FDA Places Clinical Hold on Merck's Islatravir Oral and Implant Formulations for HIV Treatment and Prevention

Compiled by Fan Dongdong

Recently, MSD announced that the U.S. FDA has placed a clinical hold on the Investigational New Drug (IND) application for oral and implant formulations of islatravir (MK-8591). The FDA’s decision to impose the clinical hold was based on previously announced observations, where trial results showed a decrease in total lymphocyte and CD4+ T-cell counts (key indicators of immune function in HIV patients) in some participants receiving islatravir during clinical studies.

The company had previously applied for islatravir for HIV-1 pre-exposure prophylaxis (PrEP), an injectable formulation of islatravir for HIV-1 treatment and prevention, as well as a combination of doravirine and islatravir (DOR/ISL) for once-daily HIV-1 treatment. Due to the current clinical hold placed on the new drug application for islatravir by the U.S. FDA, analysts believe it is unlikely that new studies for this drug will be initiated in the future.

As part of the PrEP trial, participants currently receiving islatravir (including oral and implant formulations), as well as those receiving injectable islatravir for treatment and prevention, will no longer receive the study drug. Researchers will be responsible for monitoring the recovery of CD4+ T-cell counts and total lymphocyte counts in these patients. Participants in the PrEP trial will be switched to an already approved, once-daily oral PrEP regimen. Additionally, DOR/ISL study participants who have already started treatment will continue to receive the study drug. During the partial clinical hold, no new participants will be screened or randomized into the DOR/ISL study.

Clinical trials that have been completely put on hold include the following:

MK-8591-016 is a Phase 2a PrEP trial evaluating the safety and pharmacokinetics of monthly oral islatravir in participants with low risk of HIV-1 infection;

MK-8591-022 (IMPOWER22) is a Phase 3 PrEP trial evaluating the efficacy of once-monthly oral islatravir in cisgender women at high risk of HIV-1 infection;

MK-8591-024 (IMPOWER24) is a Phase 3 PrEP trial evaluating the efficacy of once-monthly oral islatravir in cisgender men and transgender women who have sex with men and are at high risk of HIV-1 infection;

MK-8591-034 is a Phase 1 study evaluating the injection of islatravir;

MK-8591-035 is a Phase 2 PrEP trial evaluating once-monthly oral islatravir in transgender and gender-diverse individuals, and the study has not yet opened for patient recruitment.

MK-8591-043 is a Phase 2a PrEP trial evaluating the efficacy of annual islatravir injections in individuals with low risk of HIV-1 infection, and this study has not yet begun recruitment.

The following studies have been partially clinically shelved:

MK-8591-011 is a Phase 2 dose-ranging study of once-daily oral DOR/ISL and lamivudine (3TC) for treatment-naïve adults with HIV-1 infection, and patient enrollment has been completed.

MK-8591A-017 is an open-label, Phase 3 oral study conducted once daily to evaluate the efficacy of switching virologically suppressed HIV-1 adult patients from antiretroviral therapy (ART) to DOR/ISL; enrollment has been completed.

MK-8591A-018 is a Phase 3 oral study evaluating the efficacy of switching virologically suppressed HIV-1 adult patients from Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF) to DOR/ISL; patient enrollment has been completed.

MK-8591A-019 is a Phase 3 study evaluating the efficacy of once-daily oral islatravir and DOR/ISL in heavily treatment-experienced (HTE) participants infected with HIV-1.

MK-8591A-020 is a Phase 3 study evaluating once-daily oral islatravir and DOR/ISL in treatment-naïve participants with HIV-1 infection.

MK-8591A-028 is a Phase 2 open-label study evaluating once-daily oral DOR/ISL for the treatment of HIV-1 pediatric patients who have been virologically suppressed on ART for ≥3 months or are treatment-naive.

MK-8591A-033 is a Phase 3 open-label follow-up study of HIV-1 adult and pediatric participants who received once-daily oral DOR/ISL treatment in early clinical studies.

Besides, another HIV research trial of MSD's islatravir has also encountered a setback. Recently, Gilead and MSD decided to stop dosing all participants in the Phase 2 clinical study NCT05052996. The purpose of this trial was to evaluate the efficacy of a weekly combined oral regimen of MSD's investigational islatravir and Gilead's investigational lenacapavir for antiretroviral therapy in HIV-infected individuals with virological suppression.

This decision was made on November 23, following a joint announcement by the two companies that they would pause further recruitment and screening for the study, which began in October 2021. After deciding to halt drug administration to study participants, individuals in both treatment groups will stop taking the current investigational drug and resume their previous antiretroviral therapy regimens. Gilead and MSD stated that they remain committed to collaborating in the HIV field, aiming to develop long-acting new treatment options to address unmet needs of people living with HIV.

Reference Source: Merck Announces Clinical Holds on Studies Evaluating Islatravir for the Treatment and Prevention of HIV-1 Infection