islatravir (MK-8591) / Merck (MSD) - LARVOL DELTA

Kinetic investigation of resistance to Islatravir conferred by mutations in HIV-1 reverse transcriptase. (PubMed, J Mol Biol) - "The M184V mutation, commonly associated with resistance to NRTIs such as lamivudine and emtricitabine, and the M184V/A114S mutations, both located within the hydrophobic pocket, were shown to reduce Islatravir susceptibility in cell-based viral resistance selection assays. These reductions were primarily attributable to corresponding decreases in EFdA-TP incorporation rate constants of 18-fold and 105-fold, respectively. These results suggest that, unlike FDA-approved NRTIs, the clinical efficacy of Islatravir, may not be substantially compromised by the M184V mutation alone but will be significantly reduced by the M184V/A114S mutations."

Journal • Human Immunodeficiency Virus • Infectious Disease

A Study of Islatravir (ISL) and Ulonivirine (ULO) Once Weekly (QW) in Virologically Suppressed Adults With Human Immunodeficiency Virus Type 1 (HIV-1) (MK-8591B-060) (clinicaltrials.gov) - P2 | N=150 | Not yet recruiting | Sponsor: Merck Sharp & Dohme LLC

New P2 trial • Human Immunodeficiency Virus • Infectious Disease

A Biodegradable Implant Releasing Low-Dose Islatravir Protects Macaques From Rectal SHIV Infection (CROI 2025) - "The ISL-TP levels in PBMCs remained below the clinical toxicity threshold and provided complete protection to macaques against rectal SHIV infection. Our study supports the development of a PCL implant that can deliver safe and effective ISL concentrations for ultra-long-acting HIV prevention."

Human Immunodeficiency Virus • Infectious Disease

Dose-Ranging Pharmacokinetics and Efficacy of a 90-Day Multipurpose IVR Delivering Islatravir (CROI 2025) - "Systemic ISL concentration remained below the clinical toxicity threshold and prevented SHIV acquisition in macaques. These results warrant further development of the 3D printed IVR as a three-month MPT for prevention of HIV and unintended pregnancy using an already optimized hormones dose."

Clinical • PK/PD data • Human Immunodeficiency Virus • Infectious Disease • Vaginitis

Resistance Analysis of Weekly Islatravir Plus Lenacapavir in People With HIV at 48 Weeks (CROI 2025) - P2 | "Methods Participants received either ISL (2 mg QW from Day [D] 1) + LEN (600 mg D1 and D2; then 300 mg QW) orally (n=52) or remained on once-daily oral bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF; n=52). No participants with VF developed study drug resistance. These findings support the ongoing evaluation of ISL+LEN as an oral, QW treatment for HIV-1 infection."

Human Immunodeficiency Virus • Infectious Disease

Pharmacokinetic Modeling of Missed Dose Scenario of Oral Weekly Islatravir Plus Lenacapavir (CROI 2025) - P2 | "After one full missed dose (14 days after last dose), the simulated median trough concentration for ISL-TP was 2.16 µM (90% PI: 1.45–5.15), and the simulated mean trough concentration for LEN was 20.7 ng/mL (90% CI: 19.4–22.9), well above the target concentrations of 1.25 µM and 15.5 ng/mL, respectively. Conclusions The analysis showed that people with HIV-1 who miss one dose of 2/300 mg ISL/LEN FDC can continue treatment and maintain optimal drug concentrations, allowing for a one-week forgiveness window."

PK/PD data • Human Immunodeficiency Virus • Infectious Disease • CD4

Modeling Accurately Predicts Efficacious Islatravir QW Dose With No Lymphocyte and CD4 Changes (CROI 2025) - "Subsequently, a Phase 2 study was initiated (GS-US-563-6041, N=104) with virologically suppressed (VS) people with HIV-1 randomized 1:1 to switch from once-daily (QD) oral bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) to oral QW ISL 2 mg + lenacapavir (LEN) 300 mg. Conclusions Phase 2 efficacy and lymphocyte and CD4+ T-cell results are consistent with predictions that QW 2 mg ISL in combination with LEN is highly efficacious and there were no between-group differences in lymphocyte or CD4+ T-cell changes from baseline to Week 24. ISL/LEN 2/300 mg is proceeding into Phase 3 with the potential to be the first oral QW treatment option."

Human Immunodeficiency Virus • Infectious Disease • CD4

Pharmacokinetics of islatravir in participants with moderate hepatic impairment. (PubMed, Antimicrob Agents Chemother) - P1 | "The clinical relevance of the overall modest changes in M4, ISL, and ISL-TP levels with moderate hepatic impairment will be contextualized once exposure response data from ongoing clinical studies are available to elucidate the thresholds for clinical efficiency. A single oral dose of ISL 60 mg was generally well tolerated in both groups.CLINICAL TRIALSThis study is registered with Clinicaltrials.gov as NCT04515641."

Journal • PK/PD data • Hepatitis C • Hepatology • Human Immunodeficiency Virus • Infectious Disease • Liver Failure

Dose Ranging, Switch Study of Islatravir (ISL) and Ulonivirine (MK-8507) Once-Weekly in Virologically-Suppressed Adults With Human Immunodeficiency Virus Type 1 (HIV-1) [MK-8591-013] (clinicaltrials.gov) - P2 | N=161 | Completed | Sponsor: Merck Sharp & Dohme LLC | Active, not recruiting ➔ Completed

Trial completion • Human Immunodeficiency Virus • Infectious Disease • CD4

A Clinical Study of Islatravir and Its Interaction With Lamivudine (MK-8591-058) (clinicaltrials.gov) - P1 | N=20 | Completed | Sponsor: Merck Sharp & Dohme LLC

New P1 trial

Tenofovir and Doravirine Are Potential Reverse-Transcriptase Analogs in Combination with the New Reverse-Transcriptase Translocation Inhibitor (Islatravir) Among Treatment-Experienced Patients in Cameroon: Designing Future Treatment Strategies for Low- and Middle-Income Countries. (PubMed, Viruses) - "No significant covariation with M184V was observed in third-line treatment failures. Based on these covariations and on the effect of these mutations on available anti-HIV drugs, TDF (partial efficacy) and Doravirine (fully active) were identified as potentially suitable candidates in combination with ISL among patients failing the first, second, and third lines, and could serve as a valuable therapeutic option in LMICs facing similar treatment challenges."

Journal • Human Immunodeficiency Virus • Infectious Disease

Delivery of Islatravir via High Drug-Load, Long-acting Microarray Patches for the Prevention or Treatment of Human Immunodeficiency Virus. (PubMed, Adv Healthc Mater) - "Projections from animal data suggest that these dissolving MAPs can achieve effective islatravir levels for a month after a single application in humans. These findings indicate dissolving MAPs as a minimally invasive approach to sustained release of islatravir."

Journal • Human Immunodeficiency Virus • Infectious Disease

The effect of the foreign body response on drug elution from subdermal delivery systems. (PubMed, Biomaterials) - "Specifically, we investigated the pharmacokinetic impact of fibrotic encapsulation on a small molecule drug, islatravir (293 Da), and a large protein, IgG (150 kDa), administered via biocompatible implants...End-point histological analyses confirmed that the localized delivery neither incited inflammation in the surrounding tissue nor did it alter vascularization. This evidence suggests that, while acute FBR may transiently affect the release of larger molecules, in the absence of acute local inflammation, fibrotic encapsulation does not significantly impact the steady-state release of small molecule drugs from long-acting implantable delivery systems."

Journal • Fibrosis • Inflammation

Nonclinical and clinical characterization of the absorption, metabolism, and excretion of islatravir. (PubMed, Antimicrob Agents Chemother) - "The pharmacologically active islatravir triphosphate is the most abundant intracellular phosphorylated species, as shown by the results of ex vivo studies. This characterization of the absorption, metabolism, and elimination of islatravir in humans and nonclinical species supports its further development for the treatment of HIV-1."

Journal • Human Immunodeficiency Virus • Infectious Disease

Impower-024: Oral Islatravir (MK-8591) Once-Monthly as Preexposure Prophylaxis (PrEP) in Men and Transgender Women Who Are at High Risk for HIV-1 Infection (MK-8591-024) (clinicaltrials.gov) - P3 | N=494 | Terminated | Sponsor: Merck Sharp & Dohme LLC | Completed ➔ Terminated; Voluntarily terminated due to benefit/risk assessment.

Trial termination • Human Immunodeficiency Virus • Infectious Disease

A Phase 1 Study to Evaluate the Pharmacokinetic Drug-Drug Interaction Between Islatravir and Methadone in Participants on Stable Methadone Therapy. (PubMed, Clin Pharmacol Drug Dev) - P1 | "Coadministration of a single dose of islatravir and methadone was generally well tolerated. Single-dose islatravir did not affect steady-state methadone pharmacokinetics in a clinically meaningful way."

Journal • P1 data • PK/PD data • Human Immunodeficiency Virus • Infectious Disease

Reduction in estimated glomerular filtration rate (eGFR) observed with doravirine (DOR) is caused by inhibition of organic cation transporter 2 (OCT2) (HIV-Glasgow 2024) - "Materials and In vitro assays were established in OCT2- and MATE1-transfected cells using [14C]-creatinine and metformin as probes. At clinically relevant exposures, DOR inhibits OCT2- but not MATE1-mediated creatinine transport. Our in vitro observations mechanistically illustrate that the reduction in creatinine-based eGFR calculations observed with DOR is caused by inhibition of renal creatinine transport by DOR and does not reflect a reduction in renal function. These findings are consistent with clinical data showing improvement in eGFR, when calculated using cystatin-C, in treatment-naïve individuals initiating treatment with the DOR/islatravir combination [2]."

Human Immunodeficiency Virus • Infectious Disease • CST3

Dose Ranging, Switch Study of Islatravir (ISL) and Ulonivirine (MK-8507) Once-Weekly in Virologically-Suppressed Adults With Human Immunodeficiency Virus Type 1 (HIV-1) [MK-8591-013] (clinicaltrials.gov) - P2 | N=161 | Active, not recruiting | Sponsor: Merck Sharp & Dohme LLC | Trial completion date: Dec 2024 ➔ Mar 2025 | Trial primary completion date: Dec 2024 ➔ Mar 2025

Trial completion date • Trial primary completion date • Human Immunodeficiency Virus • Infectious Disease • CD4

Pharmacokinetics of Atorvastatin and Metformin after Coadministration with Islatravir in Healthy Adults. (PubMed, J Clin Pharmacol) - "Coadministration of islatravir with atorvastatin and metformin was well tolerated. Overall, coadministration of atorvastatin and metformin with a single oral dose of islatravir did not have a clinically meaningful effect on the PK profiles of either drug."

Journal • PK/PD data • Diabetes • Dyslipidemia • Human Immunodeficiency Virus • Infectious Disease • Metabolic Disorders • Type 2 Diabetes Mellitus

Once-weekly islatravir plus lenacapavir in virologically suppressed PWH: week 48 safety, efficacy, and metabolic changes (HIV-Glasgow 2024) - P2 | "Materials and methods : In this phase II, randomized, open-label, active-controlled study, 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. Adherence to this weekly oral dosing regimen was high. ISL+LEN has the potential to become the first weekly oral complete regimen for the treatment of HIV-1 infection."

Clinical • Hepatitis B • Hepatology • Human Immunodeficiency Virus • Inflammation • Novel Coronavirus Disease • Renal Calculi • Respiratory Diseases • CD4

Pharmacokinetics of oral islatravir (ISL) plus lenacapavir (LEN) given once weekly in an open‐label, active‐controlled, phase II study of virologically suppressed people with HIV‐1 (HIV-Glasgow 2024) - P2 | "Background: Once-weekly (QW) oral ISL, a nucleoside reverse transcriptase translocation inhibitor, plus LEN, an HIV-1 capsid inhibitor, is being evaluated in a phase II study of participants switching from once-daily oral bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). ISL 2 mg QW is predicted to produce ISL-TP exposures sufficient to cover both wild-type and M184V/I variants with no negative impact on CD4+ T-cell or lymphocyte counts. LEN 300 mg QW resulted in efficacious LEN exposures, consistent with approved subcutaneous LEN. These results are consistent with previous model-based predictions and support ISL/LEN 2/300 mg QW dosing in phase III."

Clinical • P2 data • PK/PD data • Human Immunodeficiency Virus • Infectious Disease • CD4

ISLEND-2: Study to Compare an Oral Weekly Islatravir/Lenacapavir Regimen With Standard of Care in Virologically Suppressed People With HIV-1 (clinicaltrials.gov) - P3 | N=600 | Recruiting | Sponsor: Gilead Sciences | Not yet recruiting ➔ Recruiting

Enrollment open • Human Immunodeficiency Virus • Infectious Disease

ISLEND-1: Study to Compare an Oral Weekly Islatravir/Lenacapavir Regimen With Bictegravir/Emtricitabine/Tenofovir Alafenamide in Virologically Suppressed People With HIV-1 (clinicaltrials.gov) - P3 | N=600 | Recruiting | Sponsor: Gilead Sciences | Not yet recruiting ➔ Recruiting

Enrollment open • Human Immunodeficiency Virus • Infectious Disease

ISLEND-2: Study to Compare an Oral Weekly Islatravir/Lenacapavir Regimen With Standard of Care in Virologically Suppressed People With HIV-1 (clinicaltrials.gov) - P3 | N=600 | Not yet recruiting | Sponsor: Gilead Sciences

New P3 trial • Human Immunodeficiency Virus • Infectious Disease

ISLEND-1: Study to Compare an Oral Weekly Islatravir/Lenacapavir Regimen With Bictegravir/Emtricitabine/Tenofovir Alafenamide in Virologically Suppressed People With HIV-1 (clinicaltrials.gov) - P3 | N=600 | Not yet recruiting | Sponsor: Gilead Sciences

New P3 trial • Human Immunodeficiency Virus • Infectious Disease