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Drug information

Drug's link(s)
Generic name

Lenacapavir

Brand names

Sunlenca

Compound type

Small molecule

Summary

Lenacapavir (LEN), also known as GS-6207, is a first in-class HIV-1 capsid inhibitor used in combination with other antiretrovirals for the treatment of multi-drug resistant HIV-1 infection, and has potential application as HIV pre-exposure prophylaxis. LEN is utilised combinatorially for HIV-1 treatment, as it displays excellent synergy and no known cross-resistance with any other currently approved class of antiretroviral, in addition to possessing antiviral activity at picomolar levels.

Approval status

Lenacapavir (SUNLENCA) 463.5mg/3ml subcutaneous injection with 300mg oral lead-in tablets are approved for use in the United States, United Kingdom, Canada, UAE, South Korea, Hong Kong, Japan, Australia, Israel, and the European Union (27-member states of the European Union, as well as Norway, Iceland and Liechtenstein) for HIV-1 treatment under certain conditions. For PrEP: Gilead submitted an application to the US FDA for Lenacapavir in December 2024 and was granted priority review with a decision expected by June 19, 2025. It is also under review in Brazil, EU (+EEA) and South Africa.

Regulatory authorities

US FDA granted Breakthrough Therapy Designation for SUNLENCA in combination with other antiretroviral drugs for heavily treatment-experienced patients (HTE) adults with multi-drug resistant (MDR) HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations. A European Marketing Authorization was issued for the use of SUNLENCA and it has also been classified as ‘Fast-Track Reimbursement’ by the Ministry of Health, Labour and Welfare, Japan, and ‘Part 1- Schedule 1 & Schedule 3 Poison’ by the Department of Health, Hong Kong.

Therapeutic area(s)

  • HIV
Use case(s)
  • Pre-Exposure Prophylaxis (PrEP)
  • Treatment
  • Prevention

Administration route

Oral, Subcutaneous, Intramuscular, To be determined

Associated long-acting platforms

Aqueous Solution, Oral solid form

Use of drug

Ease of administration
  • Administered by a community health worker
  • Administered by a nurse
  • Administered by a specialty health worker
  • Self-administered
  • To be determined
User acceptance

Not provided

Dosage

Available dose and strength

LEN oral tablets 300 mg; each injection contains 927 mg of lenacapavir in solution. Dose for investigational Once-Yearly formulation is 5000 mg.

Frequency of administration

Oral tablets 300 mg taken daily or weekly; Six-monthly injectable; Once-yearly investigational injectable.

Maximum dose

5000 mg

Recommended dosing regimen

For PrEP: Initiation Option 1: Day 1: 927 mg by subcutaneous injection and 600 mg orally (2 x 300-mg tablets). Day 2: 600 mg orally (2 x 300-mg tablets). Initiation Option 2: Day 1: 600 mg orally (2 x 300-mg tablets). Day 2: 600 mg orally (2 x 300-mg tablets). Day 8: 300 mg orally (1 x 300-mg tablet). Day 15: 927 mg by subcutaneous injection. Maintenance: 927 mg by subcutaneous injection every 26 weeks +/- 2 weeks from date of last injection. For the treatment indication, lenacapavir is administered as part of a full treatment regimen with the relevant associated medicines.

Additional comments

Not provided

Dosage link(s)

Not provided

Comment & Information

Not provided

Developer(s)

Gilead Sciences Inc.
Originator
United States

Gilead Sciences, Inc. is a multinational biopharmaceutical company that develops and manufactures innovative medicines for life-threatening diseases, including anti-viral therapeutics for HIV/AIDS, Hepatitis B, Hepatitis C and Covid-19. Headquartered in Foster City, California, Gilead was originally founded in 1987 and is currently listed on both the S&P 500 and the NASDAQ Biotechnology Index.

Drug structure

Scale-up and manufacturing prospects

Scale-up prospects

Compound is commercially manufactured.

Tentative equipment list for manufacturing

Equipment for injectable: Stainless steel pharmaceutical reactors, glass-lined reactors, rotary evaporator (rotovap), flash chromatography columns, stainless steel autoclave, cooling bath, silica gel chromatography columns, vacuum distillation apparatus, simulated moving bed chromatography system, Chiralpak columns.

Manufacturing

Storage of injectable lenacapavir in borosilicate vials is contraindicated due to issues with chemical compatibility. Instead, it is recommended that vials are made from aluminosilicate glass.

Specific analytical instrument required for characterization of formulation

Proton nuclear magnetic resonance (1H NMR), High-performance liquid chromatography (HPLC), Ultra-Performance Liquid Chromatography (UPLC).

Excipients

Proprietary excipients used

No proprietary excipient used

Novel excipients or existing excipients at a concentration above Inactive Ingredient Database (IID) for the specified route of administration

No novel excipient or existing excipient used

Residual solvents used

No residual solvent used

Delivery device(s)

No delivery device

Publications

Link JO, Rhee MS, Tse WC, Zheng J, Somoza JR, Rowe W, Begley R, Chiu A, Mulato A, Hansen D, Singer E, Tsai LK, Bam RA, Chou CH, Canales E, Brizgys G, Zhang JR, Li J, Graupe M, Morganelli P, Liu Q, Wu Q, Halcomb RL, Saito RD, Schroeder SD, Lazerwith SE, Bondy S, Jin D, Hung M, Novikov N, Liu X, Villasenor AG, Cannizzaro CE, Hu EY, Anderson RL, Appleby TC, Lu B, Mwangi J, Liclican A, Niedziela-Majka A, Papalia GA, Wong MH, Leavitt SA, Xu Y, Koditek D, Stepan GJ, Yu H, Pagratis N, Clancy S, Ahmadyar S, Cai TZ, Sellers S, Wolckenhauer SA, Ling J, Callebaut C, Margot N, Ram RR, Liu YP, Hyland R, Sinclair GI, Ruane PJ, Crofoot GE, McDonald CK, Brainard DM, Lad L, Swaminathan S, Sundquist WI, Sakowicz R, Chester AE, Lee WE, Daar ES, Yant SR, Cihlar T: Clinical targeting of HIV capsid protein with a long-acting small molecule. Nature. 2020 Aug;584(7822):614-618. doi: https://doi.org/10.1038/s41586-020-2443-1. Epub 2020 Jul 1.

Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis1-5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance6. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment-which contributes to virologic failure, resistance generation and viral transmission-as well as of pre-exposure prophylaxis, leading to new infections1,2,4,7-9. Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence10. Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log10-transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV.

Bester SM, Wei G, Zhao H, Adu-Ampratwum D, Iqbal N, Courouble VV, Francis AC, Annamalai AS, Singh PK, Shkriabai N, Van Blerkom P, Morrison J, Poeschla EM, Engelman AN, Melikyan GB, Griffin PR, Fuchs JR, Asturias FJ, Kvaratskhelia M: Structural and mechanistic bases for a potent HIV-1 capsid inhibitor. Science. 2020 Oct 16;370(6514):360-364. doi: https://doi.org/10.1126/science.abb4808

The potent HIV-1 capsid inhibitor GS-6207 is an investigational principal component of long-acting antiretroviral therapy. We found that GS-6207 inhibits HIV-1 by stabilizing and thereby preventing functional disassembly of the capsid shell in infected cells. X-ray crystallography, cryo-electron microscopy, and hydrogen-deuterium exchange experiments revealed that GS-6207 tightly binds two adjoining capsid subunits and promotes distal intra- and inter-hexamer interactions that stabilize the curved capsid lattice. In addition, GS-6207 interferes with capsid binding to the cellular HIV-1 cofactors Nup153 and CPSF6 that mediate viral nuclear import and direct integration into gene-rich regions of chromatin. These findings elucidate structural insights into the multimodal, potent antiviral activity of GS-6207 and provide a means for rationally developing second-generation therapies.

Collaborate for development

Consider on a case by case basis, collaborating on developing long acting products with potential significant public health impact, especially for low- and middle-income countries (LMICs), utilising the referred to long-acting technology

Share technical information for match-making assessment

Provide necessary technical information to a potential partner, under confidentiality agreement, to enable preliminary assessment of whether specific medicines of public health importance in LMICs might be compatible with the referred to long-acting technology to achieve a public health benefit

Work with MPP to expand access in LMICs

In the event that a product using the referred to long-acting technology is successfully developed, the technology IP holder(s) will work with the Medicines Patent Pool towards putting in place the most appropriate strategy for timely and affordable access in low and middle-income countries, including through licensing