Merck pauses 'very important' HIV program after seeing red flag in phase 2 trial of once-weekly combo

Merck
In response to MK-8507 combination data, Merck went over the results from other clinical trials of islatravir. (Merck & Co.)

A “very important” part of Merck’s HIV strategy has come off the rails. Just months after talking up the importance of MK-8507, Merck has paused development of the asset in response to mid-phase data that also raised questions about the backbone of all the company’s planned HIV regimens.

Merck paused development of MK-8507 after seeing decreases in white blood cells in HIV patients who took the non-nucleoside reverse transcriptase inhibitor in combination with backbone therapy islatravir in a phase 2 clinical trial. The external data monitoring committee concluded the decreases were linked to the investigational once-weekly combination, with the biggest falls in total lymphocyte and CD4+ T-cell counts seen in patients who received the highest doses of MK-8507.

The dose-dependent response led Merck to finger MK-8507 as the culprit, stop dosing in the trial and pause development of the asset. The setback to MK-8507 is a blow to Merck’s attempt to develop an oral, once-weekly treatment for HIV patients.

In June, Merck EVP Dean Li, M.D., Ph.D., told (PDF) investors that, with islatravir providing a “beachhead” in HIV, “advancing MK-8507 becomes very important.” Merck’s plan was to use MK-8507 to take islatravir beyond the once-daily setting enabled by its combination with doravirine, thereby establishing the company as a player as the HIV market moves to more convenient regimens.

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The good news for Merck is that it “remains confident in islatravir’s overall profile” and is continuing development of the drug, which is at the heart of its internal treatment and PrEP programs as well as its long-acting oral and injectable collaboration with Gilead. Yet, the problems with MK-8507 have led Merck to uncover evidence that islatravir may affect white blood cell counts to some extent.

In response to the MK-8507 combination data, Merck went over the results from other clinical trials of islatravir. The review revealed a dose-dependent decrease in white blood cell counts in an ongoing phase 2 trial that is testing a monthly islatravir formulation for PrEP. Merck said the decreases were “in the normal range,” adding there was no increase in adverse events related to infection. 

Merck also saw “a small, treatment-related mean decrease in CD4+ T-cell counts” in the two phase 3 trials of its once-daily islatravir-doravirine combination therapy. Again, Merck found no evidence of increased incidence of infections in patients on the combination compared to the control group.

Having posted positive topline data last month, Merck is now preparing to share full results from the phase 3 clinical trials at an upcoming medical meeting. The results will also face scrutiny if Merck, as is expected, uses the data as the basis of global regulatory submissions covering the once-daily drug regimen.

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RBC Capital Markets said Merck's setback is positive for Gilead, which has a number of HIV products approved and in development outside of the collaboration. Even if islatravir is ultimately approved, the safety concerns could discourage patients from switching off of Gilead's regimens.

As for the partnered combo of Gilead's lenacapavir and islatravir, the companies are trying to create a long-acting treatment to be administered by injection and orally. The setback may mean that Gilead has to go back to the drawing board to develop new long-acting cocktails as the market potential for the partnered combo dwindles, RBC said. 

Editor's Note: This story was updated at 8:30 a.m. ET on Nov. 19, 2021, to include analyst commentary.