P4‐036: Pharmacokinetics and Pharmacodynamics to Support Clinical Studies of MK‐8719: an O‐Glcnacase Inhibitor for Progressive Supranuclear Palsy

MK-8719 is a selective and potent small molecule inhibitor of the O-GlcNAcase (OGA) enzyme in early clinical trials for the treatment for Progressive Supranuclear Palsy (PSP). This presentation highlights the pharmacokinetic-pharmacodynamic (PK/PD) aspects of MK-8719 to support first-in-human trials. Pharmacokinetics of MK-8719 were studied in preclinical species (mice, rats, dogs and monkeys) following intravenous (1 to 2 mg/kg) and oral (3 to 10 mg/kg) administration. Additional data on plasma/brain PK and retention of O-GlcNAc residues on protein extracts (O-protein) in peripheral blood mononuclear cells (PBMCs) and brain were collected in rats and mice. Markers of pathological tau and brain volume were evaluated at doses of 10 to 100 mg/kg in the Tg4510 transgenic mouse model that overexpresses a mutant form of tau. A physiologically-based pharmacokinetic model (PBPK) was developed to predict PK properties of MK-8719 in humans and guide dosing in the clinic. In a Phase I safety and tolerability study, pharmacokinetics and pharmacodynamics were evaluated following administration of single ascending oral doses between 5 and 1200 mg to healthy volunteers (n=16). OGA inhibition was evaluated by measuring the O-protein from PBMCs. MK-8719 exhibited moderate to high systemic clearance in preclinical species and moderate to large volume of distribution and high oral bioavailability. MK-8719 administration significantly increased O-protein levels in PBMCs (in rats) and brain tissue (in rats and mice) that correlated with efficacy endpoints in the Tg4510 transgenic mice. In the Phase I study in healthy volunteers, single doses up to 1200 mg were generally well tolerated. Plasma exposure increased in a dose proportional manner between 5 and 600 mg. MK-8719 administration elicited PBMC O-protein increases in a dose-dependent manner, consistent with preclinical observations. The PK in humans was well predicted based on the PBPK model. The preclinical and clinical data suggest that MK-8719 is a promising molecule to test the hypothesis that OGA inhibition is a viable therapy for PSP. A model-informed strategy can be employed to understand the relationship amongst plasma drug concentration, brain exposure, and brain and PBMC O-protein fold changes.