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 并且最初由淀粉样蛋白β（Aβ）积累触发。我们已经描述了一种途径， 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 谷氨酸受体亚型5（mGluR 5）作为共受体，并激活PTK 2B（Pyk 2）和Fyn激酶 与Tau的病理和突触缺失有关阻断mGluR 5功能可挽救临床前AD 表型，使其成为一个有吸引力的药物靶标。然而，mGluR 5具有生理作用， 谷氨酸受体和完全抑制损害功能。因此，典型的拮抗剂具有 狭窄的治疗窗口 我们已经鉴定了一种高效的、口服生物可利用的mGluR 5配体，其不改变基础或 谷氨酸活性，但阻断Aβo/PrPC对mGluR 5的活化。这个化合物被认为是一个无声的 mGluR 5的变构调节剂或SAM，意味着对谷氨酸“沉默”，而 Aβo/PrPC拮抗。初步研究表明，该SAM具有稳健的疗效 用于多种临床前小鼠AD表型的化合物作为治疗恢复突触密度， 恢复长时程增强并恢复记忆性能。临床前研究表明， 毒性和高耐受性。 总体目标是开发疾病缓解口服疗法，有效减缓，停止或部分缓解 逆转轻度认知障碍（MCI）和轻度痴呆阶段的AD进展， 将大大改善美国近600万患有AD的人的生活 以及世界范围内更多的人，对他们来说，不存在改善疾病的药物治疗。 为了评价BMS-9884923的安全性和耐受性并检测其作用机制，我们 我建议进行1b期试验，并结合使用新型突触密度体内成像的初步研究 用石油成像靶点是突触囊泡糖蛋白2（SV 2），一种重要的突触蛋白。 囊泡膜蛋白，其亚型之一，SV 2A，在几乎所有的细胞中普遍表达。 突触我们最近开发了[C]UCB-J，一种用于体内定量SV 2A成像的PET示踪剂。我们 对遗忘型MCI和AD所致痴呆的研究表明， 在内侧颞叶最为明显因此，[UUC]UCB-J PET可用作体内 AD中突触密度损失和再生长的生物标志物。 我们的长期目标是开发有效的AD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，耐受性良好，并且突触 密度PET将是对靶向突触的治疗反应的早期标记物， 修复在AD受试者中完成本研究将对1. 评估药物在AD临床试验中的进展，2.通知的设计和方法， BMS-984923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.