Islatravir/Lenacapavir for HIV

(ISLEND-2 Trial)

Recruiting at 101 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

600 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

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 people with human immunodeficiency virus (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 PWH at Week 48.

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.

What is known about the safety of Islatravir and Lenacapavir for HIV treatment?

Islatravir and Lenacapavir have been studied for their safety in treating HIV. Islatravir has shown a long-lasting effect and a high barrier to resistance, while Lenacapavir has been reviewed for its safety and role in treating HIV-1 infection. ^{1 2 3 4 5}

What makes the drug Islatravir/Lenacapavir unique for treating HIV?

Islatravir/Lenacapavir is unique because it combines two novel components: Islatravir, which has a long-lasting effect as a reverse transcriptase inhibitor, and Lenacapavir, a first-in-class capsid inhibitor effective against multi-drug-resistant HIV. This combination offers a long-acting treatment option that may be more convenient for patients with limited access to healthcare. ^{1 2 5 6 7}

What data supports the effectiveness of the drug Islatravir/Lenacapavir for HIV?

Lenacapavir (LEN) is effective for treating multidrug-resistant HIV-1 and is approved by health authorities like the USFDA. Islatravir (ISL) shows promising antiretroviral activity in early studies, and combining LEN with other drugs, including ISL, has shown additive or synergistic effects, enhancing its effectiveness against HIV. ^{1 2 5 7 8}

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

Published Research Related to This Trial

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]

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]

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]

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 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 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]

Citations

1. Switzerland 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. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Lenacapavir: A Novel Long-Acting Capsid Inhibitor for HIV. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Islatravir for the treatment and prevention of infection with the human immunodeficiency virus type 1. [2021]

4. United States 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. [2022]

5. Netherlands 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. [2020]

6. United States 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). [2022]

7. England pubmed.ncbi.nlm.nih.gov

Cross-resistance to entry inhibitors and lenacapavir resistance through Week 52 in study CAPELLA. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Safety and Pharmacokinetics of Once-Daily Multiple-Dose Administration of Islatravir in Adults Without HIV. [2023]