Lenacapavir (LEN)

Associated long-acting platforms

Aqueous Solution, Oral solid form

Administration route

Oral, Subcutaneous, Intramuscular, To be determined

Therapeutic area(s)

Use case(s)

Use of drug

Dosage

Drug information

Delivery device(s)

No delivery device

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).

CAPELLA

Identifier

NCT04150068

Link

https://clinicaltrials.gov/ct2/show/NCT04150068

Phase

Phase II/III

Status

Active, not recruiting

Sponsor

Gilead Sciences

More details

Not provided

Purpose

Evaluate the antiviral activity of Lenacapavir (formerly GS-6207) administered as an add-on to a failing regimen (functional monotherapy) in people living with HIV with multi-drug resistance.

Interventions

Intervention 1

Intervention 2

Intervention 3

Intervention 4

Intervention 5

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2019-11-21 00:00:00

Anticipated Date of Last Follow-up
2024-06-26 00:00:00

Estimated Primary Completion Date
Not provided

Estimated Completion Date
2027-01-01 00:00:00

Actual Primary Completion Date
2020-10-05 00:00:00

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Children
• Adolescents
• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

Adult aged ≥ 18 years (at all sites) or adolescent aged ≥ 12 and weighing ≥ 35 kg (at sites in North America and Dominican Republic). Currently receiving a stable failing ARV regimen for > 8 weeks. Have HIV-1 RNA ≥ 400 copies/mL at screening. Have multidrug resistance (resistance to ≥2 agents from ≥3 of the 4 main classes of ARV). Have no more than 2 fully active ARV remaining from the 4 main classes that can be effectively combined to form a viable regimen. Able and willing to receive an Optimized Background Regimen (OBR) together with Lenacapavir.

Health status

Study type

Interventional (clinical trial)

Enrollment

72

Allocation

Randomized

Intervention model

Sequential assignment

Intervention model description

Not provided

Masking

Quadruple-blind masking

Masking description

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key results

CALIBRATE

Identifier

NCT04143594

Link

https://clinicaltrials.gov/ct2/show/NCT04143594

Phase

Phase II

Status

Completed

Sponsor

Gilead Sciences

More details

Not provided

Purpose

Evaluate the efficacy of Lenacapavir containing regimens in people living with HIV

Interventions

Intervention 1

Intervention 2

Intervention 3

Intervention 4

Intervention 5

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2019-11-22 00:00:00

Anticipated Date of Last Follow-up
2023-10-03 00:00:00

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2021-09-30 00:00:00

Actual Completion Date
2023-09-13 00:00:00

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

Antiretroviral (ARV) naïve with no use of any ARV within one month of screening. Use of pre-exposure prophylaxis (PrEP) (any duration), post-exposure prophylaxis (PEP) (any duration), or HIV-1 treatment (< 10 days therapy total) > 1 month prior to screening is permitted. HIV-1 RNA ≥ 200 copies/mL at screening. CD4+ cell count ≥ 200 cells/microliter at screening.

Health status

Study type

Interventional (clinical trial)

Enrollment

183

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Open label

Masking description

None (Open Label)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key results

GS-US-536-5816

Identifier

NCT04811040

Link

https://clinicaltrials.gov/ct2/show/NCT04811040

Phase

Phase I

Status

Completed

Sponsor

Gilead Sciences

More details

Not provided

Purpose

Evaluate the safety and tolerability of a combination of the broadly neutralizing antibodies (bNAbs) teropavimab (formerly GS-5423) and GS-2872 in combination with the HIV capsid inhibitor lenacapavir

Interventions

Intervention 1

Intervention 2

Intervention 3

Intervention 4

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2021-04-08 00:00:00

Anticipated Date of Last Follow-up
2023-10-26 00:00:00

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2023-04-18 00:00:00

Actual Completion Date
2023-10-17 00:00:00

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

On first-line antiretroviral therapy (ART) for ≥ 2 years prior to screening. A change in ART regimen ≥ 28 days prior to screening for reasons other than virologic failure (VF) (eg, tolerability, simplification, drug-drug interaction profile) is allowed.

Health status

Study type

Interventional (clinical trial)

Enrollment

32

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Double-blind masking

Masking description

Double (Participant, Investigator). Clinical pharmacologist and sponsor are not masked to treatment assignment.

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key results

GS-US-200-4072

Identifier

NCT03739866

Link

https://clinicaltrials.gov/ct2/show/NCT03739866

Phase

Phase I

Status

Completed

Sponsor

Gilead Sciences

More details

Not provided

Purpose

Separately evaluate the short-term antiviral activity of both lenacapavir and tenofovir alafenamide with respect to plasma HIV-1 RNA reduction in antiretroviral or capsid inhibitor naïve patients

Interventions

Intervention 1

Intervention 2

Intervention 3

Intervention 4

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2018-11-26 00:00:00

Anticipated Date of Last Follow-up
2021-03-16 00:00:00

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
2019-11-14 00:00:00

Actual Completion Date
2020-06-15 00:00:00

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
No

Accepts lactating individuals
No

Accepts healthy individuals
No

Comments about the studied populations

Treatment naïve or experienced but CAI and integrase strand transfer inhibitor (INSTI) naïve, and have not received any antiretroviral therapy (ART) within 12 weeks of screening.

Health status

Study type

Interventional (clinical trial)

Enrollment

53

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Double-blind masking

Masking description

Double (Participant, Investigator)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key results

GS-US-536-5939

Identifier

NCT05729568

Link

https://clinicaltrials.gov/study/NCT05729568

Phase

Phase II

Status

Active, not recruiting

Sponsor

Gilead Sciences

More details

Not provided

Purpose

Evaluate the Safety and Efficacy of bNAbs GS-5423 and GS-2872 in Combination With Lenacapavir as Long-Acting Treatment Dosed Every 6 Months in Virologically Suppressed Adults With HIV-1 Infection.

Interventions

Intervention 1

Intervention 2

Intervention 3

Intervention 4

Intervention 5

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2023-05-15 00:00:00

Anticipated Date of Last Follow-up
2024-07-12 00:00:00

Estimated Primary Completion Date
2025-03-01 00:00:00

Estimated Completion Date
2029-12-01 00:00:00

Actual Primary Completion Date
2024-07-02 00:00:00

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

Participants are required to be receiving a stable ART regimen with no clinically significant documented resistance (except isolated NRTI mutations). Plasma HIV-1 RNA < 50 copies/mL at screening visit 2 and documented plasma HIV-1 RNA < 50 copies/mL for ≥ 12 months preceding screening visit 2.

Health status

Study type

Interventional (clinical trial)

Enrollment

83

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Open label

Masking description

None (Open Label)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key results

IMEA 070

Identifier

NCT06289361

Link

https://clinicaltrials.gov/study/NCT06289361

Phase

Marketed

Status

Not yet recruiting

Sponsor

Institut de Médecine et d'Epidémiologie Appliquée - Fondation Internationale Léon M'Ba

More details

Immunovirological follow-up and safety of HIV-infected patients receiving lenacapavir under compassionate access in France between 01/01/2021 and 12/31/2023

Purpose

Cohort IMEA 070 -Lenacapavir Compassional

Interventions

Not provided

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
2024-04-01 00:00:00

Actual Start Date
Not provided

Anticipated Date of Last Follow-up
2024-03-20 00:00:00

Estimated Primary Completion Date
2024-04-15 00:00:00

Estimated Completion Date
2024-07-30 00:00:00

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
No

Comments about the studied populations

Not provided

Health status

Study type

Observational studies (incl. patient registries)

Enrollment

58

Allocation

Not provided

Intervention model

Not provided

Intervention model description

Not provided

Masking

Not provided

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

Treatment

Key results

Pharmacokinetics and safety of once-yearly lenacapavir: a phase 1, open-label study

Identifier

Not provided

Link

https://doi.org/10.1016/S0140-6736(25)00405-2

Phase

Phase I

Status

Not provided

Sponsor

Gilead Sciences Inc.

More details

Not provided

Purpose

Not provided

Interventions

Intervention 1

Intervention 2

Countries

Not provided

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
Not provided

Anticipated Date of Last Follow-up
Not provided

Estimated Primary Completion Date
Not provided

Estimated Completion Date
Not provided

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
Yes

Comments about the studied populations

Not provided

Health status

Not provided

Study type

Interventional (clinical trial)

Enrollment

40

Allocation

Not provided

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Not provided

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

PrEP

Key results

PURPOSE 1

Identifier

NCT04994509

Link

https://clinicaltrials.gov/study/NCT04994509

Phase

Phase III

Status

Active, not recruiting

Sponsor

Gilead Sciences

More details

The goal of this study is to evaluate the efficacy in preventing HIV infection of the study drugs, lenacapavir (LEN) and emtricitabine/tenofovir alafenamide (F/TAF), in adolescent girls and young women.

Purpose

Pre-Exposure Prophylaxis Study of Lenacapavir and Emtricitabine/Tenofovir Alafenamide in Adolescent Girls and Young Women at Risk of HIV Infection

Interventions

Intervention 1

Intervention 2

Intervention 3

Intervention 4

Intervention 5

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2021-08-30 00:00:00

Anticipated Date of Last Follow-up
2024-02-26 00:00:00

Estimated Primary Completion Date
2024-09-01 00:00:00

Estimated Completion Date
2027-07-01 00:00:00

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Children
• Adults

Genders

• Female

Accepts pregnant individuals
Yes

Accepts lactating individuals
Yes

Accepts healthy individuals
Yes

Comments about the studied populations

Key Inclusion Criteria: * Incidence Phase * HIV-1 status unknown at initial screening and no prior human immunodeficiency virus (HIV)-1 testing within the last 3 months. * Sexually active (has had \> 1 vaginal intercourse within the last 3 months) with cisgender male individuals (CGM). * Randomized Phase * Negative fourth generation HIV-1 antibody (Ab)/antigen (Ag) test confirmed with central HIV-1 testing. * Estimated glomerular filtration rate (GFR) ≥ 60 mL/min at screening. * Body weight ≥ 35 kg. Key Exclusion Criteria: * Prior receipt of an HIV vaccine. * Prior use of long-acting systemic HIV pre-exposure prophylaxis (PrEP) or or HIV PEP (postexposure prophylaxis). Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Health status

Study type

Interventional (clinical trial)

Enrollment

5368

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Double-blind masking

Masking description

Double (Participant, Investigator)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

PrEP

Key results

PURPOSE 2

Identifier

NCT04925752

Link

https://clinicaltrials.gov/study/NCT04925752

Phase

Phase III

Status

Active, not recruiting

Sponsor

Gilead Sciences

More details

The goal of this clinical study is to test how well the study drug, lenacapavir (LEN), works in preventing the risk of HIV.

Purpose

Study of Lenacapavir for HIV Pre-Exposure Prophylaxis in People Who Are at Risk for HIV Infection

Interventions

Intervention 1

Intervention 2

Intervention 3

Intervention 4

Intervention 5

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2021-06-28 00:00:00

Anticipated Date of Last Follow-up
2024-07-11 00:00:00

Estimated Primary Completion Date
2024-12-01 00:00:00

Estimated Completion Date
2028-05-01 00:00:00

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Children
• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
Yes

Comments about the studied populations

Key Inclusion Criteria: Incidence Phase * CGM, TGW, TGM, and GNB who have condomless receptive anal sex with partners assigned male at birth and are at risk for HIV infection. * HIV-1 status unknown at screening and no prior HIV-1 testing within the last 3 months. * Sexually active with ≥ 1 partner assigned male at birth (condomless receptive anal sex) in the last 12 months and 1 of the following: * Condomless receptive anal sex with ≥ 2 partners in the last 12 weeks. * History of syphilis, rectal gonorrhea, or rectal chlamydia in the last 24 weeks. * Self-reported use of stimulants with sex in the last 12 weeks. Randomized Phase * Negative local rapid fourth generation HIV-1/2 Ab/Ag, central fourth generation HIV-1/2 Ab/Ag, and HIV-1 RNA quantitative nucleic acid amplification

Health status

Study type

Interventional (clinical trial)

Enrollment

3295

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Double-blind masking

Masking description

Double (Participant, Investigator)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

PrEP

Key results

PURPOSE 3

Identifier

NCT06101329

Link

https://clinicaltrials.gov/study/NCT06101329

Phase

Phase II

Status

Recruiting

Sponsor

Gilead Sciences

More details

Not provided

Purpose

Evaluate the Pharmacokinetics, Safety, and Acceptability of Twice Yearly Long-acting Subcutaneous Lenacapavir for Pre-Exposure Prophylaxis in Cisgender Women in the United States.

Interventions

Intervention 1

Intervention 2

Intervention 3

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2023-11-17 00:00:00

Anticipated Date of Last Follow-up
2024-08-12 00:00:00

Estimated Primary Completion Date
2028-01-01 00:00:00

Estimated Completion Date
2028-01-01 00:00:00

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• Cisgender female

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
Unspecified

Comments about the studied populations

Cisgender women aged 18 and older who report at least one episode of condomless vaginal or anal sex with a cisgender man in the twelve months prior to enrollment.

Health status

Study type

Interventional (clinical trial)

Enrollment

250

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Open label

Masking description

None (Open Label)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

PrEP

Key results

PURPOSE 4

Identifier

NCT06101342

Link

https://clinicaltrials.gov/study/NCT06101342

Phase

Phase II

Status

Recruiting

Sponsor

Gilead Sciences

More details

PWUD (People Who Use Drugs).

Purpose

Evaluate the Pharmacokinetics and Safety of Twice Yearly Long-Acting Subcutaneous Lenacapavir for Pre-Exposure Prophylaxis in People Who Inject Drugs.

Interventions

Intervention 1

Intervention 2

Intervention 3

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2023-12-13 00:00:00

Anticipated Date of Last Follow-up
2024-08-08 00:00:00

Estimated Primary Completion Date
2027-07-01 00:00:00

Estimated Completion Date
2027-07-01 00:00:00

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
Yes

Comments about the studied populations

Participant inclusion criteria requires a positive urine drug screen for any drug of misuse including (but not limited to) opioids (eg, fentanyl, heroin), stimulants (eg, cocaine, amphetamines), psychoactive drugs (eg, benzodiazepines), or a combination of these drugs. Participants must also display evidence of recent injection(s) (eg, track marks) and self-report of injection paraphernalia sharing within the last 30 days.

Health status

Study type

Interventional (clinical trial)

Enrollment

250

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Open label

Masking description

None (Open Label)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

PrEP

Key results

PURPOSE 5

Identifier

NCT06513312

Link

https://clinicaltrials.gov/study/NCT06513312

Phase

Phase II

Status

Not yet recruiting

Sponsor

Gilead Sciences

More details

The goals of this clinical study are to learn more about the study drug lenacapavir (LEN), by comparing the consistent and continuous use of LEN and emtricitabine/tenofovir disoproxil fumarate (coformulated; Truvada®) (F/TDF), then by observing the safety of LEN and F/TDF, evaluating the acceptability of LEN injections and oral F/TDF, and observe how LEN moves throughout the body in people who would benefit from pre-exposure prophylaxis (PrEP). The primary objective of this study is to compare LEN and F/TDF consistent and continuous use among people who would benefit from PrEP.

Purpose

Study of Lenacapavir Taken Twice a Year for HIV Pre-Exposure Prophylaxis (PrEP)

Interventions

Intervention 1

Intervention 2

Intervention 3

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
2024-09-01 00:00:00

Actual Start Date
Not provided

Anticipated Date of Last Follow-up
2024-08-22 00:00:00

Estimated Primary Completion Date
2027-01-01 00:00:00

Estimated Completion Date
2029-07-01 00:00:00

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Adults
• Older Adults

Genders

• All
• Cisgender female
• Cisgender male
• Transgender female
• Transgender male
• Gender non-binary

Accepts pregnant individuals
Unspecified

Accepts lactating individuals
Unspecified

Accepts healthy individuals
Yes

Comments about the studied populations

Key Inclusion Criteria: - Able to comprehend and provide a signed written informed consent, which must be obtained prior to initiation of study procedures. - Cisgender men who have sex with men, transgender women, transgender men, cisgender women, and nonbinary people - Increased likelihood of HIV acquisition as indicated by at least one of the following: - Condomless sex with ≥ 2 partners in the past 6 months - Diagnosis of a bacterial sexually transmitted infection (STI) in the past 12 months - Engagement in sex work or transactional sex in the past 12 months - Use of ≥ 2 courses of nonoccupational HIV post-exposure prophylaxis (nPEP) in the past 12 months - Condomless sex with a partner living with HIV who has unknown or unsuppressed viral load (≥ 200 copies/mL) in the past 12 months

Health status

Study type

Interventional (clinical trial)

Enrollment

262

Allocation

Randomized

Intervention model

Parallel Assignment

Intervention model description

Not provided

Masking

Open label

Masking description

None (Open Label)

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

PrEP

Key results

Proprietary excipients used

No proprietary excipient used

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

No novel excipient or existing excipient used

Residual solvents used

No residual solvent used

There are either no relevant patents or these were not yet submitted to LAPaL

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.

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	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 Not provided

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