Pipeline Medications Research

Conclusion: ISL/DOR-based regimens maintained viral suppression through week 96. ISL/DOR regimens were well tolerated regardless of dose.

Islatravir Patient Information

While A114S conferred reduced susceptibility to ISL, it increased susceptibility to approved nucleoside reverse transcriptase inhibitors (NRTIs). This differential impact of A114S on ISL, an NRTTI, compared to NRTIs likely results from the different mechanisms of action. Altogether, the results demonstrate that ISL has a high barrier to resistance and a differentiated mechanism compared to approved NRTIs.

While the Islatravir biocatalytic cascade is an efficient and green synthetic route, the production of three non-isolated intermediates presented an analytical challenge. A robust and quantitative ion-pairing HPLC-CAD method was successfully developed and validated for use across all key intermediates within the biocatalytic cascade, providing a streamlined approach to in-process monitoring and quantification of intermediates within reaction streams. All intermediates were successfully resolved using a single method, saving time and space necessary to set up multiple instruments.

In de novo resistance selection studies in MT4-GFP cells (MT4 cells engineered to express green fluorescent protein), DOR/ISL synergistically prevented viral breakthrough at a threshold of 2× the half-maximal inhibitory concentration (IC50). DOR/ISL exhibited a higher barrier to resistance than DOR/3TC and dolutegravir (DTG)/3TC. Resistance analysis showed no emergence of substitutions at F227, an observation consistent with its ability to confer hypersusceptibility to ISL. Overall, the data demonstrate that DOR/ISL creates a 2-drug combination with a higher barrier to resistance, consistent with the reported clinical activity.

This study will evaluate the safety, tolerability, antiretroviral activity, and pharmacokinetics of 3 doses of islatravir (MK-8591) in combination with doravirine (DOR) and lamivudine (3TC) administered to antiretroviral treatment-naïve adult participants with human immunodeficiency virus type 1 (HIV-1) infection.

Given intracellular pharmacology differences, these preclinical models may be a conservative estimate of EFdA’s intracellular pharmacokinetics and efficacy in humans.

Research scientists are working together to see if a combination of medications – lenacapavir and islatravir – can improve HIV management. Both of these medications have a big advantage over current antiretroviral therapy (ART): they can be taken once a week, rather than daily.

A phase 1 clinical trial was conducted to evaluate the DDI (drug-drug interactions) of islatravir and the combination of oral contraceptive levonorgestrel (LNG)/ethinyl estradiol (EE). The results of this trial support the use of LNG/EE contraceptives in combination with islatravir without dose adjustment.

Investigational new drug applications were halted for the oral and implant formulations of islatravir, a nucleoside reverse transcriptase translocation inhibitor, for pre-exposure prophylaxis (PrEP); the injectable formulation of islatravir for treatment and prophylaxis; and the oral doravirine/islatravir (DOR/ISL) once-daily treatment, the company announced this week.

The health regulator’s move is based on observations of a drop in T-cell counts in some participants receiving the drug in clinical studies, the company said. T-cells are a critical component of the immune system that help the body fight infections.

U.S. Food and Drug Administration (FDA) has placed clinical holds on the investigational new drug applications (INDs) for the oral and implant formulations of islatravir (MK-8591) for HIV-1 pre-exposure prophylaxis (PrEP); the injectable formulation of islatravir for HIV-1 treatment and prophylaxis; and the oral doravirine/islatravir (DOR/ISL) HIV-1 once-daily treatment.