O1‐12‐05: Phase 1 Study in Healthy Volunteers of the O‐glcnacase Inhibitor Asn120290 as a Novel Therapy for Progressive Supranuclear Palsy and Related Tauopathies

In widely-utilized preclinical models, O-GlcNAcase enzyme inhibition has been demonstrated to reduce the accumulation of toxic neurofibrillary tangles consisting of abnormally hyperphosphorylated tau protein. O-GlcNAcase inhibitors therefore hold the promise for disease modification in many tau-driven neurodegenerative diseases, from orphan tauopathies to Alzheimer's disease. Preclinical proof-of-concept has previously been demonstrated in P301S tau transgenic mice treated for 3.5 months with ASN120290. Based on the supportive outcome of preclinical GLP toxicology and safety pharmacology studies, the orally bioavailable and highly brain penetrant O-GlcNAcase inhibitor ASN120290 has completed testing in a Phase 1 healthy volunteer study. ASN120290 was studied in a single-center, randomized, double-blind, placebo-controlled Phase 1 trial to evaluate its safety, tolerability and pharmacokinetic (PK) properties. This initial human trial of orally-administered ASN120290 consisted of 61 subjects enrolled into 3 parts: (1) in Part 1a, single ascending doses were administered to healthy young males (2) in Part 1b, single doses were administered to healthy elderly subjects under fasted and fed conditions (3) in Part 2, multiple ascending doses were administered BID to healthy elderly subjects over a period of 10 days. After completion of Part 2, a subset of healthy elderly subjects assigned to the ASN120290 arm underwent serial cerebrospinal fluid (CSF) PK sampling over 36 hours via an indwelling catheter. ASN120290 was safe and well-tolerated at single oral doses up to 1000 mg and multiple oral doses up to 500 mg BID. No dose-limiting toxicities were identified and no SAEs were reported. Most AEs were of mild severity and no subject discontinued due to an AE. Plasma PK was consistent and predictable after single and multiple doses. Overall exposures were comparable in the fasted and fed conditions, with a somewhat delayed Tmax and lower Cmax for fed subjects. CSF sampling confirmed predicted rapid and passive ASN120290 brain penetration, with CSF drug concentrations similar to free concentrations in plasma. ASN120290 at oral single and multiple daily doses up to 1000 mg in healthy young and elderly subjects demonstrates an excellent safety, tolerability and PK profile that is supportive of further clinical development in appropriate Phase 2 tauopathy patient populations.