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）中的脑突触损失与认知症状密切相关 最初是由β淀粉样蛋白（Aβ）积累触发的。我们已经描述了一条途径，其中 可溶性 Aβ 寡聚体 (Aβo) 与细胞朊病毒蛋白 (PRPC) 结合，从而参与代谢型 谷氨酸受体亚型 5 (mGluR5) 作为辅助受体，并激活 PTK2B (Pyk2) 和 Fyn 激酶 与 Tau 蛋白病理学和突触损失相结合。中断 mGluR5 功能可挽救临床前 AD 表型，使其成为有吸引力的药物靶点。然而，mGluR5 具有作为 谷氨酸受体和完全抑制会损害功能。因此，典型的拮抗剂具有 治疗窗窄。 我们已经鉴定出一种高效、口服生物可利用的 mGluR5 配体，它不会改变基础或 谷氨酸活性，但阻断 mGluR5 的 Aβo/PrPC 激活。该化合物被认为是沉默的 mGluR5 的变构调节剂（SAM），意思是谷氨酸“沉默”，而 与 Aβo/PrPC 呈拮抗作用。初步研究表明该 SAM 具有强大的功效 当治疗恢复突触密度时，针对多种临床前小鼠 AD 表型的化合物， 恢复长期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具有毒性和高耐受性。 总体目标是开发有效减缓、停止或部分缓解疾病的口服疗法 在轻度认知障碍 (MCI) 和轻度痴呆阶段逆转 AD 进展， 将大幅改善美国近 600 万 AD 患者的生活 世界各地还有许多人，对他们来说尚无缓解疾病的药物治疗方法。 为了评估 BMS-9884923 的安全性和耐受性并测试其作用机制，我们 提议进行 1b 期试验，并结合使用新颖的突触密度体内成像进行初步研究 与 PET。成像目标是突触小泡糖蛋白 2 (SV2)，一种重要的突触 囊泡膜蛋白，其亚型之一 SV2A 几乎在所有细胞中普遍表达 突触。我们最近开发了 [11C]UCB-J，一种用于体内定量 SV2A 成像的 PET 示踪剂。我们的 对遗忘性 MCI 和 AD 引起的痴呆的研究表明，突触密度普遍降低， 内侧颞叶最为明显。因此，[11C]UCB-J PET 可用作体内 AD 中突触密度损失和再生的生物标志物。 我们的长期目标是开发 AD 的有效治疗方法和治疗的生物标志物 功效。 我们的中心假设是 BMS-984923 将是安全的且耐受性良好，并且突触 密度 PET 将成为针对突触治疗的治疗反应的早期标志 恢复。完成这项研究将对 AD 参与者产生重大影响 1。 评估药物在 AD 临床试验中的进展，2. 告知试验的设计和方法 随后的 BMS-984923 试验和 3. 告知突触密度 PET 生物标志物在 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.