Lenacapavir

Last updated

Lenacapavir
Lenacapavir.svg
Clinical data
Pronunciation /ˌlɛnəˈkæpəvɪər/
LEN-ə-KAP-ə-veer
Trade names Sunlenca, Yeztugo, others
Other namesGS-CA2, GS-6207
AHFS/Drugs.com Monograph
MedlinePlus a623005
License data
Pregnancy
category
Routes of
administration 		By mouth, subcutaneous
Drug class Capsid inhibitors
ATC code
Legal status
Legal status
Identifiers
  • N-[(1S)-1-{3-[4-chloro-3-(methanesulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl]-6-[3-(methanesulfonyl)-3-methylbut-1-yn-1-yl]pyridin-2-yl}-2-(3,5-difluorophenyl)ethyl]-2-[(3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl]acetamide
CAS Number
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
Chemical and physical data
Formula C39H32ClF10N7O5S2
Molar mass 968.28 g·mol−1
3D model (JSmol)
  • CC(C)(C#Cc1ccc(-c2ccc(Cl)c3c(NS(C)(=O)=O)nn(CC(F)(F)F)c23)c([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)n1)S(C)(=O)=O
  • InChI=1S/C39H32ClF10N7O5S2/c1-36(2,63(3,59)60)10-9-21-5-6-22(23-7-8-26(40)30-32(23)57(17-37(43,44)45)54-35(30)55-64(4,61)62)31(51-21)27(13-18-11-19(41)14-20(42)12-18)52-28(58)16-56-34-29(33(53-56)39(48,49)50)24-15-25(24)38(34,46)47/h5-8,11-12,14,24-25,27H,13,15-17H2,1-4H3,(H,52,58)(H,54,55)/t24-,25+,27-/m0/s1
  • Key:BRYXUCLEHAUSDY-WEWMWRJBSA-N

Lenacapavir, sold under the brand names Sunlenca and Yeztugo, is an antiretroviral medication used to treat and prevent HIV/AIDS. [9] [11] It is taken by mouth or by subcutaneous injection. [9] [11] Lenacapavir is a human immunodeficiency virus type 1 (HIV-1) capsid inhibitor. [9] [10]

Contents

The most common side effects include reactions at the injection site and nausea. [11] [12]

Lenacapavir was approved for medical treatment in the European Union in August 2022, [11] [13] in Canada in November 2022, [5] [6] and in the United States in December 2022. [9] [12] [14] [15] It is the first of a class of drugs called capsid inhibitors to be approved by the US Food and Drug Administration (FDA) for treating HIV/AIDS. [12] [16] In June 2025, lenacapavir, as Yeztugo, received approval in the US for HIV prevention. [10] [17] [18] [19]

Medical uses

Lenacapavir, as Sunlenca, in combination with other antiretrovirals, is indicated for the treatment of HIV/AIDS. [9] It is used in heavily treatment-experienced adults with multiple drug resistance in whom current antiretroviral therapy is ineffective due to resistance, intolerance or safety considerations. [9] [12]

Lenacapavir, as Yeztugo, is indicated for pre‑exposure prophylaxis to reduce the risk of sexually acquired HIV-1 in adults and adolescents weighing more than 35 kilograms (77 lb) who are at risk for HIV-1 acquisition. [10]

Mechanism of action

Lenacapavir works by binding directly to the interface between HIV-1 viral capsid protein (p24) subunits in capsid hexamers, [20] interfering with essential steps of viral replication, including capsid-mediated nuclear uptake of HIV-1 proviral DNA (it over-stabilizes the capsid, preventing it from properly releasing its contents), [21] virus assembly and release, production of capsid protein subunits, and capsid core formation. [9] [12] The US Food and Drug Administration considers it to be a first-in-class medication. [16] [22]

Because lenacapavir is the first medication that targets the p24 capsid, mutations that confer resistance to other antiretrovirals have no effect on lenacapavir. However, mutations of the capsid can still confer resistance, especially when the drug is used without an optimized background therapy. [23]

History

Lenacapavir was developed by Gilead Sciences. [24]

The safety and efficacy of lenacapavir were established through a multicenter clinical trial with 72 participants whose HIV infections were resistant to multiple classes of HIV medications. [12] These participants had to have high levels of virus in their blood despite being on antiretroviral drugs. [12] Participants were enrolled into one of two study groups. [12] One group was randomized to receive either lenacapavir or placebo in a double-blind fashion, and the other group received open-label lenacapavir. [12] The primary measure of efficacy was the proportion of participants in the randomized study group who achieved a certain level of reduction in virus during the initial 14 days compared to baseline. [12]

The US Food and Drug Administration granted the application for lenacapavir priority review, fast track, and breakthrough therapy designations. [12] In 2025, lenacapavir was approved by the FDA. [25]

In 2024, lenacapavir was named the "2024 Breakthrough of the Year", citing its "astonishing 100% efficacy" in one large efficacy trial in women to prevent HIV and "99.9% efficacy in gender diverse people who have sex with men," while highlighting that research providing a "new understanding of the structure and function of HIV's capsid protein" led to the drug's "off-the-charts success". [26]

Society and culture

In June 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Sunlenca, intended for the treatment of adults with multidrug‑resistant human immunodeficiency virus type 1 (HIV‑1) infection. [27] The applicant for this medicinal product is Gilead Sciences Ireland UC. [27]

Lenacapavir was authorized for medical use in the European Union in August 2022, [11] [28] in Canada in November 2022, [5] [6] and in the United States in December 2022. [12]

In February 2025, the FDA accepted Gilead Sciences's drug application for twice-yearly lenacapavir under priority review. [29] The FDA approved lenacapavir for HIV prevention in June 2025. It will be sold under the brand name Yeztugo for this application. [18] [19]

In July 2025, the CHMP adopted a positive opinion recommending the granting of a marketing authorization for the medicinal product Yeytuo (lenacapavir) intended for the prophylaxis against sexually acquired human immunodeficiency virus type 1 (HIV-1) infection. [30] [31]

Economics

As of 2024 the medication, produced by Gilead Sciences, costs US$42,250 for the first year. A study presented in July 2024 [32] found that mass production of a generic version would allow a profit margin of 30% on an annual price of $40 if used by 10 million people. The authors said that lowering world HIV levels significantly would probably require 60 million people to take the drug preventatively. [33]

Gilead Sciences set the list price for Yeztugo at $28,218 in 2025. [18]

Research

Studies have been conducted for the use of lenacapavir in treatment-naive individuals. [34] For virally suppressed individuals switching treatment, early studies have tested lenacapavir injections in combination with infusions of the broadly neutralizing antibodies teropavimab and zinlirvimab [35] as well as lenacapavir with islatravir. [36]

A phase III clinical trial study examined efficacy for pre-exposure HIV prevention (PrEP). [37] [38] [39] [40] It found an incidence rate ratio of 0.00 (as no cases occurred in the lenacapavir group) with a 95% confidence interval of 0.00–0.04 with p<.001. Injection site reactions led to discontinuation by 0.2% of lenacapavir patients

Another lenacapavir phase III study, examined the incidence compared to the background rate for men persons. [41] It found an incidence rate ratio of 0.04 with a 95% confidence interval of 0.01 to 0.18, at p<.001. Injection site reactions led to discontinuation by 1.2% of patients.

Lenacapavir has been found to be effective as HIV pre-exposure prophylaxis (PrEP) in heterosexual cisgender women in Africa. [42]

References

  1. 1 2 "Sunlenca". Therapeutic Goods Administration. 6 April 2023. Archived from the original on 8 April 2023. Retrieved 7 April 2023.
  2. ↑ "Sunlenca lenacapavir (as sodium) 300 mg film coated tablet blister pack (392350)". Therapeutic Goods Administration. 28 March 2023. Archived from the original on 8 April 2023. Retrieved 7 April 2023.
  3. ↑ "Sunlenca lenacapavir (as sodium) 463.5 mg/1.5 mL solution for injection vial (386895)". Therapeutic Goods Administration. 28 March 2023. Archived from the original on 8 April 2023. Retrieved 7 April 2023.
  4. ↑ "AusPAR: Sunlenca".
  5. 1 2 3 "Sunlenca Oral Product information". Health Canada . 25 April 2012. Archived from the original on 15 January 2023. Retrieved 23 December 2022.
  6. 1 2 3 "Sunlenca Subcutaneous Product information". Health Canada . 25 April 2012. Archived from the original on 15 January 2023. Retrieved 23 December 2022.
  7. ↑ "Summary Basis of Decision - Sunlenca". Health Canada . 10 March 2023. Archived from the original on 25 April 2023. Retrieved 24 April 2023.
  8. ↑ "Details for: Sunlenca". Health Canada . 15 March 2023. Archived from the original on 3 March 2024. Retrieved 3 March 2024.
  9. 1 2 3 4 5 6 7 8 "Sunlenca- lenacapavir sodium tablet, film coated Sunlenca- lenacapavir sodium kit". DailyMed. 21 December 2022. Archived from the original on 21 January 2023. Retrieved 21 January 2023.
  10. 1 2 3 4 "Yeztugo- lenacapavir sodium tablet, film coated; Yeztugo- lenacapavir sodium kit". DailyMed. 18 June 2025. Retrieved 6 July 2025.
  11. 1 2 3 4 5 6 "Sunlenca EPAR". European Medicines Agency (EMA). 22 June 2022. Archived from the original on 26 August 2022. Retrieved 25 August 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  12. 1 2 3 4 5 6 7 8 9 10 11 12 "FDA Approves New HIV Drug for Adults with Limited Treatment Options" (Press release). U.S. Food and Drug Administration (FDA). 22 December 2022. Archived from the original on 15 January 2023. Retrieved 23 December 2022.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  13. ↑ "Gilead Announces First Global Regulatory Approval of Sunlenca (Lenacapavir), the Only Twice-Yearly HIV Treatment Option". Gilead Sciences (Press release). 22 August 2022. Archived from the original on 15 January 2023. Retrieved 23 December 2022.
  14. ↑ "Sunlenca (lenacapavir) Receives FDA Approval as a First-in-Class, Twice-Yearly Treatment Option for People Living With Multi-Drug Resistant HIV". Gilead Sciences (Press release). 22 December 2022. Archived from the original on 23 December 2022. Retrieved 23 December 2022.
  15. ↑ Paik J (September 2022). "Lenacapavir: First Approval". Drugs. 82 (14): 1499–1504. doi:10.1007/s40265-022-01786-0. PMC   10267266 . PMID   36272024.
  16. 1 2 "Advancing Health Through Innovation: New Drug Therapy Approvals 2022". U.S. Food and Drug Administration . 10 January 2023. Archived from the original on 21 January 2023. Retrieved 22 January 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  17. ↑ "FDA approves the world's only twice-a-year shot to prevent HIV". AP News. 18 June 2025. Retrieved 18 June 2025.
  18. 1 2 3 Mandavilli A (18 June 2025). "Regulators Approve Lenacapavir for H.I.V. Prevention". The New York Times . Retrieved 18 June 2025.
  19. 1 2 "Yeztugo (Lenacapavir) Is Now the First and Only FDA-Approved HIV Prevention Option Offering 6 Months of Protection" (Press release). Gilead Sciences. 18 June 2025. Retrieved 20 June 2025– via Business Wire.
  20. ↑ Lang S (18 June 2025). "Understanding the HIV-CA protein and the ligands that bind at the N-terminal domain (NTD) - C-terminal domain (CTD) interface". RSC Medicinal Chemistry. 16 (6): 2373–2387. doi:10.1039/D5MD00111K. ISSN   2632-8682. PMC   12018806 . PMID   40291137.
  21. ↑ Faysal KM, Walsh JC, Renner N, Márquez CL, Shah VB, Tuckwell AJ, et al. (February 2024). "Pharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failure". eLife. 13 e83605. doi: 10.7554/eLife.83605 . PMC   10863983 . PMID   38347802.
  22. ↑ New Drug Therapy Approvals 2022 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2024. Archived from the original on 14 January 2024. Retrieved 14 January 2024.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  23. ↑ Margot NA, Jogiraju V, Pennetzdorfer N, Naik V, VanderVeen LA, Ling J, et al. (June 2025). "Resistance Analyses in Heavily Treatment-Experienced People With HIV Treated With the Novel HIV Capsid Inhibitor Lenacapavir After 2 Years". The Journal of Infectious Diseases. 231 (5): 1239–1245. doi:10.1093/infdis/jiaf050. PMID   39873394.
  24. ↑ Link JO, Rhee MS, Tse WC, Zheng J, Somoza JR, Rowe W, et al. (August 2020). "Clinical targeting of HIV capsid protein with a long-acting small molecule". Nature. 584 (7822): 614–618. Bibcode:2020Natur.584..614L. doi:10.1038/s41586-020-2443-1. PMC   8188729 . PMID   32612233. S2CID   220293679.
  25. ↑ Howard J (18 June 2025). "FDA approves twice-a-year injection for HIV prevention". CNN. Retrieved 24 August 2025.
  26. ↑ Cohen J (December 2024). "Science's 2024 Breakthrough of the Year: Opening the door to a new era of HIV prevention". Science. 386 (6727): 1208–1209. doi:10.1126/science.adv2100. PMID   39666802.
  27. 1 2 "Sunlenca: Pending EC decision". European Medicines Agency (EMA). 23 June 2022. Archived from the original on 26 June 2022. Retrieved 26 June 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  28. ↑ "Sunlenca Product information". Union Register of medicinal products. Archived from the original on 3 March 2023. Retrieved 3 March 2023.
  29. ↑ "U.S. FDA Accepts Gilead's New Drug Applications for Twice-Yearly Lenacapavir for HIV Prevention Under Priority Review". BioSpace. 18 February 2025. Retrieved 21 February 2025.
  30. ↑ "Yeytuo EPAR". European Medicines Agency (EMA). 25 July 2025. Retrieved 27 July 2025. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  31. ↑ "New injection for easier prevention of HIV infection in the EU and worldwide". European Medicines Agency (EMA) (Press release). 25 July 2025. Retrieved 27 July 2025. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  32. ↑ "AIDS 2024, the 25th International AIDS Conference". International AIDS Society (IAS). Retrieved 23 July 2024.
  33. ↑ Lay K (23 July 2024). "HIV 'vaccine' could be made for just $40 a year for every patient". The Guardian.
  34. ↑ Gupta S (January 2023). "Lenacapavir administered every 26 weeks or daily in combination with oral daily antiretroviral therapy for initial treatment of HIV: a randomised, open-label, active-controlled, phase 2 trial" . The Lancet HIV. 10 (1): 15–23. doi:10.1016/S2352-3018(22)00291-0. PMID   36566079 . Retrieved 10 March 2024.
  35. ↑ Highleyman L (28 February 2023). "Lenacapavir plus broadly neutralising antibodies may offer twice-yearly treatment option". Aidsmap. Retrieved 10 March 2024.
  36. ↑ Highleyman L (6 March 2024). "Islatravir plus lenacapavir could be the first once-weekly oral HIV treatment". Aidsmap. Retrieved 10 March 2024.
  37. ↑ Bekker LG, Das M, Abdool Karim Q, Ahmed K, Batting J, Brumskine W, et al. (October 2024). "Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women". The New England Journal of Medicine. 391 (13): 1179–1192. doi:10.1056/NEJMoa2407001. PMID   39046157.
  38. ↑ "Lenacapavir Shows 100% Efficacy and Zero Infections in HIV Prevention". www.precisionvaccinations.com. Retrieved 25 July 2024.
  39. ↑ "Full Efficacy and Safety Results for Gilead Investigational Twice-Yearly Lenacapavir for HIV Prevention Presented at AIDS 2024". www.gilead.com. Retrieved 25 July 2024.
  40. ↑ Bekker LG (3 July 2024). "HIV breakthrough: drug trial shows injection twice a year is 100% effective against infection". The Conversation. Retrieved 25 July 2024.
  41. ↑ Kelley CF, Acevedo-Quiñones M, Agwu AL, Avihingsanon A, Benson P, Blumenthal J, et al. (November 2024). "Twice-Yearly Lenacapavir for HIV Prevention in Men and Gender-Diverse Persons". The New England Journal of Medicine. 392 (13): 1261–1276. doi:10.1056/NEJMoa2411858. PMID   39602624.
  42. ↑ Bekker LG, Das M, Abdool Karim Q, Ahmed K, Batting J, Brumskine W, et al. (July 2024). "Twice-Yearly Lenacapavir or Daily F/TAF for HIV Prevention in Cisgender Women". The New England Journal of Medicine. 391 (13): 1179–1192. doi:10.1056/NEJMoa2407001. PMID   39046157.
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