BMS-984923 Non-Clinical Development to Support Phase 2 Trials

总结/摘要 该项目旨在通过靶向潜在的阿尔茨海默病（AD）， 突触丢失的机制。突触丧失与认知能力下降密切相关，最初由以下因素引发： 淀粉样β肽寡聚体蓄积。可溶性淀粉样蛋白-β寡聚体与朊病毒蛋白结合， mGluR 5作为共受体，并激活PTK 2B（Pyk 2）和Fyn激酶以与Tau病理学偶联， 突触丧失啮齿类动物的基因敲除研究表明，mGluR 5的敲除可预防疾病发作， 我们的目标正好位于PTK 2B的上游AD中的GWAS攻击这些特征有力地证明了 mGluR 5作为开发新型阿尔茨海默病治疗的有前途的治疗靶点。 Allyx Therapeutics已获得BMS-984923在神经退行性疾病中的独家使用许可 来自布里斯托迈耶斯施贵宝和耶鲁大学。初步研究表明，这种小的 分子治疗在多种临床前小鼠AD模型中的应用。药物治疗恢复突触密度， 海马活动，并将记忆力恢复到正常水平。临床前开发 特征为高度药物样特征，允许最近批准BMS-984923商业IND用于 首次开展人体临床研究。总体目标是开发改善疾病的口服药物 有效减缓、停止或部分逆转MCI状态和轻度痴呆中的AD进展。

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. 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.