Extended-Duration MK-8591-Eluting Implant as a Candidate for HIV Treatment and Prevention

Abstract

Regimen adherence remains a major hurdle to the success of daily oral drug regimens for the treatment and prevention of human immunodeficiency virus (HIV) infection. Long-acting drug formulations requiring less-frequent dosing offer an opportunity to improve adherence and allow for more forgiving options with regard to missed doses. The administration of long-acting formulations in a clinical setting enables health care providers to directly track adherence. MK-8591 (4'-ethynyl-2-fluoro-2'-deoxyadenosine [EFdA]) is an investigational nucleoside reverse transcriptase translocation inhibitor (NRTTI) drug candidate under investigation as part of a regimen for HIV treatment, with potential utility as a single agent for preexposure prophylaxis (PrEP). The active triphosphate of MK-8591 (MK-8591-TP) exhibits protracted intracellular persistence and, together with the potency of MK-8591, supports its consideration for extended-duration dosing. Toward this end, drug-eluting implant devices were designed to provide prolonged MK-8591 release and Implants, administered subcutaneously, were studied in rodents and nonhuman primates to establish MK-8591 pharmacokinetics and intracellular levels of MK-8591-TP. These data were evaluated against pharmacokinetic and pharmacodynamic models, as well as data generated in phase 1a (Ph1a) and Ph1b clinical studies with once-weekly oral administration of MK-8591. After a single administration in animals, MK-8591 implants achieved clinically relevant drug exposures and sustained drug release, with plasma levels maintained for greater than 6 months that correspond to efficacious MK-8591-TP levels, resulting in a 1.6-log reduction in viral load. Additional studies of MK-8591 implants for HIV treatment and prevention are warranted.

Meeting report: 32nd International Conference on Antiviral Research

“…Long-acting drug formulations requiring less-frequent dosing offer an opportunity to improve adherence, providing patients with a valuable alternative in treatment forgiveness and convenience. Antiretroviral drugs may be formulated for extended duration dosing (ExDD) options, leading to prolonged (> 6 months) dosing intervals (Barrett et al, 2018).…”

“…Further, it has a half-life in peripheral blood mononuclear cells (PBMCs) from HIV-1-infected subjects of 78.5-128 h, which renders is compatible with a variety of potential dosing regimens. Single-dose treatment with MK-8591 at doses as low as 0.5 mg leads to robust VL decline in treatment-naïve HIV-1-infected subjects (Barrett et al, 2018;Matthews et al, 2007). As a result of its exquisite potency, long-acting PK profile, and robust efficacy, MK-8591 is a candidate for ExDD formulations.…”

“…Drugs such as MK-8591 may be dispersed within polymers that exhibit controlled degradation (bioerodible and nonerodible) to generate monolithic matrix implants of dimensions suitable for subcutaneous administration. Implants are designed to achieve a broad range of drug release characteristics and durations, achieved through optimization of drug loading and polymer composition of the implants (Barrett et al, 2018). The presentation highlighted back-up medicinal chemistry efforts to MK-8591, novel nucleoside chemistry development, as well as optimization of implant formulations.…”

HIV Antiretroviral Pre‐Exposure Prophylaxis: Development Challenges and Pipeline Promise

“…Subcutaneously implanted devices, designed to very slowly release ARVs over months or years, would dramatically extend PrEP duration, avoid adherence challenges, and greatly reduce healthcare system interactions. Several groups have reservoir (TAF and CAB) and matrix (EFdA) implants in preclinical development, some with promise for yearly implants in humans . In particular, EFdA, a nucleoside reverse transcriptase translocation inhibitor, is very well suited for implantation with sub‐nM antiviral potency and longer intracellular triphosphate half‐life than even TFV‐DP.…”

Modern Human Immunodeficiency Virus Therapy: Progress and Prospects

“…The most advanced of these, containing the investigational antiretroviral MK‐8591 (4′‐ethynyl‐2‐fluoro‐2′‐deoxyadenosine), a potent nucleoside analog reverse transcriptase translocation inhibitor, is expected to be in early phase human trials in 2019 . The results of animal studies with this product suggest that a single 4′‐ethynyl‐2‐fluoro‐2′‐deoxyadenosine implant could deliver effective drug concentrations for 6–12 months or longer . Human trials are also proposed for an implant containing tenofovir alafenamide (TAF); this implant system can deliver protective intracellular concentrations of tenofovir for several weeks in laboratory animals .…”