Positive Data for Doravirine/Islatravir

In both trials, DOR/ISL met the primary efficacy success criterion for non-inferiority to comparator antiretroviral therapies and primary safety objectives at Week 48. The findings were shared at the 32nd Conference on Retroviruses and Opportunistic Infections (CROI) held in San Francisco. Merck plans to begin submitting applications for marketing authorization to regulatory agencies by mid-2025.

In the double-blind trial MK-8591A-052 (Abstract #204A), results for the primary endpoint (HIV-1 RNA ≥50 copies/mL) showed that 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 48, 91.5% of participants who switched to DOR/ISL maintained viral suppression (HIV-1 RNA <50 copies/mL) compared to 94.2% of participants who continued receiving BIC/FTC/TAF (treatment difference -2.6%, 95% CI -7.1, 2.6; secondary endpoint).

In the open-label trial MK-8591A-051 (Abstract #204B), results for the primary endpoint (HIV-1 RNA ≥50 copies/mL) showed that 1.4% of participants who received DOR/ISL had a viral load of ≥50 copies/mL at Week 48, compared to 4.9% on bART (treatment difference -3.6%, 95% CI -7.8, -0.8. At Week 48, 95.6% of participants who switched to DOR/ISL maintained viral suppression (HIV-1 RNA <50 copies/mL) compared to 91.9% of participants who continued on bART (treatment difference 3.7%, 95% CI -0.3, 8.9; secondary endpoint).

Across both trials, the safety profile of DOR/ISL was generally comparable to the comparator antiretroviral regimens, including BIC/FTC/TAF in MK-8591A-052. At Week 48, the mean percent change in total lymphocyte and CD4 counts were similar for DOR/ISL and comparator regimens. No treatment-emergent resistance to DOR or ISL was observed in either trial.

“Despite the availability of multiple daily antiretroviral therapies, the needs of people living with HIV are evolving. Many people living with HIV are older and also managing comorbidities, making it important to have daily treatment options that can help meet each person’s unique health needs,” said Professor Chloe Orkin, Dean for Healthcare Transformation, Queen Mary University of London, United Kingdom. “I’m excited to see that DOR/ISL has potential as a new daily treatment option for people living with HIV who may benefit from this two-drug regimen.”

Islatravir, Merck’s investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI), blocks HIV-1 replication by multiple mechanisms including inhibition of reverse transcriptase translocation resulting in immediate chain termination and delayed chain termination from structural changes induced in the viral DNA.

“We are excited 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, in a Phase III pivotal trial,” said Dr. Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories. “Merck has been a research pioneer in HIV for decades. These data and our work on the longer-acting islatravir-based therapies in our pipeline show our continued commitment to help find new options that address the evolving needs of people living with HIV.”

About the Phase III data from MK-8591A-052 - MK-8591A-052 is a Phase III, double-blind randomized, active-controlled, clinical trial to evaluate the efficacy and safety of a switch to investigational, oral, once-daily DOR/ISL (100mg/0.25mg) in adults with HIV-1 infection that has been virologically suppressed on BIC/FTC/TAF (50mg/200mg/25mg). The primary efficacy endpoint was the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48 (non-inferiority 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 or Latine. The median duration of BIC/FTC/TAF treatment prior to trial enrollment was 3.4 years (IQR 2.0-5.0).

Results for the primary efficacy endpoint showed that five participants (1.5%) treated with DOR/ISL and one participant (0.6%) in the BIC/FTC/TAF group had a viral load of ≥50 copies/mL at Week 48, demonstrating non-inferiority of DOR/ISL to BIC/FTC/TAF (treatment difference 0.9%, 95% CI -1.9, 2.9). The superiority criteria were not met. Results for a secondary endpoint, the proportion of individuals with HIV-1 RNA <50 copies/mL at Week 48, showed that participants who switched to treatment with DOR/ISL or continued BIC/FTC/TAF maintained comparable rates of viral suppression at Week 48 (91.5% on DOR/ISL vs. 94.2% on BIC/FTC/TAF (treatment difference -2.6%, 95% CI -7.1, 2.6). No treatment-emergent resistance to DOR or ISL was observed.

At Week 48, the mean percent change in total lymphocyte and CD4 counts were similar for DOR/ISL and BIC/FTC/TAF. There were identical rates of discontinuation for protocol-specified decreases in total lymphocyte and/or CD4 counts (two participants (0.6%) in the DOR/ISL group and one participant (0.6%) in the BIC/FTC/TAF group).

Drug-related adverse events (AEs) and discontinuations due to drug-related AEs were similar between groups (n=35, 10.2% for DOR/ISL and n=16, 9.4% for BIC/FTC/TAF; n=4, 1.2% for DOR/ISL and n=2, 1.2% for BIC/FTC/TAF, respectively). Rates of toxicity grade 3 or 4 AEs and serious AEs were similar for DOR/ISL and BIC/FTC/TAF (n=25, 7.3% for DOR/ISL and n=13, 7.6% for BIC/FTC/TAF; n=15, 4.4% for DOR/ISL and n=11, 6.4% for BIC/FTC/TAF, respectively). Mean change in weight from baseline to Week 48 was minimal (-0.03 kg for DOR/ISL versus 0.28 kg for BIC/FTC/TAF; difference -0.30 kg, 95% CI -1.13, 0.53). The most common AEs (>6% in either study arm) were arthralgia, COVID-19, nasopharyngitis, and fatigue. One participant on DOR/ISL discontinued due to a drug-related serious AE (immune thrombocytopenia). There were two cases of low-level hepatitis B (HBV) viremia (HBV DNA <50 IU/mL) with no antigenemia or elevated transaminases in the DOR/ISL group and no cases in the BIC/FTC/TAF group; there were no cases of clinical HBV reactivation.

About the Phase III data from MK-8591A-051 - MK-8591A-051 is a Phase III, open-label randomized, active-controlled, clinical trial evaluating the efficacy and safety of a switch to investigational, oral, once-daily DOR/ISL (100mg/0.25mg) in adults with HIV-1 infection that has been virologically suppressed using ART. The primary efficacy endpoint was percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48 (non-inferiority margin 4%). In this trial, 551 adults with HIV-1 RNA <50 copies/mL for three months or more on oral 2- or 3-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 baseline antiretroviral therapy (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% 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 (PI)-based regimen, with median duration on current ART of 3.8 years (IQR 2.0-6.3).

Results for the primary efficacy endpoint showed that five participants (1.4%) in the DOR/ISL group and nine participants (4.9%) in the bART group had a viral load of ≥50 copies/mL at Week 48, demonstrating non-inferiority of DOR/ISL to bART (treatment difference -3.6%, 95% CI -7.8, -0.8). Results for a secondary endpoint, the proportion of individuals with HIV-1 RNA <50 copies/mL at Week 48, showed that participants who switched to treatment with DOR/ISL or continued bART maintained comparable rates of viral suppression at Week 48 (95.6% on DOR/ISL vs. 91.9% on bART; treatment difference 3.7%, 95% CI -0.3, 8.9). No treatment-emergent resistance to DOR or ISL was observed. Two participants discontinued DOR/ISL early after virologic failure at Week 4 with multiple resistance-associated mutations that were also present in baseline proviral DNA. These two participants were later found to be not eligible for the trial due to history of prior virologic failure and exclusionary DOR resistance.

At Week 48, the mean percent change in total lymphocyte and CD4 counts were similar for DOR/ISL and bART. No participants discontinued treatment due to decrease in total lymphocyte and/or CD4 counts.

In this open-label study, drug-related AEs were more commonly reported with DOR/ISL (n=44; 12.0%) than bART (n=9; 4.9%). Rates of toxicity grade 3 or 4 AEs and serious AEs were similar for DOR/ISL and bART (n=39, 10.7% for DOR/ISL and n=18, 9.7% for bART and n=23, 6.3% for DOR/ISL and n=9, 4.9% for bART, respectively). There were no drug-related serious AEs and there were no discontinuations due to serious AEs in the DOR/ISL group; there was one drug-related serious AE and two discontinuations due to serious AEs in the bART group. The most common drug-related AEs were diarrhea (DOR/ISL 3.3%, bART 0%), fatigue (1.9%, 0.5%), dizziness (1.9%, 0.5%), abdominal distention (1.6%, 0%), weight increased (1.6%, 0%), and headache (1.6%, 1.1%).

Change in lipid parameters from baseline were similar between treatment groups for all bART strata. Mean change in weight from baseline to Week 48 was 0.94 kg for DOR/ISL and -0.18 kg for bART (difference -1.13 kg, 95% CI 0.31, 1.94). For baseline regimens without EFV or TDF, the difference in weight between DOR/ISL and bART was 0.82 kg (95% CI -0.22, 1.87). There was one case of low-level HBV viremia with no antigenemia or elevated transaminases in the DOR/ISL group and no cases in the bART group; there were no cases of clinical HBV reactivation.