By IDSE News Staff
The FDA accepted for review the New Drug Application (NDA) for doravirine-islatravir (DOR/ISL, Merck), an investigational, once-daily, oral, two-drug regimen for adults with HIV-1 infection that is virologically suppressed on antiretroviral therapy (ART). The FDA has set a target action date of April 28, 2026, for the application under the Prescription Drug User Fee Act.
Islatravir (MK-8591), Merck’s investigational nucleoside reverse transcriptase translocation inhibitor, blocks HIV-1 replication by multiple mechanisms including inhibition of reverse transcriptase translocation, resulting in immediate chain termination and induction of structural changes in the viral DNA, causing delayed chain termination.
The NDA is based on findings at week 48 of two pivotal phase 3 clinical trials (MK-8591A-051 and MK-8591A-052) where DOR/ISL was demonstrated to be noninferior to baseline ART (bART) in the open-label MK-8591A-051 trial and noninferior to bictegravir-emtricitabine-tenofovir alafenamide (BIC/FTC/TAF; Biktarvy, Gilead) in the double-blind MK-8591A-052 trial. Across both trials, the safety profile of DOR/ISL was comparable with bART regimens in trial MK-8591A-051 and BIC/FTC/TAF in trial MK-8591A-052. Data from these trials were presented at CROI 2025, in San Francisco.
MK-8591A-051 is a phase 3, open-label, randomized, active-controlled clinical trial evaluating the efficacy and safety of a switch to investigational, oral, once-daily DOR/ISL (100/0.25 mg) in adults with HIV-1 infection that has been virologically suppressed using ART. The primary efficacy end point was the percentage of participants with HIV-1 RNA of at least 50 copies/mL at week 48 (noninferiority margin, 4%). In this trial, 551 adults with HIV-1 RNA less than 50 copies/mL for three months or more on oral two- or three-drug ART, with no history of treatment failure and no known virologic resistance to DOR, were randomized 2:1 and switched to DOR/ISL (n=366) or continued bART (n=185), stratified by bART regimen. The median age of participants was 51 years; 39.7% were assigned female sex at birth, 45.4% were Black or African American, and 14.5% were Hispanic or Latino. At baseline, 64.2% were treated with a regimen based on integrase strand transfer inhibitors, 30.3% with an non-nucleoside reverse transcriptase inhibitors–based regimen and 5.4% with a protease inhibitor–based regimen, with median duration on current ART of 3.8 years (IQR, 2.0-6.3).
MK-8591A-052 is a phase 3, double-blind, randomized, active-controlled clinical trial to evaluate the efficacy and safety of a switch to investigational, oral, once-daily DOR/ISL (100/0.25 mg) in adults with HIV-1 infection that has been virologically suppressed on BIC/FTC/TAF (50/200/25 mg). The primary efficacy end point was the percentage of participants with HIV-1 RNA of at least 50 copies/mL at week 48 (noninferiority margin, 4%). In this trial, 513 adults with HIV-1 who had virologic suppression for three months or more on BIC/FTC/TAF, no history of treatment failure and no known resistance to DOR were randomized 2:1 and switched to DOR/ISL (n=342) or continued treatment with BIC/FTC/TAF (n=171). The median age of participants was 47 years; 21.4% were assigned female sex at birth, 30.8% were Black or African American, and 22.8% were Hispanic. The median duration of BIC/FTC/TAF treatment prior to trial enrollment was 3.4 years (IQR, 2.0-5.0).
“Merck has been at the forefront of HIV research for more than 35 years, and we are pleased to continue our work to innovate and deliver new options that aim to meet the needs of the HIV community,” said Eliav Barr, MD, the senior vice president, head of global clinical development and chief medical officer at Merck Research Laboratories. “The health needs of people living with HIV often change over time, whether it’s managing comorbidities or navigating complex medication regimens. We believe DOR/ISL, if approved, will represent an important new complete regimen option designed to help meet their diverse needs.”
From company press materials.
