Islatravir/Lenacapavir for HIV

(ISLEND-2 Trial)

Not currently recruiting at 115 trial locations

Overseen By Gilead Clinical Study Information Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Gilead Sciences

Must be taking: Antiretrovirals

Disqualifiers: Hepatitis B, Hepatitis C, Tuberculosis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 96 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if a once-weekly tablet regimen, specifically Islatravir/Lenacapavir (ISL/LEN), offers a better option for people with HIV compared to their usual daily medication routine. It targets individuals who have successfully maintained low virus levels on their current treatment for at least six months. Participants will either switch to the new once-weekly tablet or continue their standard treatment. The trial seeks individuals who have their HIV under control with a stable medication routine. As a Phase 3 trial, it represents the final step before FDA approval, providing participants an opportunity to contribute to potentially groundbreaking treatment advancements.

Do I need to stop my current medications for the trial?

The trial does not specify if you need to stop your current medications, but it mentions that participants must be on a stable standard of care regimen for at least 6 months before starting the trial. It seems like you may need to continue your current treatment until the trial begins.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of islatravir and lenacapavir is generally safe for people with HIV. In one study, participants taking this combination maintained low HIV levels, indicating effective virus control. Importantly, their CD4+ T-cell counts remained stable, supporting a strong immune system. Over 96 weeks, participants continued to have undetectable virus levels, demonstrating the treatment's long-term effectiveness and safety. This evidence suggests the treatment is safe for those considering joining the trial. ^{1 2 3 4 5}

Why are researchers excited about this study treatment for HIV?

Researchers are excited about Islatravir/Lenacapavir (ISL/LEN) for HIV because it represents a novel approach to treatment. Unlike the standard of care, which typically involves daily regimens of multiple antiretroviral drugs like integrase inhibitors, protease inhibitors, or nonnucleoside reverse transcriptase inhibitors, ISL/LEN combines two innovative agents that can be administered as a once-weekly dose. This new combination not only offers the potential for a more convenient dosing schedule but also utilizes unique mechanisms of action; Islatravir is an NRTTI (nucleoside reverse transcriptase translocation inhibitor) and Lenacapavir is a capsid inhibitor, both targeting the virus in different ways. This could enhance treatment adherence and efficacy, offering a fresh hope for people living with HIV.

What evidence suggests that the ISL/LEN treatment might be an effective treatment for HIV?

In this trial, participants will receive either the combination of islatravir and lenacapavir (ISL/LEN) or continue with standard care treatment. Research has shown that islatravir and lenacapavir hold promise for people with HIV who already have very low viral levels. Studies indicate that taking this pill once a week kept the virus undetectable for up to 96 weeks. Specifically, after 48 weeks, the virus remained well-controlled, maintaining very low levels. This treatment is still under study and not yet approved, but early results are encouraging. The goal of this combination is to simplify HIV management with fewer pills. ^{1 3 4 5 6}

Who Is on the Research Team?

Gilead Study Director

Principal Investigator

Gilead Sciences

Are You a Good Fit for This Trial?

This trial is for people with HIV who have had low virus levels (under 50 copies/mL) for at least 6 months. They must be on a stable regimen of antiretroviral drugs as recommended by health guidelines and agree to use contraception if applicable. Those with occasional 'blips' in viral load are also eligible.

Inclusion Criteria

My HIV-1 viral load was under 50 copies/mL before the last 24 weeks.

I agree to use birth control as required by the study.

My HIV-1 RNA levels have been below 50 copies/mL in the last 24 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either the ISL/LEN regimen or continue standard of care treatment

96 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Extension

Participants may opt into receiving ISL/LEN tablets until they become available or the study is discontinued

What Are the Treatments Tested in This Trial?

Interventions

• ISL/LEN

Trial Overview The study compares the effectiveness of switching to a once-weekly oral tablet combining two drugs, Islatravir and Lenacapavir (ISL/LEN), against continuing the current standard HIV treatment. The main goal is to see how well ISL/LEN works after 48 weeks compared to the usual care.

How Is the Trial Designed?

Group I: ISL/LEN Experimental Treatment 1 Intervention

Participants will receive an initial dose of ISL/LEN (Dose A), followed by once weekly ISL/LEN (Dose B) from Day 8 onwards up to Week 96.

Group II: Extension Phase Experimental Treatment 1 Intervention

At the end of randomized treatment visit, if safety and efficacy of ISL/LEN are demonstrated following review of randomized data, participants will be given the option to receive ISL/LEN tablets in an extension phase until ISL/LEN becomes available or until the sponsor elects to discontinue the study, whichever occurs first. Participants receiving ISL/LEN during the randomized phase will continue to take ISL/LEN weekly. Participants receiving standard of care during the randomized phase will take an initial dose of ISL/LEN (Dose A), followed by once weekly ISL/LEN (Dose B) from Day 8 onwards.

Group III: Standard of Care Treatment Active Control 2 Interventions

Participants will continue standard of care treatment with 2-3 ARVs up to Week 96: * Integrase Strand Transfer Inhibitor (INSTI) class: INSTI combined with 1 or 2 nucleoside reverse transcriptase inhibitors (NRTIs; bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF; coformulated; Biktarvy®), dolutegravir (DTG)/abacavir (ABC)/lamivudine (3TC), DTG+ TAF or TDF (TXF)/emtricitabine (FTC; Emtriva®), DTG/tenofovir disoproxil fumarate (TDF; Viread®)/3TC, DTG/3TC, raltegravir (RAL) + TXF/FTC, RAL+TDF/3TC, elvitegravir (EVG; Vitekta®)/cobicistat (c; Tybost®)/TXF/FTC), or * PI class: Boosted protease inhibitor (PI) combined with 2 NRTIs (darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF; coformulated), boosted darunavir (DRV)+TXF/FTC, boosted DRV+TDF/3TC), or * NNRTI class: Nonnucleoside reverse transcriptase inhibitor (NNRTI) combined with 2 NRTIs (doravirine (DOR)/TDF/3TC, DOR+TXF/FTC, DOR+TDF/3TC, rilpivirine (RPV)/TXF/FTC, RPV+TXF/FTC, RPV+TDF/3TC)

ISL/LEN is already approved in European Union, Canada, United States for the following indications:

Approved in European Union as Lenacapavir for:

• HIV/AIDS in heavily treatment-experienced adults with multiple drug resistance

Approved in Canada as Lenacapavir for:

• HIV/AIDS in heavily treatment-experienced adults with multiple drug resistance

Approved in United States as Lenacapavir for:

• HIV/AIDS in heavily treatment-experienced adults with multiple drug resistance

Who Is Running the Clinical Trial?

Gilead Sciences

Lead Sponsor

Trials

1,150

Recruited

878,000+

Daniel O'Day

Gilead Sciences

Chief Executive Officer since 2019

MBA from Columbia University

Dietmar Berger

Gilead Sciences

Chief Medical Officer

MD and PhD from Albert-Ludwigs University School of Medicine

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

Islatravir, a novel nucleoside analog for HIV treatment and prevention, demonstrated potent antiviral activity with a long intracellular half-life, achieving therapeutic concentrations in both plasma and tissue after daily administration for up to 6 weeks.

The study involving 36 adults showed that islatravir was generally well tolerated at doses up to 5 mg, with effective levels of its active form (ISL-TP) reached after just one dose, indicating its potential for effective HIV treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Pharmacokinetics of Once-Daily Multiple-Dose Administration of Islatravir in Adults Without HIV. Matthews, RP., Jackson Rudd, D., Zhang, S., et al.[2023]

Lenacapavir (LEN) is the first HIV-1 capsid inhibitor approved for multidrug-resistant HIV-1 infection, showing efficacy with a low level of drug-related mutations and no cross-resistance to other anti-HIV drugs.

LEN can be administered as a long-acting treatment, making it suitable for patients with limited access to healthcare, and it has demonstrated potential for synergistic effects when combined with other anti-HIV medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Highlights on the Development, Related Patents, and Prospects of Lenacapavir: The First-in-Class HIV-1 Capsid Inhibitor for the Treatment of Multi-Drug-Resistant HIV-1 Infection. Dzinamarira, T., Almehmadi, M., Alsaiari, AA., et al.[2023]

Islatravir (ISL) is a promising treatment for HIV-1 that works by inhibiting reverse transcriptase, showing a high barrier to resistance with only specific mutations (M184I and M184V) significantly reducing its effectiveness.

The mutation A114S can reduce susceptibility to ISL but increases susceptibility to other approved NRTIs, highlighting ISL's unique mechanism of action and its potential advantages over traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Islatravir Has a High Barrier to Resistance and Exhibits a Differentiated Resistance Profile from Approved Nucleoside Reverse Transcriptase Inhibitors (NRTIs). Diamond, TL., Ngo, W., Xu, M., et al.[2022]

Lenacapavir (LEN) is effective against HIV-1, showing no cross-resistance with entry inhibitors in a study of 72 participants, making it a viable treatment option for heavily treatment-experienced individuals with multidrug resistance.

In the CAPELLA study, only 13% of participants developed resistance mutations to LEN after 52 weeks, indicating that LEN maintains its efficacy even in patients with a history of treatment failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cross-resistance to entry inhibitors and lenacapavir resistance through Week 52 in study CAPELLA. Margot, N., Pennetzdorfer, N., Naik, V., et al.[2023]

Islatravir, a new treatment for HIV-1, was found to be generally well tolerated in a phase 1b trial with 30 treatment-naive adults, showing that it can significantly reduce HIV-1 RNA levels by more than 1.0 log after just 7 days, even at low doses of 0.5 mg.

The study demonstrated that islatravir has a long intracellular half-life of 78.5-128.0 hours, which may contribute to its prolonged effects against the virus, and no serious adverse events or signs of viral resistance were reported, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, pharmacokinetics, and antiretroviral activity of islatravir (ISL, MK-8591), a novel nucleoside reverse transcriptase translocation inhibitor, following single-dose administration to treatment-naive adults infected with HIV-1: an open-label, phase 1b, consecutive-panel trial. Schürmann, D., Rudd, DJ., Zhang, S., et al.[2020]

Islatravir (ISL) is a novel long-acting reverse transcriptase translocation inhibitor that has shown strong antiviral activity in both daily and weekly dosing regimens for HIV-1 treatment, achieving high levels of virologic suppression in clinical trials.

In preclinical studies, ISL demonstrated effectiveness as a once-weekly pre-exposure prophylaxis (PrEP) against SHIV infection in rhesus macaques, and recent data suggest the potential for a once-yearly implantable formulation for HIV-1 prevention in healthy individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Islatravir for the treatment and prevention of infection with the human immunodeficiency virus type 1. Markowitz, M., Grobler, JA.[2021]

In the CAPELLA study, lenacapavir (LEN) combined with an optimized background regimen (OBR) achieved viral suppression in 81% of heavily treatment-experienced individuals with multidrug-resistant HIV after 26 weeks, demonstrating its efficacy in a challenging patient population.

However, resistance mutations to lenacapavir were observed in 8 participants, indicating that using LEN as an unintended monotherapy can lead to the development of resistance, highlighting the importance of proper treatment adherence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Resistance Analyses in Highly Treatment-Experienced People With Human Immunodeficiency Virus (HIV) Treated With the Novel Capsid HIV Inhibitor Lenacapavir. Margot, NA., Naik, V., VanderVeen, L., et al.[2022]

Lenacapavir (LEN) is a novel capsid inhibitor that offers a unique treatment option for heavily treatment-experienced (HTE) HIV-1 patients, demonstrating efficacy in achieving viral suppression and immune restoration when combined with other antiretrovirals.

Administered subcutaneously twice a year, lenacapavir provides a convenient dosing schedule, making it a well-tolerated and effective addition to existing HIV treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lenacapavir: A Novel Long-Acting Capsid Inhibitor for HIV. Tailor, MW., Chahine, EB., Koren, D., et al.[2023]

Citations

1. gilead.com gilead.com/news/news-details/2025/gilead-presents-new-hiv-research-data-at-eacs-2025--driving-scientific-innovation-in-treatment-and-prevention

Gilead Presents New HIV Research Data at EACS 2025 The use of lenacapavir in virologically suppressed people with HIV is investigational and the safety and efficacy of this use have not been established. There ...

2. eatg.org eatg.org/hiv-news/eacs-2025-once-weekly-hiv-pill-maintains-viral-suppression-for-96-weeks/

EACS 2025: Once-weekly HIV pill maintains viral ... At 96 weeks, all participants on the islatravir-lenacapavir combination maintained undetectable viral loads, and mean adherence-assessed by pill ...

3. hivglasgow.org hivglasgow.org/once-weekly-combination-of-islatravir-and-lenacapavir-safe-and-effective-in-48-week-study/

Once-weekly combination of islatravir and lenacapavir safe ... A once-weekly oral combination of two investigational antiretrovirals, islatravir and lenacapavir, maintained high rates of viral suppression 48 weeks after a ...

4. gileadclinicaltrials.com gileadclinicaltrials.com/study?id=GS-US-563-6041

Study Evaluating the Safety and Efficacy of Islatravir in ... The primary objective of this study is to evaluate the efficacy of oral weekly islatravir (ISL) in combination with lenacapavir (LEN) in virologically ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT05052996?tab=results

Study Evaluating the Safety and Efficacy of Islatravir in ... Participants were enrolled at study sites in the United States. This is the primary results analysis including data up to Week 48 for the outcome measures.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11777299/

577. Week 48 Results of a Phase 2 Study Evaluating Once- ... 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 ...