Lenacapavir Once-Yearly

Drug information

Delivery device(s)

No delivery device

Scale-up prospects

LEN is already being manufactured at scale by Gilead for the twice-yearly SC product. For yearly IM, similar industrial processes will form the basis but with adaptations to the higher concentration and altered vehicle (ethanol content for IM depot). 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.

Tentative equipment list for 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. High-precision mixing tanks with capability for viscous, ethanol-containing solutions. Aseptic filling/isolation units compatible with ethanol/PEG vehicles.Sterile filtration units for low-volume injectables.Standard lyophilisation (if relevant to final formulation.

Manufacturing

Vehicles with ethanol (often 5% or 10%) require specialised mixing times and solvent management to control viscosity and precipitation, which impact overall plant throughput and quality assurance. PEG and ethanol vehicles restrict direct steam sterilisation due to oxidation risk; sterile filtration is therefore preferred for terminal sterilisation—requiring high-quality, compatible filter assemblies with low extractable profiles.

Specific analytical instrument required for characterization of formulation

Proton nuclear magnetic resonance (1H NMR), High-performance liquid chromatography (HPLC), Ultra-Performance Liquid Chromatography (UPLC). Container closure integrity testers (for glass vials or prefilled syringes). Stability chambers for long-term and accelerated conditions.

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 resources

GS-US-712-7286

Identifier

NCT07047716

Link

https://clinicaltrials.gov/study/NCT07047716

Phase

Phase III

Status

Recruiting

Sponsor

Gilead Sciences

More details

The goal of this clinical study is to learn more about the study drug lenacapavir (LEN), safety, tolerability, and pharmacokinetics (how LEN is absorbed, modified, distributed, and removed from the body of the participants) of once-yearly intramuscular for HIV pre-exposure prophylaxis (PrEP) in people with an indication for PrEP. The primary objective of this study is to evaluate the pharmacokinetics (PK) and the safety and tolerability of intramuscular (IM) every 12 months (Q12M) LEN for PrEP among people with an indication for PrEP.

Purpose

Study of Lenacapavir as a Once-Yearly Injection for HIV Pre-exposure Prophylaxis (PrEP)

Interventions

Intervention 1

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
2025-07-01

Actual Start Date
2025-07-22

Anticipated Date of Last Follow-up
2026-01-08

Estimated Primary Completion Date
2028-09-01

Estimated Completion Date
2028-09-01

Actual Primary Completion Date
Not provided

Actual Completion Date
Not provided

Studied populations

Age Cohort

• Adults
• Older Adults
• Adolescents

Genders

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

Accepts pregnant individuals
Yes

Accepts lactating individuals
Yes

Accepts healthy individuals
Yes

Comments about the studied populations

Key Inclusion Criteria: * At least 16 years of age at screening. * Receptive anal or vaginal sex in the past 6 months and at least 1 of the following: 1. Condomless receptive sex (vaginal or anal) with 1 or more sex partners of unknown HIV status during the past 6 months 2. For a person who has engaged in anal sex in the past 6 months: diagnosis of syphilis, gonorrhea, or chlamydia in the past 6 months 3. For a person who has engaged in vaginal sex in the past 6 months: diagnosis of syphilis or gonorrhea in the past 6 months 4. Sex with partner known to be living with HIV with an unknown or detectable viral load in the past 6 months * Negative local rapid fourth generation HIV-1/2 antibody (Ab)/antigen (Ag) test, central fourth generation HIV-1/2 Ab/Ag, and HIV-1 RNA quantitative

Health status

Study type

Interventional (clinical trial)

Enrollment

300

Allocation

Not provided

Intervention model

Single group assignment

Intervention model description

Not provided

Masking

Open label

Masking description

Not provided

Frequency of administration

Studied LA-formulation(s)

Studied route(s) of administration

Use case

PrEP

Key resources

Proprietary excipients used

Not provided

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

Not provided

Residual solvents used

Not provided

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

Publications

Pharmacokinetics and safety of once-yearly lenacapavir: a phase 1, open-label study. Jogiraju, Vamshi et al. The Lancet, Volume 405, Issue 10485, 1147 - 1154

Background

Long-acting antiretrovirals can address barriers to HIV pre-exposure prophylaxis (PrEP), such as stigma and adherence. In two phase 3 trials, twice-yearly subcutaneous lenacapavir was safe and highly efficacious for PrEP in diverse populations. Furthering long-acting PrEP efforts, this study assessed the pharmacokinetics and safety of two once-yearly intramuscular lenacapavir formulations.

Methods

This phase 1, open-label study in participants aged 18–55 years without HIV evaluated the pharmacokinetics, safety, and tolerability of two lenacapavir free acid formulations administered by ventrogluteal intramuscular injection as a single 5000 mg dose (formulation 1 with 5% w/w ethanol, formulation 2 with 10% w/w ethanol). Pharmacokinetic samples were collected at prespecified timepoints up to 56 weeks. Lenacapavir plasma concentrations were measured with a validated liquid chromatography–tandem mass spectrometry method and summarised with non-compartmental analysis. Pharmacokinetic parameters evaluated included the area under the concentration–time curve for the once-yearly dosing interval calculated from days 1 to 365 (AUCdays 1–365), peak plasma concentration, time to reach peak plasma concentration, and trough concentration (Ctrough). Plasma concentration data from phase 3 studies of twice-yearly subcutaneous lenacapavir (PURPOSE 1 and PURPOSE 2) were pooled for comparison with once-yearly intramuscular lenacapavir formulations. Safety and tolerability, including participant-reported pain scores, were assessed.

Findings

20 participants received lenacapavir formulation 1 and 20 received lenacapavir formulation 2. For estimation of pharmacokinetic parameters, sample size varied over time with at least 13 participants (formulation 1) and at least 19 participants (formulation 2) due to early discontinuations for reasons unrelated to the study drug. Following administration of intramuscular lenacapavir, concentrations increased rapidly, and median time to maximum concentration was 84·1 days (IQR 56·1–112·0) for formulation 1 and 69·9 days (55·3–105·5) for formulation 2. The highest median concentration of once-yearly intramuscular lenacapavir (247·0 ng/mL [IQR 184·0–346·0] for formulation 1, 336·0 ng/mL [233·5–474·3] for formulation 2) remained above the highest median twice-yearly subcutaneous lenacapavir concentration (67·3 ng/mL [46·8–91·4]). Median Ctrough at the end of 52 weeks for formulation 1 was 57·0 ng/mL (IQR 49·9–72·4) and for formulation 2 was 65·6 ng/mL (41·8–87·1), exceeding the median twice-yearly subcutaneous lenacapavir Ctrough of 23·4 ng/mL (15·7–34·3) at the end of 26 weeks. Median AUCdays 1–365 for formulation 1 was 1011·1 h*μg/mL (IQR 881·0–1490·2) and for formulation 2 was 1274·0 h*μg/mL (1177·3–1704·8). Adverse events were mostly grade 1 or 2. The most common was injection-site pain (16 [80%] participants given formulation 1, 15 [75%] given formulation 2), which was generally mild, resolved within 1 week, and was substantially reduced by pretreatment with ice.

Interpretation

Following administration of once-yearly intramuscular lenacapavir, median plasma concentrations exceeded those associated with efficacy in phase 3 studies of twice-yearly subcutaneous lenacapavir for PrEP for at least 56 weeks. Both formulations were safe and well tolerated. These data show the potential for biomedical HIV prevention with a once-yearly dosing interval.

Additional documents

No documents were uploaded

Useful links

• First Clinical Data for Gilead’s Investigational Once-Yearly Lenacapavir for HIV Prevention Presented at CROI 2025 and Published in The Lancet

• Pharmacokinetics and Safety of Once-Yearly Lenacapavir - CROI2025

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

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