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CROI 2016: Long-Acting MK-8591 Could Be Future Option for HIV Treatment and Prevention

Merck's MK-8591, an investigational antiretroviral agent that maintains drug levels that are able to inhibit HIV up to 6 months after dosing could represent a "paradigm shift" in HIV therapy and prophylaxis, according to research presented at the recent Conference on Retroviruses and Opportunistic Infections (CROI 2016) in Boston.

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Jay Grobler from Merck reported that a single oral dose of MK-8591 suppressed simian immunodeficiency virus (SIV) viral load in monkeys and was effective a week after dosing. The investigators also evaluated an oral dose of the drug in HIV-negative individuals, finding that cellular levels sufficient to inhibit HIV could be maintained over the long term. Results of preliminary research involving people with HIV were also encouraging. An injected formulation of the drug achieved excellent cellular levels over 6 months when administered to rodents.

The development of antiretroviral agents that require less frequent dosing have the potential to enhance adherence to both HIV treatment and the use of anti-HIV drugs as prevention, or PrEP.

MK-8591 is a nucleoside reverse transcriptase inhibitor (NRTI) in the early stages of development. The properties of the drug mean that it has protracted persistence in human peripheral blood mononuclear cells (PBMCs) and macrophages. Laboratory trials have shown that such cells were protected from infection with HIV, even in the absence of continued antiretroviral exposure.

In the study presented at CROI, SIV-infected rhesus macaques received weekly oral MK-8591 therapy, with doses ranging from 1.3 to 18.2 mg/kg. Plasma viral load was measured pre-dosing through day 42 post-dose. Concentrations of MK-8591 were also evaluated throughout this period.

The investigators used the results of the animal study to select a once-weekly oral dose for evaluation in HIV-negative people.

Baseline SIV viral load in the monkeys was between 10⁶ to 10⁸ copies/mL. After dosing with MK-8591, macaques with a viral load below 10⁸ copies/mL experienced an up to 2 log fall in viral load, with suppression sustained for at least 7 days. Concentrations of the investigational agent in PBMCs of 0.53 pmol/10⁶ and above were associated with maximal falls in viral load 1 week after dosing.

In the study involving HIV-negative individuals, doses of 10 mg were able to achieve optimal drug levels needed for prolonged viral suppression. The drug was well tolerated.

The investigators also presented data from an early clinical trial involving people with HIV. These showed that a single 10 mg oral dose resulted in a 1.6 log fall in viral load by days 7 to 10. Intracellular drug levels were good and there were no signs of resistance.

A long-acting injected formulation of MK-8591 provided continuous, extended drug release in rodents. Plasma levels were similar to those observed in monkeys and humans, with release of the drug exceeding 6 months.

The investigators believe their findings show the potential for weekly oral dosing of MK-8591.

MK-8591 oral and long-acting parenteral (injected) formulations with potential for 6 months or longer duration "would represent a potential paradigm shift as a single agent for the prevention of HIV infection or as a component of an extended dosing regimen for HIV treatment," concluded the researchers. "Ongoing studies suggest the potential to provide coverage for durations up to 1 year." 


4/6/16

Reference

J Grobler, E Friedman, SE Barrett, et al. Long-Acting Oral and Parenteral Dosing of MK-8591 for HIV Treatment or Prophylaxis
Jay Grobler. Conference on Retroviruses and Opportunistic Infections. Boston, February 22-25, 2016. Abstract 98.