First-in-Class NRTTI Demonstrates Potential as Long-Acting Oral PrEP Against HIV


Islatravir exerts multiple mechanisms against HIV, demonstrates treatment effectiveness with doravirine, and is a potential weekly or monthly oral PrEP.


Islatravir, a first-in-class agent with multiple mechanisms of action and high potency against HIV, is in phase 3 clinical trials alone and in combination with doravirine as long-acting oral treatment, and recently evidenced potential in two phase 1 clinical trials as weekly, and possibly monthly oral pre-exposure prophylaxis (PrEP).

"One medication option for PrEP is not enough," declared Kenneth Mugwanya, MBChB , MS, PhD, and Jared Baeten, MD, PhD, Department of Global Health,University of Washington, Seattle, WA, in commentary that accompanied a published preclinical study of islatravir. That study found the potency of the long-acting oral form to be approximately 10 to 1000-fold greater than other antiretrovirals against rhesus simian/human immunodeficiency virus (SHIV).

Describing the challenges of access and adherence that have confounded the promise of PrEP to markedly reduce the prevalence of HIV, Mugwanya and Baeten were enthusiastic about the prospect of islatravir and other candidates to reduce reliance on a daily regimen, and traveling to injection clinics for longer acting agents.

"For PrEP, alternative options to a daily oral pill are needed to provide options that fit into people's diverse life experiences and preferences," Mugwanya and Baeten indicated. "Such next-generation PrEP candidates would ideally improve on TDF/FTC (tenofovir disoproxil fumarate/emtricitabine), with characteristics like less frequent or nonoral dosing, a better ability to be taken privately, and even greater forgiveness to less-than-perfect adherence."

Following the favorable preclinical toxicity and pharmacokinetics profiles of islatravir, a first-in-class nucleoside reverse transcriptase translocation inhibitor (NRTTI), two phase 1 clinical trials were conducted in participants without HIV to assess safety and pharmacokinetics of rising single and multiple oral doses, and to inform dosage selection for further clinical trials in patients with HIV.

In their report on the two phase 1 trials, Randolph Matthews, MD, PhD, Department of Translational Pharmacology, Merck & Co, and colleagues explain that the dosages were selected to cover those that preclinical in vitro and in vivo data projected to be clinically efficacious, while maintaining adequate safety margins determined from the preclinical toxicology data.They found generally good tolerance of single doses up to 400mg or following multiple dosing up to 100mg once weekly for 3 weeks.

They confirmed a long intracellular half-life, which could be consistent with extended dosing schedules. As is the case with a number of HIV-1 antiretrovirals, preclinical studies with islatravir showed that the antiviral efficacy is related to the trough concentrations in peripheral blood mononuclear cells (PBMCs) rather than to trough concentrations in plasma. Consequently, the investigators reported that PBMC stabilization procedures were updated for study 2, to improve the accuracy of pharmacokinetic determinations.

The investigators report a "modest" accumulation of intracellular islatravir-TP (the metabolite, islatravir-triphosphate) with weekly administration, on the order of 1.5 fold, which they consider consistent with the extended half-life.Although concurrent food intake appeared to reduce islatravir plasma concentration, it did not affect intracellular levels of islatravir-TP. There was also no clinically meaningful effect of a high-fat meal found in study 1, although it was not evaluated in study 2.

"The studies described demonstrate that the safety and pharmacokinetic profile of islatravir are sufficient to continue clinical investigation," Matthews and colleagues report. "The potency of islatravir-TP coupled with its long intracellular half-life, suggest potential for a variety of dosing regimens and formulations, including longer-acting formulations for both the treatment and prevention of HIV-1 infection."

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