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.