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Selected Presentations from CROI 2018
Multiple Low Doses of Nucleoside MK-8591 Strong in Healthy Volunteers
25th Conference on Retroviruses and Opportunistic Infections (CROI), March 4-7, 2018, Boston
Mark Mascolini

Once-daily doses of the nucleoside MK-8591 as low as 0.25 mg appear able to suppress HIV replication in humans, according to results of a study in healthy volunteers [1]. A single 0.25-mg dose yielded concentrations that exceed the 50% effective concentration (EC50) of this experimental antiretroviral, but it took 28 for the active form of the drug to reach steady-state concentrations in peripheral blood mononuclear cells (PBMCs).

MK-8591 (EFdA) inhibits HIV reverse transcriptase through multiple mechanisms [2]. Merck, developer of the novel agent, calls it a nucleoside reverse transcriptase translocation inhibitor (NRTTI). As preexposure prophylaxis (PrEP), oral doses of MK-8591 shield monkeys from rectal or vaginal infection with simian HIV (SHIV) [3,4].

Merck is also studying MK-8591 as a long-acting agent for treatment of chronic HIV infection [5]. Previous work showed that MK-8591-triphosphate (MK-8591-TP), the active metabolized form of the compound, has a half-life of 78 to 128 hours in human PBMCs. In antiretroviral-naive people with HIV, single oral doses ranging from 0.5 to 30 mg lowered viral load 10-fold or more for 7 to 10 days [6].

The new double-blind placebo-controlled study explored pharmacokinetics of MK-8591 in healthy volunteers. In 3 groups of 12 adult volunteers, 9 people took once-daily MK-8591 and 3 took placebo. MK-8591 doses were 5 mg for 6 weeks, 0.75 mg for 4 weeks, or 0.25 mg for 4 weeks. All volunteers gave blood samples to measure MK-8591 levels in plasma and MK-8591-TP levels in PBMCs. A day after the final dose, asubset of participants had biopsies for vaginal and rectal tissue sampling.

The volunteers tolerated MK-8591 well. There were 4 drug-related adverse events in this brief study. All were mild or moderate and all resolved.

In the 24 hours after the first 0.25-mg dose of the new agent, MK-8591-TP concentrations in PBMCs exceeded the EC50 of the compound (0.05 pmol/million cells). The two higher doses also exceeded that target within 24 hours. After 2 to 3 weeks of dosing, PBMCs had average MK-8591-TP levels above 1.0 pmol/million cells, a concentration seen with weekly dosing of 10 mg. MK-8591-TP reached steady state in PBMCs by day 28.

Steady-state levels of MK-8591-TP in vaginal and rectal tissue compared with levels reported for tenofovir diphosphate in rectal tissue after single doses of tenofovir/emtricitabine. The investigators believe MK-8591 reached tissue concentrations "likely to be efficacious."

The Merck team proposed that "MK-8591 would be expected to lead to HIV suppression after multiple daily doses as low as 0.25 mg."

A phase 2 trial, DRIVE2Simplify (NCT03272347), partners MK-8591 with the nonnucleoside doravirine and the nucleoside lamivudine (3TC).

1. Matthews RP, Rudd DJ, Levine V, et al. Multiple daily doses of MK-8591 as low as 0 25 mg are expected to suppress HIV. 25th Conference on Retroviruses and Opportunistic Infections (CROI). March 4-7, 2018. Boston. Abstract 22.
2. Michailidis E, Huber AD, Ryan EM, et al. 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) inhibits HIV-1 reverse transcriptase with multiple mechanisms. J Biol Chem. 2014;289:24533-24548.
3. Markowitz M, Gettie A, St. Bernard L, et al.  Weekly oral MK-8591 protects male rhesus macaques against repeated low dose intrarectal challenge with SHIVC109P3. 9th IAS Conference on HIV Science (IAS 2017), July 23-26, 2017, Paris. Abstract MOAX0203LB. http://www.natap.org/2017/IAS/IAS_10.htm
4. Markowitz M, Gettie A, St. Bernard L, et al. Low dose MK-8591 protects rhesus macaques against rectal SHIV infection. 25th Conference on Retroviruses and Opportunistic Infections (CROI). March 4-7, 2018. Boston. Abstract 89LB.
5. Jacobson JM, Flexner CW. Universal antiretroviral regimens: thinking beyond one-pill-once-a-day. Curr Opin HIV AIDS. 2017;12:343-350.
6. Matthews RP, Schurmann D, Rudd D, et al. Single doses as low as 0.5 mg of the novel NRTI MK-8591 suppress HIV for at least seven days. 9th IAS Conference on HIV Science. July 23-26, 2017. Paris. http://www.natap.org/2017/IAS/IAS_36.htm