Clinical evaluation of BMS-984923 metabolism.

SUMMARY/ABSTRACT This project seeks to develop a novel disease-modifying compound for AD (AD) by targeting the underlying mechanism of synapse loss. Synapse loss is tightly correlated with cognitive decline and is triggered initially by amyloid-β peptide oligomer accumulation. Soluble amyloid-β oligomers bind to Prion Protein, thereby engaging mGluR5 as a co-receptor, and activating PTK2B (Pyk2) and Fyn kinases to couple with Tau pathology and synapse loss. Genetic knockout studies in rodents have shown that knockout of mGluR5 prevents disease onset, and our target sits directly upstream of PTK2B, a GWAS hit in AD. These features provide strong evidence of mGluR5 as a promising therapeutic target for developing novel Alzheimer’s treatments. Allyx Therapeutics has obtained an exclusive license for use of BMS-984923 in neurodegenerative diseases from Bristol Meyers Squibb and Yale University. Preliminary studies demonstrate robust efficacy of this small molecule treatment in multiple preclinical mouse AD models. Drug treatment recovers synapse density, restores hippocampal activity, and returns memory performance to normal levels. Pre-clinical development has characterized a highly drug-like profile allowing for the recent approval of the BMS-984923 commercial IND for the initiation of first time in human clinical studies. Phase 1 clinical studies demonstrate a robust safety profile and complete receptor occupancy at low doses indicating a favorable drug profile for advancement into Phase 2 proof of concept studies. The overall goal is to develop disease-modifying oral drug effective to slow, halt or partially reverse AD progression both in the MCI state and in mild dementia.