FDA Accepts Merck's Application for Novel Two-Drug HIV Regimen Doravirine/Islatravir
Key Insights
The FDA has accepted Merck (search)'s New Drug Application for doravirine/islatravir (DOR/ISL), a once-daily, oral, two-drug regimen for adults with virologically suppressed HIV-1 (search) infection.
If approved, DOR/ISL would be the first FDA-approved two-drug regimen without an integrase inhibitor that demonstrated non-inferior efficacy to three-drug regimens in Phase 3 trials.
The application is based on 48-week data from two pivotal Phase 3 trials (MK-8591A-051 and MK-8591A-052) showing non-inferiority to baseline therapy and BIC/FTC/TAF respectively.
The U.S. Food and Drug Administration has accepted for review Merck (search)'s New Drug Application for doravirine/islatravir (DOR/ISL), marking a significant milestone in HIV treatment innovation. The investigational once-daily, oral, two-drug regimen is designed for adults with HIV-1 (search) infection that is virologically suppressed on antiretroviral therapy, with the FDA setting a target action date of April 28, 2026, under the Prescription Drug User Fee Act (PDUFA).
If approved, DOR/ISL would represent a groundbreaking advancement as the first FDA-approved two-drug regimen without an integrase inhibitor that demonstrated non-inferior efficacy and a generally comparable safety profile to the three-drug InSTI-based regimen, BIC/FTC/TAF, in Phase 3 pivotal trials.
Clinical Trial Foundation
The NDA submission is based on findings at Week 48 of two pivotal Phase 3 clinical trials: MK-8591A-051 and MK-8591A-052. In both studies, DOR/ISL demonstrated non-inferiority to comparator regimens while maintaining a generally comparable safety profile.
Dr. Eliav Barr, senior vice president, head of global clinical development and chief medical officer at Merck (search) Research Laboratories, emphasized the potential clinical impact: "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."
MK-8591A-051 Trial Results
The Phase 3, open-label, randomized, active-controlled trial MK-8591A-051 evaluated the efficacy and safety of switching to investigational DOR/ISL (100mg/0.25mg) in 551 adults with HIV-1 (search) infection that had been virologically suppressed using ART. Participants were randomized 2:1 to switch to DOR/ISL (n=366) or continue baseline antiretroviral therapy (n=185).
The study population had a median age of 51 years, with 39.7% assigned female sex at birth, 45.4% Black or African American, and 14.5% Hispanic or Latine. At baseline, 64.2% were treated with an InSTI-based regimen, 30.3% with an NNRTI-based regimen, and 5.4% with a protease inhibitor-based regimen, with a median duration on current ART of 3.8 years.
MK-8591A-052 Trial Results
The Phase 3, double-blind, randomized, active-controlled trial MK-8591A-052 specifically evaluated switching from BIC/FTC/TAF to DOR/ISL in 513 adults with virologically suppressed HIV-1 (search). Participants were randomized 2:1 to switch to DOR/ISL (n=342) or continue BIC/FTC/TAF treatment (n=171).
The study population had a median age of 47 years, with 21.4% assigned female sex at birth, 30.8% Black or African American, and 22.8% Hispanic or Latine. The median duration of BIC/FTC/TAF treatment prior to trial enrollment was 3.4 years.
Innovative Mechanism of Action
The regimen combines doravirine, an established non-nucleoside reverse transcriptase (search) inhibitor (NNRTI), with islatravir (MK-8591), Merck (search)'s investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI). Islatravir blocks HIV-1 (search) replication through multiple mechanisms, including inhibition of reverse transcriptase translocation resulting in immediate chain termination and induction of structural changes in viral DNA resulting in delayed chain termination.
Broader Development Program
Islatravir is under evaluation in multiple ongoing early and late-stage clinical trials in combination with other antiretrovirals for potential daily and once-weekly treatments for HIV-1 (search). The compound serves as the anchor medicine in treatment regimens based on its potency and resistance profile.
Ongoing Phase 3 trials of daily DOR/ISL (100mg/0.25mg) include MK-8591A-053 in treatment-naïve people with HIV, and MK-8591A-054 evaluating open-label DOR/ISL in individuals who participated in earlier Phase 3 trials. Additionally, islatravir in combination with Gilead's lenacapavir is in Phase 3 development as a novel oral once-weekly treatment for HIV-1 (search).
Merck's HIV Legacy
Merck (search) has maintained a commitment to HIV research for more than 35 years, having helped pioneer the development of new options across multiple drug classes. The company's current portfolio includes PIFELTRO (doravirine) and DELSTRIGO (doravirine, lamivudine, and tenofovir disoproxil fumarate), both approved by the FDA for HIV treatment.
The potential approval of DOR/ISL represents Merck (search)'s continued effort to innovate in HIV treatment, focusing on transformational innovations and collaborations with the global HIV community aimed at helping to end the HIV epidemic.