Merck's Investigational Doravirine/Islatravir Combination Meets Primary Endpoints in Two Pivotal Phase 3 Trials, Supporting Regulatory Submission

On October 25, 2021, MSD announced that a combination therapy comprising the novel nucleoside reverse transcriptase translocation inhibitor (NRTTI) islatravir and the approved non-nucleoside reverse transcriptase inhibitor doravirine achieved positive topline results in two pivotal Phase 3 trials conducted in adults with HIV-1 infection.

These patients had achieved virologic suppression while on various antiretroviral therapy (ART) regimens or while receiving the commonly used HIV combination therapy of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). They were switched to the once-daily oral fixed-dose combination regimen of doravirine/islatravir (DOR/ISL) or continued their existing treatment for 48 weeks. Detailed trial results will be presented at upcoming medical conferences and will serve as the basis for regulatory submissions.

Both trials met the primary efficacy endpoint. At Week 48, compared with either the ART regimen group or the BIC/FTC/TAF regimen group, the doravirine/islatravir combination demonstrated comparable antiviral efficacy. To date, the safety and tolerability profile of doravirine/islatravir during the trials has been consistent with that previously reported in Phase 2 studies.

Doravirine is a novel, once-daily oral non-nucleoside reverse transcriptase inhibitor developed by MSD. By binding to HIV-1 reverse transcriptase, it prevents the virus from converting its RNA into DNA, thereby inhibiting HIV-1 replication. It has been approved in the United States for the treatment of antiretroviral-naïve adult patients with HIV-1 infection.

With the advancement of antiretroviral therapy, most people living with HIV can now achieve viral suppression through daily medication. However, 2019 statistics indicate that there are still 1.7 million new HIV infections globally. Currently, the development of long-acting HIV therapies is a key focus in HIV drug research and development, as these long-acting regimens may improve treatment adherence among patients.

▲ Molecular structure of islatravir (Image source: Edgar181, Public domain, via Wikimedia Commons)

Preclinical studies indicate that islatravir inhibits HIV reverse transcriptase function through multiple mechanisms. Its mechanism of action differs from currently approved anti-HIV therapies and traditional nucleoside reverse transcriptase inhibitors (NRTIs). Currently, MSD has initiated multiple clinical trials to evaluate its efficacy as a monotherapy for pre-exposure prophylaxis (PrEP) and in combination with other antiviral therapies for the treatment of HIV infection. A previous Phase 1 trial demonstrated that a 56 mg dose of islatravir is expected to maintain drug concentrations above the threshold for over one year. In other words, as a long-acting PrEP therapy, it may provide up to 12 months of protective efficacy with a single administration.

References:

[1] Merck Announces Positive Top-Line Results from Pivotal Phase 3 Trials Evaluating Investigational, Once-Daily Oral Fixed Dose Combination of Doravirine/Islatravir for the Treatment of People with HIV-1 Infection. Retrieved October 25, 2021, from https://www.merck.com/news/merck-announces-positive-top-line-results-from-pivotal-phase-3-trials-evaluating-investigational-once-daily-oral-fixed-dose-combination-of-doravirine-islatravir-for-the-treatment-of-people-with-hiv-1/

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