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

摘要/摘要 该项目旨在通过靶向潜在的阿尔茨海默病(AD)来开发一种新的AD疾病修改化合物 突触丢失的机制。突触丢失与认知功能下降密切相关，最初由 淀粉样蛋白-β多肽低聚体聚集。可溶性淀粉样蛋白-β寡聚体与蛋白结合，从而与 MGluR5作为共受体，激活PTK2B(PYK2)和FYN激酶与Tau病理和 突触丢失。对啮齿动物的基因敲除研究表明，mGluR5的敲除可以防止疾病的发生， 我们的目标位于PTK2B的正上游，PTK2B在公元后的GWA中很受欢迎。这些特征提供了强有力的证据证明 MGluR5作为开发阿尔茨海默病新疗法的有前途的治疗靶点。 Allyx Treeutics已获得在神经退行性疾病中使用BMS-984923的独家许可证 来自布里斯托尔迈耶斯施贵宝和耶鲁大学。初步研究表明，这种小分子药物具有很强的疗效 多种临床前小鼠AD模型的分子治疗。药物治疗恢复突触密度，恢复 海马体活动，并将记忆能力恢复到正常水平。临床前开发已经 具有高度类似药物的特征，允许最近批准BMS-984923商业Ind用于 这是人类临床研究的第一次。总体目标是开发治疗疾病的口服药物 有效延缓、阻止或部分逆转轻度痴呆和MCI状态下的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.