ADC Reviews

Merck’s HIV-1 drug Islatravir enters phase III clinical trial


On September 20, Merck announced that it would initiate a new Phase III clinical trial designed to evaluate once-daily oral administration of Islatravir (100 mg) in combination with a lower dose of Doravirine (0.75 mg)—DOR/ISL against HIV-1 Efficacy in infected patients. Currently, the FDA has reviewed and agreed to the plan. Additionally, the development of monthly oral islatravir for pre-exposure prophylaxis (PrEP) will be discontinued.

Phase III clinical trials will include one study evaluating DOR/ISL in untreated HIV-1 infected adult patients and two evaluating DOR/ISL in patients receiving antiretroviral therapy (ART) A study of virologically suppressed HIV-infected individuals.

Islatravir is an investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) that inhibits HIV reverse transcriptase function through multiple mechanisms. Islatravir’s mechanism of action differs from currently approved anti-HIV therapies and traditional nucleoside reverse transcriptase inhibitors (NRTIs). There are three special chemical structures in the islatravir molecule: (1) 3′-hydroxyl group, which is related to high affinity; (2) 4′-ethynyl group, which enables islatravir to block primer translocation, resulting in chain termination; (3) 2 -Fluoro group, inhibits the metabolism of islatravir and prolongs the half-life.

Chemical Structure of Islatravir

The development process of Islatravir can be described as twists and turns. In November 2021, Merck suspended the development of a non-nucleoside reverse transcriptase inhibitor (MK-8507). Because HIV patients developed leukopenia after taking MK-8507 in combination with islatravir. Total lymphocyte and CD4+ T-cell counts decreased the most in HIV patients who received the highest dose of MK-8507.

In December 2021, the FDA announced a clinical hold on islatravir’s New Drug Application (IND) based on the side effects of MK-8507 in combination with islatravir. At the same time, after accepting the recommendation of the external data monitoring committee for islatravir pre-exposure prophylaxis (PrEP), Merck also announced the suspension of patient recruitment in two phase III trials evaluating islatravir (IMPOWER 22 and IMPOWER 24) so ​​that the company can conduct further analysis of these studies.

Notably, a Phase II trial (NCT05052996) evaluating the combination of once-weekly oral administration of islatravir plus Gilead’s investigational capsid inhibitor lenacapavir in virologically suppressed HIV-infected patients will be based on a revised The protocol resumed with a lower dose of islatravir, and the IND of the study remains on partial clinical hold.