A Phase 1b Multiple Ascending Dose Study of the Safety and Tolerability of BMS-984923 in Alzheimer's Disease

阿尔茨海默病(AD)的脑突触丢失与认知症状密切相关 最初由淀粉样β蛋白(Aβ)积累触发。我们已经描述了一种途径，其中 可溶性Aβ寡聚体(Aβo)与细胞内的PrPC结合，从而促进新陈代谢 谷氨酸受体亚型5(MGluR5)作为辅助受体，激活PTK2B(PYK2)和FYN激酶 结合Tau病理和突触丢失。阻断mGluR5功能挽救临床前AD 表型，使其成为有吸引力的药物靶标。然而，mGluR5具有生理作用，即 谷氨酸受体和完全抑制会损害功能。因此，典型的对手有一个 治疗窗口狭窄。 我们已经确定了一种高度有效的口服生物利用的mGluR5配体，它不会改变基础或 谷氨酸活性，但阻断Aβo/PrPC激活mGluR5。这个化合物被认为是沉默的 变构调节剂，或SAM，用于mGluR5，意思是关于谷氨酸的“沉默的”，而 关于Aβo/PrPc的拮抗。初步研究表明这种SAM具有强大的疗效 治疗多种临床前小鼠AD表型的化合物恢复突触密度， 恢复长时程增强并恢复记忆性能。临床前研究表明低 在建议的治疗剂量下毒性和高耐受性。 总体目标是开发有效延缓、停止或部分缓解疾病的口服疗法。 逆转轻度认知障碍(MCI)和轻度痴呆阶段的AD进展，这 将大大改善美国近600万阿尔茨海默病患者的生活 以及全世界更多的人，对他们来说，没有治疗疾病的药物疗法。 为了评估BMS-9884923的安全性和耐受性，并测试其作用机制，我们 提出一项1b期试验和一项使用新的突触密度体内成像的先导研究 用PET。成像靶点是突触囊泡糖蛋白2(Sv2)，这是一种重要的突触 囊泡膜蛋白及其亚型之一SV2a在几乎所有的 突触。我们最近开发了一种用于体内SV2A定量成像的PET示踪剂[？C]UCB-J。我们的 对遗忘型MCI和AD所致痴呆的研究表明，突触密度普遍降低， 最明显的部位是内侧颞叶。因此，UCB-J PET可以作为体内的 阿尔茨海默病突触密度丢失和再生的生物标志物。 我们的长期目标是开发一种治疗AD的有效方法和一种治疗的生物标记物 功效。 我们的中心假设是BMS-984923将是安全和耐受性良好的，并且突触 密度正电子发射计算机断层扫描将成为针对突触的治疗反应的早期标志 修复。这项研究的完成将对AD参与者产生重大影响。 在AD临床试验中评估一种药物的进步，2.通知设计和方法 随后使用bms-984923和3.告知突触密度正电子发射计算机断层扫描生物标记物在 随后的临床试验。

Brain synapse loss in Alzheimer’s disease (AD) has been tightly correlated with cognitive symptoms and is triggered initially by amyloid beta (Aβ) accumulation. We have described a pathway in which soluble Aβ oligomers (Aβo) bind to cellular prion protein (PRPC), thereby engaging metabotropic glutamate receptor subtype 5 (mGluR5) as a co-receptor, and activating PTK2B (Pyk2) and Fyn kinases to couple with Tau pathology and synapse loss. Interrupting mGluR5 function rescues preclinical AD phenotypes, making it an attractive drug target. However, mGluR5 has a physiological role as a glutamate receptor and full inhibition impairs function. Consequently, typical antagonists have a narrow therapeutic window. We have identified a highly potent, orally bioavailable mGluR5 ligand that does not alter basal or glutamate activity, but blocks Aβo/PrPC activation of mGluR5. This compound is considered a silent allosteric modulator, or SAM, for mGluR5, meaning "silent" with regard to glutamate, while antagonistic with regard to Aβo/PrPC. Preliminary studies demonstrate robust efficacy of this SAM compound for multiple preclinical mouse AD phenotypes as treatment recovers synapse density, restores long term potentiation and returns memory performance. Preclinical studies indicate low toxicity and high tolerability at proposed therapeutic doses. The overall goal is to develop disease-modifying oral therapy effective to slow, halt or partially reverse AD progression both in the mild cognitive impairment (MCI) and mild dementia stages, which would substantially improve the lives of the nearly 6 million people in the US suffering from AD and many more worldwide, for whom no disease-modifying pharmacological treatments exist. To evaluate the safety and tolerability of BMS-9884923 and to test its mechanism of action, we propose a Phase 1b trial coupled with a pilot study using novel in vivo imaging of synaptic density with PET. The imaging target is synaptic vesicle glycoprotein 2 (SV2), an essential synaptic vesicle membrane protein, with one of its isoforms, SV2A, ubiquitously expressed in virtually all synapses. We recently developed [¹¹C]UCB-J, a PET tracer for quantitative SV2A imaging in vivo. Our studies in amnestic MCI and dementia due to AD show widespread reductions of synaptic density that are most pronounced in the medial temporal lobe. Thus, [¹¹C]UCB-J PET can be used as an in vivo biomarker of synaptic density loss and regrowth in AD. Our long-term goals are to develop an effective treatment for AD and a biomarker of treatment efficacy. Our central hypotheses are that BMS-984923 will be safe and well tolerated, and that synaptic density PET will be an early marker of therapeutic response to treatments that target synapse restoration. Completion of this study in AD participants will have a significant impact by 1. evaluating a drug for advancement in AD clinical trials, 2. informing the design and methods of the subsequent trials with BMS-984923 and 3. informing the use of synaptic density PET biomarkers in subsequent clinical trials.