Pipeline Medications Research
- All
- Islatravir
Islatravir: evaluation of clinical development for HIV and HBV
Islatravir (ISL) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) that disrupts HIV reverse transcriptase through multiple mechanisms and retains a 3’OH group, unlike other approved NtRTIs. The drug has demonstrated high potency and tolerability in both in vitro and clinical studies. The review covers the historical development of ISL, its mechanisms of action against HIV and HBV, resistance patterns, and summarizes the outcomes of Phase I and Phase II clinical trials.
Gillespie SW, Reddy AS, Burris DM, et al. Islatravir: evaluation of clinical development for HIV and HBV. Expert Opin Investig Drugs. 2024;33(2):85-93. doi:10.1080/13543784.2024.2305130.
Modeling of HIV-1 prophylactic efficacy and toxicity with islatravir shows non-superiority for oral dosing, but promise as a subcutaneous implant
HIV prevention with pre-exposure prophylaxis (PrEP) is crucial, but daily oral adherence can be challenging. Long-acting (LA) PrEP formulations, such as islatravir (ISL), offer a solution with less frequent dosing. A mathematical model using phase II trial data found that ISL implants at 56–62 mg effectively reduce HIV risk without adversely affecting lymphocyte counts, whereas daily oral doses of 0.1 mg and weekly or biweekly doses provide comparable efficacy but with potential lymphocyte count reductions.
Kim H-Y, Zhang L, Hendrix CW, Haberer JE, von Kleist M. Modeling of HIV-1 prophylactic efficacy and toxicity with islatravir shows non-superiority for oral dosing, but promise as a subcutaneous implant. Pharmacotherapy. 2024;44(7):772-782. doi:10.1002/psp4.13212.
Antiviral potency of long-acting islatravir subdermal implant in SHIV-infected macaques
Treatment nonadherence in people living with HIVÂ poses significant risks, including drug resistance, disease progression, and increased morbidity and mortality. Long-acting antiretroviral therapies, such as islatravir (ISL), offer a potential solution by minimizing the need for frequent dosing. This study demonstrates that a subdermal long-acting nanofluidic implant delivering ISL effectively reduces viral load in SHIV-infected macaques.
Pons-Faudoa FP, Di Trani N, Capuani S, et al. Antiviral potency of long-acting islatravir subdermal implant in SHIV-infected macaques. Antiviral Research. 2024;207:105451. doi:10.1016/j.antiviral.2023.105451.
Current status of the small molecule anti-HIV drugs in the pipeline or recently approved
HIV/AIDs presents significant treatment challenges due to increasing resistance to current antiretroviral drugs. This resistance is exacerbated in low- and middle-income countries due to drug misuse, inadequate drug supply, and poor treatment monitoring. Despite these challenges, there has been progress in developing new ARV drugs targeting various components of HIV. This review, updated as of July 2024, provides an overview of new ARV drugs at different clinical trial stages. It discusses the mechanism of action, target biomolecule, associated resistance genes, efficacy, safety, drug class, and clinical trial phase for each compound. The review covers nucleoside reverse transcriptase inhibitors (NRTIs) like islatravir ; non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as rilpivirine, elsulfavirine, and doravirine; integrase inhibitors like cabotegravir and dolutegravir.
Nongnuj P, Torkin R, Azzarito V, et al. Current status of the small molecule anti-HIV drugs in the pipeline or recently approved. Bioorganic & Medicinal Chemistry. 2024;32:117860. doi:10.1016/j.bmc.2024.117860.
Efficacy and safety of oral islatravir once daily in combination with doravirine through 96 weeks for treatment-naïve adults with HIV-1 infection receiving initial treatment with islatravir, doravirine, and lamivudine
Conclusion: ISL/DOR-based regimens maintained viral suppression through week 96. ISL/DOR regimens were well tolerated regardless of dose.
Molina JM, Yazdanpanah Y, Saud AA, et al. Efficacy and safety of oral islatravir once daily in combination with doravirine through 96 weeks for treatment-naïve adults with HIV-1 infection receiving initial treatment with islatravir, doravirine, and lamivudine. J Acquir Immune Defic Syndr. 2021;Publish Ahead of Print. doi:10.1097/qai.0000000000002879
Islatravir
Islatravir Patient Information
Islatravir - patient. Hiv.gov. Accessed July 11, 2022. https://clinicalinfo.hiv.gov/en/drugs/islatravir/patient
Islatravir Has a High Barrier to Resistance and Exhibits a Differentiated Resistance Profile from Approved Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
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.
Diamond TL, Ngo W, Xu M, et al. Islatravir has a high barrier to resistance and exhibits a differentiated resistance profile from approved nucleoside reverse transcriptase inhibitors (NRTIs). Antimicrob Agents Chemother. 2022;66(6):e0013322. doi:10.1128/aac.00133-22
Development and validation of ion-pairing HPLC-CAD chromatography for measurement of Islatravir’s phosphorylated intermediates
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.
Gunsch MJ, Schwalm EL, Ouimet CM, et al. Development and validation of ion-pairing HPLC-CAD chromatography for measurement of Islatravir’s phosphorylated intermediates. J Pharm Biomed Anal. 2022;213(114684):114684. doi:10.1016/j.jpba.2022.114684
Doravirine and Islatravir Have Complementary Resistance Profiles and Create a Combination with a High Barrier to Resistance
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.
Lai MT, Feng M, Xu M, et al. Doravirine and islatravir have complementary resistance profiles and create a combination with a high barrier to resistance. Antimicrob Agents Chemother. 2022;66(5):e0222321. doi:10.1128/aac.02223-21
Islatravir (MK-8591) With Doravirine and Lamivudine in Participants Infected With Human Immunodeficiency Virus Type 1 (MK-8591-011)
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.
Islatravir (MK-8591) With Doravirine and Lamivudine in Participants Infected With Human Immunodeficiency Virus Type 1 (MK-8591-011). Clinicaltrials.gov. Accessed July 11, 2022. https://clinicaltrials.gov/ct2/show/NCT03272347
Intracellular islatravir pharmacology differs between species in an in vitro model: implications for preclinical study design
Given intracellular pharmacology differences, these preclinical models may be a conservative estimate of EFdA’s intracellular pharmacokinetics and efficacy in humans.
Sykes C, Van Horne B, Jones J, et al. Intracellular islatravir pharmacology differs between species in an in vitro model: implications for preclinical study design. J Antimicrob Chemother. 2022;77(4):1000-1004. doi:10.1093/jac/dkac015
A Once-A-Week ART Trial with Lenacapavir and Islatravir
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 once-A-week ART trial with lenacapavir and islatravir. H-i-v.net. Published January 13, 2022. Accessed July 11, 2022. https://h-i-v.net/research-studies/lenacapavir-islatravir-once-week-arv-trial