Doravirine/Islatravir

Merck secured another win on Wednesday in its plan to bolster its HIV portfolio. The pharma giant said its two-drug combination was non-inferior to a three-drug package in a Phase 3 trial in adults with HIV-1 who were not previously on antiretroviral treatment. Merck said the study of the single-tablet combination of doravirine and islatravir met the primary efficacy hypothesis at week 48. The safety of DOR/ISL was also “comparable” to the three-drug combination of Gilead’s Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide, or BIC/FTC/TAF). Both are once-daily regimens. DOR/ISL is already under FDA review for a different patient population : people with HIV who are already on an antiretroviral regimen. The regulatory body is slated to decide whether to approve the treatment in that population by April 28 . Merck hopes DOR/ISL will become part of a broader HIV portfolio that could be a $5 billion business . Its existing medicines in the space made $412 million in revenue in the first half of this year, but it’s studying additional combinations and a once-monthly oral PrEP that just entered Phase 3. Merck has been involved in HIV science since the early days of the epidemic, and brought the protease inhibitor Crixivan to market in 1996. Multiple HIV treatment options now exist, and companies like Gilead and GSK’s ViiV make long-acting HIV medicines, but for different patient populations. Merck’s existing HIV work is a small piece of the pharma’s efforts to pad the revenue gap that will come from Keytruda’s patent cliff. Merck has spent more than $19 billion this year on acquisitions, namely for respiratory biotech Verona Pharma and influenza antiviral developer Cidara Therapeutics . The new Phase 3 data will be presented at a future medical conference. Merck said it plans to use the data in applications to health regulators. With the non-inferiority results, Merck hopes to go up against Biktarvy, which brought in $3.7 billion in sales for Gilead in the third quarter of this year. “These data support the potential for this regimen to be a meaningful treatment option for virally suppressed people living with HIV who are looking to switch to a new regimen or people who have not previously been on antiretroviral therapy to start treatment,” Merck Research Laboratories chief medical officer Eliav Barr said in a press release. Merck chief marketing officer Chirfi Guindo said on an investor call in July that the company believes DOR/ISL will be “the preferred switch option for many individuals.” Guindo said the drug combination provides “robust viral control” and a “high barrier to resistance.” Doravirine is an approved HIV medicine known as Pifeltro and part of an HIV pill marketed as Delstrigo. Islatravir, meanwhile, is in multiple clinical trials assessing whether it can be a once-daily or weekly treatment for HIV when paired up with other medicines. The drug is in Phase 3 with Gilead’s lenacapavir as a potential once-weekly oral treatment. Islatravir is also in a Phase 2b in combination with Merck’s ulonivirine, an experimental non-nucleoside reverse transcriptase inhibitor (NNRTI). That pairing is “back on track,” Luisa Stamm, Merck’s associate VP and section head for HIV, said in an interview with Endpoints in July. The drug combo had a safety signal for a prior Phase 2, but Merck is now looking at a lower dosing schedule to assuage concerns.

The race for a simplified HIV antiretroviral regimen is heating up. Days after Gilead shared data on its experimental two-drug, single-tablet treatment, Merck & Co. has countered with late-stage findings for its own drug duo — though this batch of pivotal results is in treatment-naïve patients. The current standard-of-care HIV viral suppressor is Gilead's Biktarvy, an oral, once-daily tablet that comprises integrase strand transfer inhibitor (INSTI) bictegravir plus emtricitabine and tenofovir alafenamidei. The drug is Gilead's best-seller, bringing in $3.7 billion in revenue for the third quarter (see – Vital Signs: Gilead's fastest growing drugs).Last week, Gilead revealed data from the Phase III ARTISTRY-1 study evaluating a single-tablet combination of bictegravir plus lenacapavir, a long-acting HIV-1 capsid inhibitor marketed as Sunlenca for multidrug-resistant HIV and as Yeztugo for pre-exposure prophylaxis. In the 689 participants — all of whom were virologically suppressed, but were taking anywhere from two to 11 pills daily — bictegravir/lenacapavir was statistically non-inferior to multi-tablet regimens at the 48-week mark. Integrase inhibitor not needed?Merck is comparing its single-tablet, two-drug combo of doravirine/islatravir against Biktarvy in a Phase III study. Unlike Biktarvy or Gilead's experimental duo, Merck's pill does not include an INSTI; islatravir is a nucleoside reverse transcriptase translocation inhibitor designed to block HIV-1 replication via chain termination and  induction of structural changes.The MK-8591A-053 trial enrolled 537 patients with HIV-1 infection who've never received an antiretroviral. After 48 weeks, Merck's tablet met its primary endpoint, demonstrating non-inferiority to Biktarvy as measured by the percentage of participants with HIV-1 RNA levels <50 copies/mL. The pharma added that the safety profile of doravirine/islatravir was comparable to Gilead's drug. Doravirine/islatravir "is the first two-drug regimen without an integrase inhibitor showing non-inferior efficacy and safety when compared to the three-drug INSTI-based regimen [Biktarvy] in this population," said Eliav Barr, head of global clinical development and the chief medical officer at Merck Research Laboratories. "These data support the potential for this regimen to be a meaningful treatment option for virally suppressed people living with HIV who are looking to switch to a new regimen or people who have not previously been on antiretroviral therapy to start treatment."Merck's two-drug combo is already under review at the FDA for adults with HIV who are virologically suppressed on antiretroviral therapy. With a PDUFA date of April 28, 2026, it has a head-start on Gilead's bictegravir/lenacapavir in the pre-treated population, where the biopharma is still waiting for results to read out from a second Phase III trial, ARTISTRY-2.Detailed results of doravirine/islatravir in treatment-naïve patients will be presented at a future scientific meeting, and submitted to global regulators.