MK-8591D (Islatravir and Lenacapavir)

Drug information

Delivery device(s)

No delivery device

Scale-up prospects

Lenacapavir is commercially manufactured by Gilead Sciences. Several synthetic chemical processes describing the manufacture of islatravir (ISL) have been published. However, these approaches have proved to be complex and highly inefficient, with marked difficulty in controlling 2’-deoxyribonucleoside anomer stereochemistry and the requirement for several protecting-group manipulations. To counter these issues, Merck developed a highly innovative and extraordinarily efficient approach utilising directed evolution to create a novel three-step biocatalytic cascade for ISL synthesis.

Tentative equipment list for manufacturing

Islatravir: EasyMax 102 and 402 equipped with FireStringO2 sensors and the EasySampler 1210 system. A thermal gas flow controller (Aalborg, USA) to monitor and control oxidation air-gas flow to the reactor, with a suitable compressed air-source. Lenacapavir: 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

For Islatravir synthesis, the automated lab reactor platforms EasyMax 102 and 402 (Mettler-Toledo AG, AutoChem, Switzerland) were utilised by Merck for reaction scale-up. Although ISL+LEN is currently being evaluated as a fixed-dose oral regimen, future studies may permit LEN to be administered via subcutaneous injection. In this instance, 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

Islatravir: 400 MHz Briker AVANCE III and 500MHz Bruker Ultrashield spectrometer (or equivalent) for 1H, 19F, 31P and 13C NMR. An Accurate-Mass Time-of-Flight (TOF) high resolution mass spectrometer. Molecular Devices plate reader Spectra Max Plus for Spectrophotomeric analyses, alongside a Perkin Elmer polarimeter with a PCB 1500 water Peltier system for optical rotation measurements. Lenacapavir: Proton nuclear magnetic resonance (1H NMR), High-performance liquid chromatography (HPLC), Ultra-Performance Liquid Chromatography (UPLC).

GS-US-563-6041

Identifier

NCT05052996

Link

https://clinicaltrials.gov/study/NCT05052996

Phase

Phase II

Status

Active, not recruiting

Sponsor

Gilead Sciences

More details

The primary objective of this study is to evaluate the efficacy of oral weekly islatravir (ISL) in combination with lenacapavir (LEN) in virologically suppressed people with HIV (PWH) at Week 24.

Purpose

Study Evaluating the Safety and Efficacy of Islatravir in Combination With Lenacapavir in Virologically Suppressed People With HIV

Interventions

Intervention 1

Intervention 2

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2021-10-05

Anticipated Date of Last Follow-up
2025-06-27

Estimated Primary Completion Date
Not provided

Estimated Completion Date
2027-11-01

Actual Primary Completion Date
2023-12-19

Actual Completion Date
Not provided

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

Key Inclusion Criteria: - Received bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) for ≥ 24 weeks at screening. - Documented plasma human immunodeficiency virus type 1 (HIV-1) ribonucleic acid (RNA) < 50 copies/mL (or undetectable HIV-1 RNA level according to the local assay being used if the limit of detection is ≥ 50 copies/mL) for ≥ 24 weeks before and at screening. - Plasma HIV-1 RNA < 50 copies/mL at screening. Key Exclusion Criteria: * History of prior virologic failure while receiving treatment for HIV-1. * Prior use of, or exposure to, islatravir (ISL) or lenacapavir (LEN). * Active, serious infections requiring parenteral therapy < 30 days before randomization.

Health status

Study type

Interventional (clinical trial)

Enrollment

142

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 resources

ISLEND-1

Identifier

NCT06630286

Link

https://clinicaltrials.gov/study/NCT06630286

Phase

Phase III

Status

Active, not recruiting

Sponsor

Gilead Sciences

More details

Recruitment complete. MSD reported on April 24, 2025 "partial clinical hold for higher doses of islatravir than those used in current clinical trials". The goal of this clinical study is to learn about the safety and efficacy of switching to once weekly tablet of islatravir/lenacapavir (ISL/LEN) regimen versus continuing standard treatment of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in people with human immunodeficiency virus (PWH) who are virologically suppressed (HIV-1 RNA levels \< 50 copies/mL) on B/F/TAF for ≥ 6 months prior to screening. The primary objective is to evaluate the efficacy of switching to oral weekly ISL/LEN tablet regimen versus continuing B/F/TAF in virologically suppressed PWH at Week 48.

Purpose

Study to Compare an Oral Weekly Islatravir/Lenacapavir Regimen With Bictegravir/Emtricitabine/Tenofovir Alafenamide in Virologically Suppressed People With HIV-1

Interventions

Intervention 1

Intervention 2

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2024-10-09

Anticipated Date of Last Follow-up
2025-07-08

Estimated Primary Completion Date
2026-04-01

Estimated Completion Date
2030-08-01

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

Key Inclusion Criteria: - HIV-1 RNA < 50 copies/mL for ≥ 6 months before screening, as documented by: 1. One HIV-1 RNA < 50 copies/mL immediately preceding the 24 week period prior to screening. 2. Within 24 weeks prior to screening, if HIV-1 RNA results are available, all levels must be < 50 copies/mL. 3. During the 6 to 12 months period prior to screening, transient detectable viremia ≥ 50 copies/mL is acceptable ("blip"), as long as it is not confirmed on 2 consecutive visits. - Plasma HIV-1 RNA levels < 50 copies/mL at screening. - Individuals are receiving B/F/TAF for ≥ 6 months prior to screening and willing to continue until Day 1. - Individuals assigned female at birth and of childbearing potential who engage in heterosexual intercourse must agree to use contraception.

Health status

Study type

Interventional (clinical trial)

Enrollment

609

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 resources

ISLEND-2

Identifier

NCT06630299

Link

https://clinicaltrials.gov/study/NCT06630299

Phase

Phase III

Status

Active, not recruiting

Sponsor

Gilead Sciences

More details

Recruitment complete. MSD reported on April 24, 2025 "partial clinical hold for higher doses of islatravir than those used in current clinical trials". The goal of this clinical study is to learn more about the safety and efficacy of switching to a once weekly tablet of islatravir/lenacapavir (ISL/LEN) regimen versus continuing standard of care treatment in PWH who are virologically suppressed (HIV-1 RNA levels \< 50 copies/mL) on a stable standard of care regimen for ≥ 6 months prior to screening. The standard of care includes 2 or 3 medicines, antiretroviral agents (ARVs). The primary objective of the study is to evaluate the efficacy of switching to oral weekly ISL/LEN tablet regimen versus continuing standard of care in virologically suppressed

Purpose

Study to Compare an Oral Weekly Islatravir/Lenacapavir Regimen With Standard of Care in Virologically Suppressed People With HIV-1

Interventions

Intervention 1

Intervention 2

Countries

Sites / Institutions

Not provided

Trials dates

Anticipated Start Date
Not provided

Actual Start Date
2024-10-08

Anticipated Date of Last Follow-up
2025-07-09

Estimated Primary Completion Date
2026-04-01

Estimated Completion Date
2030-08-01

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

Key Inclusion Criteria: - HIV-1 RNA < 50 copies/mL for ≥ 6 months before screening, as documented by: 1. One HIV-1 RNA < 50 copies/mL immediately preceding the 24 weeks period prior to screening. 2. Within 24 weeks prior to screening, if HIV-1 RNA results are available, all levels must be < 50 copies/mL. 3. During the 6 to 12 months period prior to screening, transient detectable viremia ≥ 50 copies/mL is acceptable ("blip") as long as it is not confirmed on 2 consecutive visits. - Plasma HIV-1 RNA levels < 50 copies/mL at screening. - Are receiving guideline-recommended standard of care treatment such as International Antiviral Society (IAS), Department of Health and Human Services (DHHS), European AIDS Clinical Society (EACS) consisting of 2 or 3 ARVs for ≥ 6 months.

Health status

Study type

Interventional (clinical trial)

Enrollment

600

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 resources

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

Formulation patent families

Publications

Amy E Colson, Gordon E Crofoot, Peter J Ruane, Moti N Ramgopal, Alexandra W Dretler, Ronald G Nahass, Gary I Sinclair, Mezgebe Berhe, Fadi Shihadeh, Shan-Yu Liu, Stephanie Klopfer, Sharline Madera, Hadas Dvory-Sobol, Martin Rhee, Elizabeth G Rhee, Jared Baeten, Joseph J Eron, 577. Week 48 Results of a Phase 2 Study Evaluating Once-weekly Oral Islatravir Plus Lenacapavir, Open Forum Infectious Diseases, Volume 12, Issue Supplement_1, February 2025, ofae631.015, https://doi.org/10.1093/ofid/ofae631.015

Both islatravir (ISL), a nucleotide reverse transcriptase translocation inhibitor, and lenacapavir (LEN), a capsid inhibitor, have potent anti-HIV-1 activity and pharmacokinetic profiles permitting once-weekly oral dosing. Week (W) 24 data (primary endpoint) from the current Phase 2 study were previously reported (CROI 2024); weekly oral ISL 2 mg + LEN 300 mg maintained high rates of viral suppression (HIV-1 RNA < 50 copies/mL) with no clinically relevant decreases in CD4+ T-cells or lymphocytes, which had been previously observed with higher ISL doses. Here, we report W48 results.

In this Phase 2, randomized, open-label, active-controlled study (NCT05052996), virologically suppressed adults on bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) were randomized 1:1 to receive weekly oral ISL 2 mg + LEN 300 mg or to continue daily B/F/TAF. Virologic outcomes (using FDA-defined snapshot algorithm), adverse events (AEs), CD4+ T-cells, and lymphocytes were assessed.

Additional documents

• MSD Q1 2025 Earnings call - 24 April 2025

• Modelling of missed doses of LEN+ISL weekly - poster - CROI 2025

Useful links

• Gilead and Merck Announce Phase 2 Data Showing a Treatment Switch to ISL+LEN Once Weekly.

• Gilead and Merck Announce Phase 2 Data Showing Investigational Oral Once-Weekly ISL+LEN.

• Study to Compare an Oral Weekly Islatravir/Lenacapavir Regimen With Standard of Care in Virologically Suppressed People With HIV-1 (ISLEND-2)

• Gilead and Merck Announce Phase 2 Data Showing a Treatment Switch to an Investigational Oral Once-Weekly Combination Regimen of Islatravir and Lenacapavir Maintained Viral Suppression in Adults at Wee

• Oral Weekly Islatravir Plus Lenacapavir in Virologically Suppressed People with HIV-1: 96 Week Outcomes from a Phase 2 Study - EACS2025 - October 15, Paris

	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 Not provided
	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 Not provided
	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

Update from MSD, May 2025: MK-8591D is on FDA partial clinical hold for higher doses of islatravir than those used in current clinical trials. (https://www.msd.com/research/product-pipeline/)