FDA Accepts NDA for Investigational HIV Regimen, Doravirine/Islatravir

The FDA has accepted for review Merck’s NDA for doravirine/islatravir (DOR/ISL), an investigational, once-daily, oral, two-drug regimen for adults with HIV that is virologically suppressed on antiretroviral therapy (ART), according to a news release published today. A Prescription Drug User Fee Act (PDUFA) target action date has been set for April 28, 2026.

This acceptance is based on the results of two phase 3 trials, MK-8591A-051 and MK-8591A-052, in which DOR/ISL demonstrated similar efficacy and safety to baseline antiretroviral therapy (bART), which is the initial patient evaluation after diagnosis, consisting of viral load counts and drug resistance testing, and the antiretroviral regimen of bictegravir/emtrictabine/tenofovir alafenamide (BIC/FTC/TAF). Efficacy for both trials was measured by the percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48.

MK-8591A-051 evaluated the safety and efficacy of 100 mg/0.25 mg of DOR/ISL in 551 adults with <50 copies/mL of HIV RNA for three months or more on oral 2- or 3-drug bART. Participants were randomized 2:1 to receive either DOR/ISL (n=366) or continued bART (n=185). By week 48, 95.6% of patients on DOR/ISL maintained viral suppression compared with 91.9% of participants who continued bART.

MK-8591A-052 also evaluated the safety and efficacy of 100 mg/0.25 mg of DOR/ISL, but in 513 with HIV who had virologic suppression for three months or more on bictegravir/emtrictabine/tenofovir alafenamide (BIC/FTC/TAF) (50 mg/200 mg/25 mg). Participants were randomized to either receive DOR/ISL (n=342) or to continue their treatment with BIC/FTC/TAF (n=171). Almost all (91.5%) of participants who switched to DOR/ISL maintained viral suppression (HIV-1 RNA <50 copies/mL) compared with 94.2% of participants who continued receiving BIC/FTC/TAF, according to a separate news release published in March.

The safety profile of DOR/ISL was generally comparable to baseline antiretroviral regimens in MK-8591A-051 and BIC/FTC/TAF in trial MK-8591A-052, the news release says.

Doravirine is currently sold under the brand name Pifeltro as a non-nucleoside reverse transcriptase inhibitor medication, which blocks reverse transcriptase, halting HIV DNA replication. It is approved for use in combination with other antiretroviral agents in patients with no antiretroviral history or in place of a current ART regimen. This 100 mg tablet should be taken once daily, with or without food, in patients weighing at least 77 lbs. The most common adverse reactions of Pifeltro are nausea (7%), dizziness (7%) and headache (6%).

Islatravir is an investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) that also blocks HIV replication, but by damaging the virus’s DNA so it can’t finish forming properly. Islatravir is currently under evaluation in multiple additional studies, including in combination with Gilead’s lenacapavir as a novel oral once-weekly treatment for HIV.

“The health needs of people living with HIV often change over time—whether it’s managing comorbidities or navigating complex medication regimens,” Eliav Barr, M.D., senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories, said in today's news release. “We believe DOR/ISL, if approved, will represent an important new complete regimen option designed to help meet their diverse needs.”

Trial data from MK-8591A-051 and MK-8591A-052 was presented at the 32nd Conference on Retroviruses and Opportunistic Infections (CROI) held in San Francisco from March 9 to 12, 2025.