Key Findings from Phase 3 Trials
Merck (NYSE: MRK), known as MSD outside the United States and Canada, has announced positive results from two pivotal Phase 3 trials evaluating its once-daily, oral, two-drug regimen, doravirine/islatravir (DOR/ISL). The studies focused on adults with HIV-1 infection who were virologically suppressed on either bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) or other antiretroviral therapy (bART). Both trials demonstrated that DOR/ISL met the primary efficacy success criterion for non-inferiority and achieved primary safety objectives at Week 48.
As per the Merck press release, the findings were presented in late-breaking oral sessions at the 32nd Conference on Retroviruses and Opportunistic Infections (CROI) in San Francisco and featured in a CROI press conference. Merck plans to submit applications for marketing authorization by mid-2025.
Efficacy and Safety Outcomes
Trial MK-8591A-052 (Double-Blind Study)
This study compared DOR/ISL to BIC/FTC/TAF.
- At Week 48, only 1.5% of participants who switched to DOR/ISL had a viral load of ≥50 copies/mL, compared to 0.6% of those continuing BIC/FTC/TAF (treatment difference: 0.9%, 95% CI -1.9, 2.9).
- Among participants who maintained viral suppression (HIV-1 RNA <50 copies/mL), 91.5% were on DOR/ISL, while 94.2% remained on BIC/FTC/TAF (treatment difference: -2.6%, 95% CI -7.1, 2.6).
Trial MK-8591A-051 (Open-Label Study)
This study evaluated participants who switched from bART to DOR/ISL.
- At Week 48, 1.4% of participants on DOR/ISL had a viral load of ≥50 copies/mL, compared to 4.9% on bART (treatment difference: -3.6%, 95% CI -7.8, -0.8).
- Viral suppression rates (HIV-1 RNA <50 copies/mL) were 95.6% for those on DOR/ISL versus 91.9% on bART (treatment difference: 3.7%, 95% CI -0.3, 8.9).
Across both trials, DOR/ISL showed a comparable safety profile to other antiretroviral regimens. Mean percent changes in total lymphocyte and CD4 counts were similar between DOR/ISL and comparator regimens. Importantly, no treatment-emergent resistance to DOR or ISL was observed.
Expert Perspectives
Professor Chloe Orkin is the Dean for Healthcare Transformation at Queen Mary University of London. She emphasized the evolving needs of people living with HIV, particularly older individuals managing comorbidities. She highlighted DOR/ISL’s potential as a valuable new treatment option, providing a simplified regimen without compromising efficacy or safety.
Dr. Eliav Barr, Senior Vice President and Chief Medical Officer at Merck Research Laboratories, noted that DOR/ISL is the first two-drug regimen without an integrase inhibitor to demonstrate comparable efficacy and safety to the three-drug InSTI-based regimen BIC/FTC/TAF. He reiterated Merck’s long-standing commitment to HIV research and the development of longer-acting islatravir-based therapies to address the evolving needs of people living with HIV.
Mechanism of Action
Islatravir, an investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI), works by blocking HIV-1 replication through multiple mechanisms. It inhibits reverse transcriptase translocation, leading to immediate and delayed chain termination, effectively stopping viral DNA synthesis.
Next Steps
With these promising Phase 3 results, Merck is preparing to submit regulatory applications by mid-2025. If approved, DOR/ISL could provide a new treatment option for people living with HIV. It offers a streamlined two-drug regimen without an integrase inhibitor while maintaining strong efficacy and safety outcomes.