EARLY CLINICAL RESULTS AND PRECLINICAL VALIDATION OF THE O-GLCNACASE (OGA) INHIBITOR MK-8719 AS A NOVEL THERAPEUTIC FOR THE TREATMENT OF TAUOPATHIES

Abstract

MK-8719 is a selective inhibitor of the O-GlcNAcase (OGA) enzyme that is currently in Phase 1 clinical trials for the treatment of Progressive Supranuclear Palsy (PSP). Here we summarize the preclinical validation data for MK-8719 generated in Tg4510 transgenic mice as well as human tolerability and target engagement (PET) data for MK-8719 following single dose administration. Evaluation of the pharmacodynamic activity and efficacy of MK-8719 was conducted in Tg4510 transgenic mice that overexpress human tau with P301L mutation. The effects of MK-8719 on total protein O-GlcNAcylation and the accumulation of pathological species of tau were determined by immunoassay. The influence of MK-8719 on brain atrophy of Tg4510 mice was evaluated by volumetric MRI and the formation of neurofibrillary tangles was assessed using immunohistochemistry. Safety and tolerability of single doses of MK-8719 between 5 and 1200 mg were evaluated in healthy volunteers (n=16) using an alternating-panel single ascending dose design. MK-8719 target engagement in the brain was evaluated in a separate Phase 1 study using PET with [18F]MK-8553, a radiolabeled tracer of a novel small molecule inhibitor of the OGA enzyme. In vitro studies demonstrated that MK-8719 is a competitive reversible inhibitor of the human OGA enzyme with comparable activity in rat, dog, and mouse. Subchronic administration of MK-8719 significantly increased O-protein levels in brain tissue and reduced the formation of pathological tau species in Tg4510 mouse brain. Reduction of pathological tau accumulation in Tg4510 mice was accompanied by reductions in neurodegeneration, including reduced inflammatory marker expression, attenuation of brain weight loss, and attenuation of forebrain volume loss. In a Phase 1 study, single doses up to 1200 mg were generally well tolerated. No laboratory, ECG, or vital sign adverse experiences were observed. PET studies demonstrated that dosing of MK-8719 causes a decrease of [18F]MK-8553 binding compared to baseline, indicating target engagement of the OGA enzyme in the brain. Preclinical data demonstrate that MK-8719 significantly reduced pathological tau and neurodegeneration in Tg4510 mice. Phase 1 clinical findings support further clinical development of MK-8719 and investigation of safety and efficacy in PSP patients.