Antiretroviral Agent Expected to Suppress HIV After Multiple Daily Doses as Low as 0.25 mg


All doses of MK-8591 were generally well-tolerated with a limited number of reported mild/moderate adverse events.

At the 25th Conference on Retroviruses and Opportunistic Infections (CROI), Randolph P. Matthews, MD, PhD, of Merck Pharmaceuticals, presented data on a “first of its kind,” investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI), called MK-8591, which is in development for the treatment of HIV-1 infection.

MK-8591 is a highly-potent long-acting antiretroviral agent,” Dr. Matthews said. “It’s an NRTTI with a novel mechanism of action, working by both immediate and delayed chain termination. The antiviral activity is also quite potent in macaque models, in the range of about 0.2 and 0.4 pmol/106 cells. It also has a very long half-life in both pre-clinical and early clinical studies with the triphosphate having a half-life of about 50 hours in macaque, and in early clinical studies, of about 120 hours or so in healthy adults.”

In the oral abstract session, Dr. Matthews shared that because of MK-8591’s potency and long half-life, it can be thought of as an antiretroviral that is administered daily with coverage for occasional missed doses. Furthermore, an NNRTI has been selected as a potential partner agent for MK-8591, doravirine, because of data yielded from 2 phase 3 trials which proved it to be efficacious, well-tolerated, and having a low potential for drug-drug interactions. The combination of doravirine and MK-8591 is currently under assessment in a phase 2 trial.

The investigators selected the different doses for the trial based on early clinical studies of MK-8591. “We examined pharmacokinetics (PKs) and general tolerability of daily dosing in healthy adults to prepare for this longer-term dosing in the HIV-positive participants in the phase 2 trial,” Dr. Matthews said. “We used this to compare it to the modeling for the lowest potentially efficacious dose.”

For the double-blind, placebo-controlled, 3-panel trial, healthy participants were given a daily placebo or MK-8591 at 5 mg for 6 weeks, 0.25 mg for 4 weeks, or 0.75 mg for 4 weeks (12 active and 4 placebo in each panel). The investigators also obtained rectal and vaginal tissue samples for PKs on the day after the final dose; however, this was optional, and as such, not all participants agreed to this.

MK-8591 was found to be well-tolerated; it demonstrated PKs similar to what was predicted by Dr. Matthews and his team. He reported that 17 of the participants had adverse events (AEs), 4 of which were considered drug-related. However, there was “no clear relation to dose-level or treatment duration of any of these AEs,” he noted. Furthermore, all the AEs ranged from mild to moderate in severity and all were resolved at the study completion. In addition, he mentioned only 1 serious AE, which was 1 participant who had bleeding post-rectal biopsy.

“On day 1, the PK was pretty much exactly as predicted with a 0.25 mg dose getting above the .05 pom/106 cell threshold by 4 hours and remaining that way over the first 24 hours,” Dr. Matthews explained.

Over the longer-term, the triphosphate PK was also as expected, showing the steady state of MK-8591 in peripheral blood mononuclear cells (PBMCs) being reached by day 28, which was approximately dose proportional. “We had about a 10-fold accumulation of the triphosphate in PBMCs and the levels were maintained after cessation of dosing for about 30 days or so, even at the lowest dose,” he added.

More males agreed to the rectal/vaginal tissue biopsy than females. The limited results suggested that the triphosphate levels were, in fact, present at levels considered to be efficacious.

“In summary, multiple daily dosing of MK-8591 in healthy adults is generally well-tolerated up to 5 mg for 6 weeks,” Dr. Matthews concluded. “The triphosphate PBMC levels were above the level projected for efficacy after a single dose of 0.25 mg, and the triphosphate levels in rectal and vaginal tissue in a limited analysis do appear to be above the level projected for efficacy at steady state.”

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