New NRTI MK-8591 (EFdA): weekly oral dosing and once-yearly slow-release dosing has potential for HIV treatment and PrEP
22 March 2016. Related: Conference reports, Antiretrovirals, CROI 23 (Retrovirus) 2016.
Simon Collins, HIV i-Base
One of the surprises at CROI 2016 was the first virological data from a new highly potent NRTI that in a slow-release formulation has the potential for annual dosing and that is undergoing research as both treatment and PrEP.
In an oral late-breaker, Jay Grobler from Merck presented results from a dose-ranging study in macaques to develop a model for phase 1 studies with MK-8591 (EFdA). 
Baseline SHIV viral load ranged from 6 to 8 log copies/mL and following single doses that ranged from 3.9 to 18.2 mg/kg viral load dropped by approximately 1.5 logs and was sustained for seven days.
PK data from a phase 1 multiple-dose study in HIV negative adults (using 10 mg, 30 mg and 100 mg) once-weekly for three weeks showed that with the 10 mg dose target intracellular target drug concentrations were exceeded for more than seven days.
A slightly cheeky slide was shown from the phase 1b study showing that EFdA produced more rapid viral suppressions compared to historical data for TDF and TAF.
Early data on a solid-state slow release parenteral injection formulation that has an option for removability, showed sustained release for more than 180 days in rat studies, with the potential for cover to be extended to a year.
The poster detailing the phase 1 study results in six HIV positive men reported a mean viral load reduction of 1.67 log (95%CI: 1.47 to 1.87) was seen at day 7, following a single 10 mg dose, after which ART was started. Baseline CD4 count was >400 cells/mm3 and viral load ranged from 10,000 to > 430,000 copies/mL. Although there were no serious safety concerns, there were six cases of headache. There was no detection of drug resistance. 
EFdA is active against wild-type and MDR variants of HIV-1 and HIV-2 (including with K65R) and has an EC50 in PBMCs of 0.2 nM and half life for the intracellular triphosphate in PBMCs of approximately 100 hours. It is modestly sensitive to M184V (3-5 fold) suggesting a higher dose might be appropriate given high potency and good safety data, although dose for development has not yet been selected. Preclinical studies have not shown concern for mitochondrial toxicity.
Previous reports about this compound have highlighted a similar structure to a flavour enhancement for soy sauce. Yamasa originally developed the compound before Merck acquired development rights in 2012.
The new NRTI from Merck has the potential to change everything dramatically for treatment and PrEP – with removable slow release once-yearly dosing.
This shows the real potential for pushing drug development over the next 5-10 years – and why advocacy for continued pipeline research is important.
Very early days but animal safety data has so far been good.
- Grobler J et al. Long-acting oral and parenteral dosing of MK-8591 for HIV treatment or prophylaxis
. 23rd CROI, 22-25 February 2016, Boston. Oral late breaker abstract 98.
- Friedman E et al. A single monotherapy dose of MK-8591, a novel NRTI, suppresses HIV for 10 days. 23rd CROI, 22-25 February 2016, Boston. Late breaker poster 437LB.
http://www.croiconference.org/sites/default/files/posters-2016/437LB.pdf (PDF poster)