Ulonivirine

Merck is throwing in the towel on its lead candidate for a long-acting pre-exposure prophylaxis (PrEP) for HIV after months of grappling with safety concerns. The pharma giant — which first flagged a drop in immune cell counts in a trial last November and subsequently halted multiple trials involving islatravir — is scrapping the development of a once-monthly oral islatravir for PrEP. It will, however, move on with new studies testing the daily and weekly doses of the same drug to treat (rather than prevent) HIV. Merck hits the brakes on development program as safety fears trigger alarm Notably, those new and resumed trials will give patients a lower dose of the drug, while higher doses previously being administered were still under the FDA’s clinical hold. The decision marks a setback for what Merck had hoped to be the centerpiece of a major HIV franchise. First licensed from Japan’s Yamasa in 2012, islatravir proved to be potent in keeping patients’ viruses suppressed, and Merck devised multiple clinical trials to tease out its potential in different combinations as well as dosing regimens. In monkey studies, the monthly pill offered complete protection from a viral challenge. After initially confirming safety and tolerability , Merck had designed Phase III studies to try and push forth an oral long-acting option to rival ViiV. UPDATED: Merck's pause on an HIV program snowballs as a Gilead-partnered trial is shoved into limbo But it was still caught by surprise. Investigators first sounded the alarm in a trial testing a once-weekly combination of islatravir and a non-nucleoside reverse transcriptase inhibitor dubbed MK-8507, flagging a decrease in lymphocyte and CD4+ T cell counts deemed related to treatment. Initially, Merck attributed the issue to MK-8507 and reiterated its confidence in islatravir. The impact quickly snowballed as Merck and partners at Gilead paused a trial pairing islatravir with Gilead’s lenacapavir as a once-weekly treatment. Merck ultimately also pumped the brakes on the Phase III trials evaluating monthly islatravir, which focused on different populations. Merck pumps the brakes on two more PhIII trials for its lead anti-HIV drug Here’s what the islatravir program will look like going forward, according to Merck: New Phase III studies to evaluate a once-daily oral combination of doravirine (Pifeltro) 100 mg and a lower dose of islatravir (DOR/ISL): one study will evaluate DOR/ISL in previously untreated adults with HIV-1 infection; two studies will evaluate DOR/ISL as a switch in antiretroviral therapy (ART) in adults with HIV-1 infection who are virologically suppressed; certain patients currently enrolled in old studies testing a higher islatravir dose will have the option of transitioning to a new study. The Phase II clinical trial for a islatravir/lenacapavir combo in adults with HIV-1 infection who are virologically suppressed “will resume under an amended protocol with a lower dose of islatravir.” The company added that it continues to believe in the potential of the nucleoside reverse transcriptase translocation inhibitor (NRTTI) mechanism that islatravir works under. MK-8527, a NRTTI candidate, will start Phase Ib soon. “(W)e are evaluating additional candidates with the goal of helping to address unmet needs in HIV prevention,” said Eliav Barr, head of global clinical development and chief medical officer at Merck Research Laboratories. “As part of this, we are pleased to continue our partnership with the Bill & Melinda Gates Foundation as we continue to evaluate potential long-acting PrEP opportunities.”

Merck will discontinue its development of islatravir for preexposure prophylaxis after “careful evaluation and analysis.” A path forward for Merck & Co.’s struggling HIV strategy has opened up, with the FDA releasing a nine-month clinical hold on trials of the Big Pharma’s drug islatravir as long as low doses are used. However, the company has also decided to ditch its plans to explore the drug as a preventive treatment. The agency slapped the hold on trials of islatravir to both treat and prevent HIV in December 2021, citing decreases in total lymphocyte and CD4+ T-cell counts in some patients receiving the therapy. The previous month, Merck had pumped the brakes on trials of another potential HIV asset, dubbed MK-8507, over similar concerns. Now, the FDA has given the green light to three new phase 3 trials of a 0.75-mg dose of islatravir in combination with Merck’s approved HIV drug Pifeltro. One study will evaluate the drugs in previously untreated adults with HIV-1 infection, while two more trials will evaluate it as a switch in antiretroviral therapy in adults with HIV-1 infection who are virologically suppressed. Studies of higher doses of islatravir remain on ice. Swapping in a lower dose of islatravir also means a separate phase 2 trial can now continue, namely a weekly combination regimen of the drug and Gilead Sciences' lenacapavir in adults with HIV-1 infection who are virologically suppressed, Merck added. But it’s not all good news for the reinvigorated islatravir pathway. Merck will discontinue its development of the drug for preexposure prophylaxis (PrEP) after “careful evaluation and analysis.” Participants in the ongoing phase 3 PrEP once-monthly oral studies will still be monitored, said the company, which added that it would continue its partnership with the Bill & Melinda Gates Foundation to evaluate potential long-acting PrEP opportunities. Merck also “remains committed to developing compounds for long-acting HIV prevention and believes in the potential of the nucleoside reverse transcriptase translocation inhibitor (NRTTI) mechanism.” A phase 1b study of MK-8527, a novel NRTTI candidate, is due to begin “shortly,” the company said.