Merck's Two-Drug HIV Regimen Meets Primary Endpoint in Phase 3 Trial

Merck announced the presentation of results from three pivotal Phase 3 trials evaluating the investigational, once-daily, oral, two-drug regimen of doravirine/islatravir [DOR/ISL (100 mg/0.25 mg), (MK-8591A)] in adults with HIV-1. The findings were shared in late-breaking presentations at the 33rd Conference on Retroviruses and Opportunistic Infections (CROI) held in Denver.

The Phase 3, double-blind, clinical trial MK-8591A-053 evaluating DOR/ISL versus bictegravir/emtricitabine/tenofovir alafenamide [(50 mg/200 mg/25 mg),(BIC/FTC/TAF)] in adults living with HIV-1 who had not previously received antiretroviral treatment (treatment-naïve), met its primary efficacy endpoint of percentage of participants achieving viral suppression (HIV-1 RNA <50 copies/mL), demonstrating non-inferiority for DOR/ISL compared to BIC/FTC/TAF at Week 48, 91.8% and 90.6% respectively (treatment difference 1.2%, 95% CI: -3.7, 6.2, p<0.001). The safety profile was similar between both treatment groups and consistent with that observed in previous studies.

Drug-related adverse events (AEs) and discontinuations due to drug-related AEs were similar between groups (14% for DOR/ISL and 18% for BIC/FTC/TAF; 1.1% for DOR/ISL and 2.2% for BIC/FTC/TAF, respectively). These data, which are being published simultaneously in The Lancet HIV, build on the previously reported Phase 3 data in adults with virologically suppressed HIV-1 and will form the basis of future regulatory applications.

New 96-week data from the Phase 3 MK-8591A-052 and MK-8591A-051 trials evaluating DOR/ISL vs. BIC/FTC/TAF or baseline antiretroviral therapy (bART), in participants with virologically suppressed HIV-1 and who were switched to DOR/ISL, were also presented. In both trials, DOR/ISL maintained high rates of viral suppression at Week 96 and had a similar safety profile to BIC/FTC/TAF and bART.

The 48-week data from these trials supported the initial New Drug Application (NDA) for DOR/ISL for the treatment of HIV-1 infection in adults who are virologically-suppressed on a stable antiretroviral regimen; the U.S. FDA has set a target action date of April 28, 2026 for the application under the Prescription Drug User Fee Act (PDUFA).

MK-8591A-053 is an ongoing Phase 3 randomized, active-controlled, double-blind, clinical trial evaluating the efficacy and safety of investigational, once-daily DOR/ISL (100 mg/0.25 mg) versus BIC/FTC/TAF in adults living with HIV-1 infection who had not previously received antiretroviral treatment. Participants were randomized 1:1 to DOR/ISL (n=269) or BIC/FTC/TAF (with matching placebos) (n=267), stratified by screening CD4+ T-cell count (<200 cells/mm³) and HIV-1 RNA (>100,000 copies/mL).

Of the total participants enrolled in the trial, 36.8% had baseline HIV-1 RNA >100,000 copies/mL, 10.3% had HIV-1 RNA >500,000 copies/mL and 17.2% had baseline CD4+ T-cell count <200 cells/mm. At Week 48, virological efficacy as measured by the percentage of participants with HIV-1 RNA levels <50 copies/mL was similar in both treatment groups, including in participants with baseline HIV-1 RNA >100,000 copies/mL (94.0% versus 87.6%, respectively) and >500,000 copies/mL (90.3% versus 84.4%, respectively).

Drug-related AEs were reported in 14.1% of participants on DOR/ISL and 18.0% on BIC/FTC/TAF and discontinuations due to AEs (1.1% vs. 2.2%) were similar in both groups. Immune reconstitution was similar in DOR/ISL vs. comparator with no between-group differences in mean increases in CD4+ T-cell counts or total lymphocyte counts (TLC).

MK-8591A-052 is a Phase 3, randomized, active-controlled, double-blind, clinical trial to evaluate the efficacy and safety of a switch to investigational, once-daily DOR/ISL (100 mg/0.25 mg) in adults with HIV-1 infection that has been virologically suppressed on BIC/FTC/TAF (50 mg/200 mg/25 mg). 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 primary efficacy endpoint, the percentage of participants with HIV-1 RNA =50 copies/mL at Week 48 (non-inferiority margin 4%), was met, demonstrating non-inferiority to BIC/FTC/TAF; 1.5% of participants who switched to DOR/ISL had a viral load of =50 copies/mL at Week 48, compared to 0.6% on BIC/FTC/TAF (treatment difference 0.9%, 95% CI -1.9, 2.9). At Week 96, DOR/ISL continued to demonstrate similar efficacy compared to BIC/FTC/TAF; 1.5% of participants on DOR/ISL had a viral load of =50 copies/mL compared to 1.2% of participants on BIC/FTC/TAF.

In the U.S., doravirine is approved for the treatment of adults with HIV-1 in combination with other antiretrovirals as a single agent (PIFELTRO) and a component of a single-tablet regimen [DELSTRIGO; doravirine, lamivudine, and tenofovir disoproxil fumarate (DOR/3TC/TDF)].