receiving oral lenacapavir than participants receiving placebo achieved a substantial decline in viral load levels of at least 0.5 log10 copies/mL from baseline during the 14-day functional monotherapy period (88% versus 17%, respectively).17
Additional Published Material:


Study Identifiers: GS-US-563-6041; NCT05052996
Sponsor: Gilead Sciences
Phase: 2
Status: See note below. Please refer to the ClinicalTrials.gov record and/or the drug developer’s website for updates on this study’s status.
Study Purpose: The purpose of this open-label study is to evaluate the efficacy of the investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) islatravir in combination with oral lenacapavir in participants who are virologically suppressed on Biktarvy.
Study Population:

  • Participants are adults with HIV who have been virologically suppressed on Biktarvy for at least 24 weeks before and at screening.18

Note: The developers of islatravir and lenacapavir have decided to stop all dosing of participants in the GS-US-563-6041 trial. Participants will discontinue study treatment and restart their prior ARV regimen. Please see this December 13, 2021 press release for more details.19


Additional early-phase studies evaluating lenacapavir for HIV treatment have been conducted, including:

  • GS-US-200-4072 (NCT03739866): A Phase 1b trial that evaluated the safety, pharmacokinetics and antiviral activity of SC lenacapavir in treatment-naive or -experienced adults with HIV. This study has been completed.20
  • GS-US-536-5816 (NCT04811040): A Phase 1b trial investigating the safety and efficacy of the investigational broadly neutralizing antibodies (bNAbs) GS-5423 and GS-2872 in combination with lenacapavir in virologically suppressed adults with HIV. This study is ongoing, but not recruiting participants.21


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 two-part study is to 1) estimate the background HIV incidence rate, and 2) 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.
  • Part 1 (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.
  • Part 2 (Randomized Phase): Participants are confirmed HIV-negative and at risk of acquiring HIV.4


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 two-part study is to 1) estimate the background HIV incidence rate, and 2) evaluate the efficacy of twice yearly SC lenacapavir for PrEP in cisgender men, transgender women, transgender men, and gender nonbinary people who 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.
  • Part 1 (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.
  • Part 2 (Randomized Phase): Participants are confirmed HIV-negative and at risk of acquiring HIV.5

Adverse Events

Adverse Events

CALIBRATE (NCT04143594):

In the ongoing Phase 2 CALIBRATE trial, 182 participants were randomized to one of four treatment groups (TG) and received SC lenacapavir plus other ARVs (TG 1 and 2; n = 105), oral lenacapavir plus other ARVs (TG 3; n = 52), or Biktarvy (TG4; n = 25). At Week 54, the most common adverse events (AEs), excluding injection site reactions (ISRs), occurring in participants who received lenacapavir were headache (13%), nausea (13%), and Covid-19 infection (10%). No participant experienced a drug-related serious adverse event (SAE) or a drug-related Grade 4 AE.14,15

The majority of ISRs that occurred with SC lenacapavir were Grade 1 or 2 and included temporary erythema (27%), swelling (23%), and pain (19%). Nodule and induration were also reported and persisted for several months. One Grade 3 nodule was reported after the second dose of SC lenacapavir. Three participants discontinued lenacapavir because of injection site reactions (ISRs) – two discontinuations were due to Grade 1 induration and one discontinuation was due to Grade 1 erythema and swelling.14,22

A similar proportion of participants in the combined lenacapavir groups and the Biktarvy group experienced a Grade 3 or 4 laboratory abnormality. None of the Grade 3 or 4 abnormalities were clinically relevant and none led to treatment discontinuation.14

CAPELLA (NCT04150068):

In the ongoing Phase 2/3 CAPELLA trial, results at Week 52 found that among a total of 72 randomized and nonrandomized participants who received oral and SC lenacapavir, there were no drug-related SAEs. Excluding ISRs, the most common AEs were diarrhea (13%), nausea (13%), and Covid-19 (11%).3,16

ISRs related to SC lenacapavir, most of which were Grade 1 or 2, occurred in 63% of participants and included pain, swelling, erythema, nodule, and induration. The majority of ISRs resolved within days; however, nodules (all of which were Grade 1, except two cases of Grade 2 nodules occurring in one participant) and induration lasted 180 and 118 days, respectively. Two participants experienced transient Grade 3 ISRs – swelling and erythema in one participant and pain in the other participant. One participant discontinued treatment at Week 52 because of a Grade 1 nodule.16,23

Among the 72 participants who received lenacapavir, 29% had a Grade 3 or 4 laboratory abnormality; however, none of the Grade 3 or 4 abnormalities were considered clinically relevant.16

Drug Interactions

Drug Interactions

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 UGT1A1.13

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.13

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.13

Gastric acid-reducing agents (H2 receptor antagonists and proton pump inhibitors) can be given with lenacapavir.13

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.13

A Phase 1 study evaluating single oral doses of coadministered islatravir 20 mg and lenacapavir 600 mg in healthy participants found no significant drug-drug interactions.24

References

References

  1. National Institute of Allergy and Infectious Diseases (NIAID). NIAID ChemDB, HIV Drugs in Development. https://chemdb.niaid.nih.gov/DrugDevelopmentHIV.aspx. Accessed August 4, 2022
  2. American Medical Association (AMA) website. Statement on a nonproprietary name adopted by the USAN council: lenacapavir. https://searchusan.ama-assn.org/usan/documentDownload?uri=/unstructured/binary/usan/lenacapavir-.pdf. Accessed August 4, 2022
  3. 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 August 4, 2022
  4. 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. https://clinicaltrials.gov/ct2/show/NCT04994509. Accessed August 4, 2022
  5. 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. https://www.clinicaltrials.gov/ct2/show/NCT04925752. Accessed August 4, 2022
  6. Gilead Sciences: Company Statements, dated June 27, 2022. Gilead Sciences statement on FDA acceptance of New Drug Application for investigational lenacapavir. https://www.gilead.com/news-and-press/company-statements/gilead-sciences-statement-on-fda-acceptance-of-new-drug-application-for-investigational-lenacapavir. Accessed August 4, 2022
  7. 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 August 4, 2022
  8. Dick A, Cocklin S. Recent Advances in HIV-1 Gag Inhibitor Design and Development. Molecules. 2020;25(7). doi:10.3390/molecules25071687
  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
  10. Engelman AN. HIV Capsid and Integration Targeting. Viruses. 2021;13(1). doi:10.3390/v13010125
  11. 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
  12. 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 August 4, 2022
  13. 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 August 4, 2022
  14. Gupta SK, Sims J, Brinson C, et al. Lenacapavir as part of a combination regimen in treatment naïve PWH: Week 54 results. Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 12-16, 2022; Virtual. http://www.croiwebcasts.org/console/player/50587?mediaType=slideVideo&. Accessed August 4, 2022
  15. 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 August 4, 2022
  16. 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. https://2jg4quetidw2blbbq2ixwziw-wpengine.netdna-ssl.com/wp-content/uploads/sites/2/posters/2022/CROI2022_Poster_491.pdf. Accessed August 4, 2022
  17. Segal-Maurer S, Castagna A, Berhe M, et al. Potent antiviral activity of lenacapavir in Phase 2/3 in heavily ART-experienced PWH. Webcast presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 6-11, 2021; Virtual. http://www.croiwebcasts.org/console/player/48167?mediaType=slideVideo&. Accessed August 4, 2022
  18. Gilead Sciences. A Phase 2 randomized, open-label, active-controlled study evaluating the safety and efficacy of an oral weekly regimen of islatravir in combination with lenacapavir in virologically suppressed people with HIV. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 13, 2021. NLM Identifier: NCT05052996. https://clinicaltrials.gov/ct2/show/NCT05052996. Accessed August 4, 2022
  19. Merck: Press release, dated December 13, 2021. Merck announces clinical holds on studies evaluating islatravir for the treatment and prevention of HIV-1 infection. https://www.merck.com/news/merck-announces-clinical-holds-on-studies-evaluating-islatravir-for-the-treatment-and-prevention-of-hiv-1-infection/. Accessed August 4, 2022
  20. 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 August 4, 2022
  21. Gilead Sciences. A Phase 1b randomized, blinded, proof-of-concept study to evaluate the safety and efficacy of broadly neutralizing antibodies (bNAbs) GS-5423 and GS-2872 in combination with capsid inhibitor lenacapavir (GS-6207) in virologically suppressed adults with HIV-1 infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 19, 2021. NLM Identifier: NCT04811040. https://clinicaltrials.gov/ct2/show/NCT04811040. Accessed August 4, 2022
  22. Gupta SK, Sims J, Brinson C, et al. Lenacapavir as part of a combination regimen in treatment naïve PWH: Week 54 results. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 12-16, 2022; Virtual. https://www.croiconference.org/abstract/lenacapavir-as-part-of-a-combination-regimen-in-treatment-naive-pwh-week-54-results/. Accessed August 4, 2022
  23. Ogbuagu O, Segal-Maurer S, Brinson C, et al. Long-acting lenacapavir in people with multidrug resistant HIV-1: Week 52 results. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 12-16, 2022; Virtual. https://www.croiconference.org/abstract/long-acting-lenacapavir-in-people-with-multidrug-resistant-hiv-1-week-52-results/. Accessed August 4, 2022
  24. Zhang H, Mortensen E, Rhee M, et al. Evaluation of potential drug-drug interactions between islatravir and lenacapavir. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 12-16, 2022; Virtual. https://www.croiconference.org/abstract/evaluation-of-potential-drug-drug-interactions-between-islatravir-and-lenacapavir/. Accessed August 4, 2022

Last Reviewed: August 4, 2022