O3‐04‐04: Pharmacological intervention with the novel o‐glcnacase inhibitor ASN‐561 reduces pathological tau in transgenic mice

The occurrence of intraneuronal deposits of abnormally hyperphosphorylated tau protein as neurofibrillary tangles (NFTs) is a specific hallmark of tauopathies. These are currently untreatable diseases which include Alzheimer's disease and progressive supranuclear palsy. Since the progression of NFT pathology appears to correlate with the cognitive decline in tauopathies any pharmacological intervention aimed at NFTs is thought to have a substantial therapeutic potential. One such intervention with a small molecule approach is the inhibition of the O-GlcNAcase enzyme. O-GlcNAcase inhibition blocks the removal of O-linked N-acetylglucosamine (O-GlcNAc) moieties from serine and threonine residues in tau. This leads to an accumulation of O-GlcNAcylated tau protein that appears to be less prone to aggregation into toxic oligomers and NFTs. Despite the principal validation data with the tool inhibitor Thiamet G, to date no drug-like inhibitor of the O-GlcNAcase enzyme has yet been reported to affect the levels of pathological tau. The clinical development candidate O-GlcNAcase inhibitor ASN-561 was exploited in a preventative study in a P301S tau transgenic mouse model. After 3.5 months of repeated Q.D. dosing the study was terminated and both the levels of O-GlcNAcylated tau and various pathological forms of tau were quantified utilizing biochemical methods. Chronic exposure to the O-GlcNAcase inhibitor ASN-561 for 3.5 months did not manifest in any abnormalities with respect to mortality or body weight. A sustained pharmacodynamic response was detected by a >2-fold elevation of O-GlcNAc tau 24 hours post dose with a specific S400 O-GlcNAc tau immunoassay. To date a significant reduction in abnormally phosphorylated tau was observed in the cortex and the sarcosyl-insoluble fraction of the hippocampus by biochemical quantification. Further analyses including the immunohistochemistry and histochemistry of brain slices are currently on-going. The data provides the initial proof-of-concept that ASN-561 can affect the levels of pathological tau in a transgenic mouse model. The overall preclinical profile of this inhibitor combined with a recently developed target engagement biomarker supports further exploration in regulatory toxicity and safety pharmacology studies. Overall, ASN-561 has the potential to test the tau hypothesis in humans with a small molecule approach as early as 2016.