Doravirine

Merck has identified a $5 billion-plus opportunity for its late-stage HIV portfolio. \n Merck & Co. has reported another phase 3 win for islatravir in HIV, advancing its efforts to establish the near-approval molecule as a new anchor treatment for the infectious disease.Integrase strand transfer inhibitors (INSTIs) are the backbone of current antiretroviral therapy regimens. Yet, while molecules such as Gilead Sciences\' bictegravir have cut the risk of resistance, the potential for HIV to mutate to nullify INSTIs remains a problem. Equally, drug-drug interactions, cardiometabolic toxicities and other tolerability issues associated with INSTIs are a concern for some patients. Merck is positioning islatravir as an alternative backbone for HIV drug regimens. Fresh from phase 3 wins in trials that switched patients on existing regimens to an islatravir-based treatment, Merck has reported a victory for its nucleoside reverse transcriptase translocation inhibitor in treatment-naive adults.The latest phase 3 results come from a trial that compared a combination of doravirine and islatravir (DOR/ISL) to Gilead’s three-drug, INSTI-based treatment Biktarvy. After 48 weeks of once-daily dosing, the two arms had similar proportions of patients with HIV-1 RNA levels below a certain threshold. The result caused the trial to hit its primary noninferiority endpoint.  With the trial also finding the investigational combination had a comparable safety profile to that of Biktarvy, Merck is planning to submit applications including the data to health authorities. The FDA is already reviewing a filing for approval of DOR/ISL for the treatment of HIV-1 infection in adults to replace their current antiretroviral regimen. Merck is set to receive a decision from the FDA by April 28, 2026.At an HIV investor event in July, Liz Rhee, M.D., vice president of clinical research infectious disease at Merck, said the treatment-naive data could support a label expansion in the U.S. and an initial approval application in the EU. Merck executives primarily discussed DOR/ISL as an option for the 1 in 5 patients who switch HIV regimens each year, reflecting their belief that its convenience, tolerability and low risk of drug-drug interactions will make it a go-to choice. Eliav Barr, M.D., Merck Research Laboratories’ chief medical officer, also said islatravir regimens could enable physicians to reserve INSTIs for later-line use if needed. With other trials evaluating weekly islatravir-based combinations, Merck has identified a $5 billion-plus opportunity for its late-stage HIV portfolio. Merck executives have argued that analysts underappreciate the HIV portfolio, creating an opportunity for the drugmaker to exceed expectations and partly offset threats to Keytruda if it hits its sales targets.

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.