Merck’s Phase 3 Trials Show DOR/ISL Maintains HIV-1 Suppression at 48 Weeks
Merck, known as MSD outside of the United States and Canada, has announced promising results from two pivotal Phase 3 clinical trials evaluating its investigational, once-daily, oral, two-drug regimen of doravirine/islatravir (DOR/ISL). This combination, administered at 100mg/0.25mg, was tested in adults living with HIV-1 who had previously achieved virologic suppression on other antiretroviral therapies. The findings were presented in late-breaking oral sessions at the 32nd Conference on Retroviruses and Opportunistic Infections (CROI) in San Francisco and were also highlighted in a CROI press conference. The company intends to submit applications for marketing authorization to regulatory agencies by mid-2025.
Study Design and Trial Overview
The two Phase 3 trials, MK-8591A-052 and MK-8591A-051, were designed to evaluate the efficacy and safety of DOR/ISL compared to currently approved antiretroviral regimens. The first study, MK-8591A-052, focused on virologically suppressed adults who were previously on a regimen containing bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), a widely used three-drug integrase inhibitor-based therapy. The second study, MK-8591A-051, enrolled individuals who had been receiving a broader range of baseline antiretroviral therapies (bART) and assessed the effects of switching to DOR/ISL.
Both trials were designed to determine whether the two-drug regimen of DOR/ISL was non-inferior to the comparator therapies in maintaining HIV-1 viral suppression at Week 48. Additionally, the trials evaluated the safety profile of DOR/ISL compared to existing standard-of-care regimens.
Key Findings from MK-8591A-052
In the double-blind MK-8591A-052 trial, the primary endpoint measured was the proportion of participants who experienced virologic failure, defined as having an HIV-1 RNA level of ≥50 copies/mL at Week 48. Results showed that only 1.5% of participants who switched to DOR/ISL experienced virologic failure, compared to 0.6% of those who remained on BIC/FTC/TAF. The treatment difference was 0.9% (95% confidence interval [CI] -1.9, 2.9), meeting the prespecified criteria for non-inferiority.
Secondary endpoint analysis revealed that 91.5% of participants who switched to DOR/ISL maintained viral suppression (HIV-1 RNA <50 copies/mL) at Week 48, compared to 94.2% of those who continued on BIC/FTC/TAF. The treatment difference in this analysis was -2.6% (95% CI -7.1, 2.6), again demonstrating non-inferiority.
Key Findings from MK-8591A-051
The open-label MK-8591A-051 trial evaluated participants switching from various bART regimens to DOR/ISL. For the primary endpoint, 1.4% of participants on DOR/ISL experienced virologic failure at Week 48, compared to 4.9% of those who continued on their baseline antiretroviral therapy. The treatment difference of -3.6% (95% CI -7.8, -0.8) supported the efficacy of DOR/ISL as a viable treatment alternative.
In terms of maintaining viral suppression, 95.6% of participants who switched to DOR/ISL had HIV-1 RNA levels below 50 copies/mL at Week 48, compared to 91.9% in the bART group. The treatment difference was 3.7% (95% CI -0.3, 8.9), further reinforcing the potential of this novel two-drug regimen.
Safety and Tolerability Profile
Across both trials, the safety and tolerability of DOR/ISL were generally consistent with those of comparator regimens. Adverse events leading to treatment discontinuation were infrequent and comparable between groups. No treatment-emergent resistance to DOR or ISL was detected in either study, an encouraging finding in the long-term management of HIV-1.
At Week 48, the mean percent change in total lymphocyte count and CD4 cell count was similar between DOR/ISL and the comparator regimens. These findings suggest that the regimen is effective at maintaining immune function while suppressing viral replication.
Clinical and Scientific Implications
Professor Chloe Orkin, Dean for Healthcare Transformation at Queen Mary University of London, commented on the significance of these findings: “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. 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.”
Doravirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that has demonstrated a high barrier to resistance and a favorable safety profile in prior studies. Islatravir, Merck’s investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI), exerts its antiviral activity by blocking HIV-1 replication through multiple mechanisms. These include inhibition of reverse transcriptase translocation, resulting in both immediate chain termination and delayed chain termination due to structural changes in viral DNA.
Dr. Eliav Barr, Senior Vice President and Head of Global Clinical Development at Merck Research Laboratories, emphasized the importance of these findings in the context of HIV research: “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 3 pivotal trial. 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.”
Regulatory Outlook and Next Steps
With these positive Phase 3 results, Merck is preparing to submit applications for regulatory approval of DOR/ISL. If approved, this regimen could represent an important advancement in HIV therapy, offering a two-drug option that may be particularly beneficial for individuals seeking alternatives to integrase inhibitor-based treatments.
The upcoming regulatory review will likely assess the long-term safety, tolerability, and potential benefits of DOR/ISL compared to existing therapies. Given the strong efficacy and safety results from these pivotal trials, there is optimism that this regimen could provide a new, simplified option for HIV-1 treatment.
