Merck Announces Positive Topline Results from Pivotal Phase 3 Trial of Doravirine/Islatravir in Treatment-Naïve Adults with HIV-1 Infection

Merck recently announced positive topline results from a pivotal Phase 3 clinical trial also called MK-8591A-053 evaluating the investigational, once-daily, oral, two-drug, single-tablet regimen of Doravirine/Islatravir (DOR/ISL) in adults living with HIV-1 who had not previously received antiretroviral therapy (treatment-naïve). This trial marks a significant advancement in HIV treatment development, presenting a non-integrase strand transfer inhibitor (non-INSTI) two-drug regimen that demonstrated non-inferior efficacy compared to the current standard of care, a three-drug regimen of Bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF).

About MK-8591A-053

MK-8591A-053 (NCT05705349) is the multicenter Phase 3 clinical trial randomized 537 participants 1:1 to receive either the investigational DOR/ISL single-tablet regimen or the BIC/FTC/TAF standard three-drug regimen for 48 weeks. The primary efficacy endpoint was the percentage of participants with HIV-1 RNA viral loads below 50 copies/mL at Week 48, signaling successful viral suppression. Safety was also rigorously assessed, including the incidence of adverse events (AEs) and discontinuations due to AEs.

DOR/ISL met the primary efficacy endpoint by demonstrating non-inferiority to BIC/FTC/TAF, with comparable rates of viral suppression at Week 48. This achievement is noteworthy because DOR/ISL is the first once-daily, two-drug regimen without an integrase inhibitor to show efficacy and safety comparable to INSTI-based triple therapy in treatment-naïve adults. The findings indicate that this regimen could offer a simpler, effective alternative to existing three-drug combinations.

 Safety Profile

Safety profiles were similar between the two study arms, with low numbers of participants discontinuing treatment due to adverse events. Most adverse events were mild to moderate, While DOR/ISL showed robust resistance protection, as with any antiretroviral therapy, warnings and precautions include monitoring for hypersensitivity reactions, potential interactions with other medications, hepatic impairment, and the risk of immune reconstitution syndrome; close clinical follow-up is advised to mitigate these risks and promptly manage any emerging side effects or laboratory abnormalities.

About Doravirine/ Islatravir

The investigational combination includes Doravirine, and Islatravir (MK-8591). Doravirine is an established HIV-1 treatment drug classified pharmacologically as a non-nucleoside reverse transcriptase inhibitor (NNRTI). It works by noncompetitively inhibiting HIV-1 reverse transcriptase, an enzyme critical for viral replication, thereby preventing the synthesis of viral DNA from RNA. 

Islatravir is a novel investigative drug developed by Merck, belonging to a new class called nucleoside reverse transcriptase translocation inhibitors (NRTTIs). Unlike traditional NRTIs, Islatravir uniquely disrupts the translocation step of HIV-1 reverse transcriptase, interfering with the enzyme’s ability to move along the viral RNA template. This leads to premature termination of viral DNA chain elongation and alterations in viral DNA structure, effectively halting viral replication. Islatravir innovative mechanism offers potent antiviral activity with the potential for a high barrier to resistance. It is currently in late-stage clinical development and represents a significant advancement in antiretroviral therapy.

If approved, DOR/ISL could provide people living with HIV with a convenient, once-daily, two-drug single-tablet option that reduces pill burden without compromising effectiveness. Doravirine/Islatravir (DOR/ISL) is poised to compete with Gilead’s Bictegravir and Lenacapavir by offering a once-daily, two-drug regimen without an integrase inhibitor that has demonstrated non-inferior efficacy and safety compared to the established three-drug regimen BIC/FTC/TAF in treatment-naïve adults with HIV-1.

Dr. Eliav Barr, senior vice president and chief medical officer of Merck Research Laboratories, stated, “DOR/ISL (Doravirine/Islatravir) is the first two-drug regimen without an integrase inhibitor showing non-inferior efficacy and safety compared to the three-drug INSTI-based regimen BIC/FTC/TAF in treatment-naïve adults with HIV. These data support DOR/ISL as a meaningful treatment option for people starting or switching HIV therapy.”

Participants in the trial will continue to be monitored through Week 144, with additional readouts expected, including longer-term safety and efficacy data. An open-label extension beyond Week 144 will allow participants to receive DOR/ISL while awaiting possible commercial availability. These extended evaluations will further clarify the regimen’s durability and safety profile over time.

The U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for Doravirine/Islatravir (DOR/ISL) with a target action date set for April 28, 2026, under the Prescription Drug User Fee Act (PDUFA).