Preclinical and early clinical development of a GABA-A a5 PAM

这个UO1应用的总体目标是推进BPN-27473的开发，它是一种有效的、选择性的 口服GABA-Aα5阳性变构调节剂治疗轻度认知障碍 阿尔茨海默病造成的损害(阿尔茨海默病引起的MCI)。到目前为止，还没有治疗显示出显著的和 对阿尔茨海默病患者进展的可靠治疗效果使这一领域成为极高的未被满足的领域 需要。临床前AD模型和人类患者的大力支持，特别是在这个早期阶段 阿尔茨海默病，海马区的神经元回路变得过度活跃，导致神经元病理 和大脑功能障碍。Agene Bio的GABA-Aα5 PAM计划代表了一种新的方法来解决 患痴呆症的高危人群中，海马体活动过度。 减少海马区过度活动在治疗上是有益的这一概念最近得到了支持 使用非典型抗癫痫药左乙拉西坦的临床前和临床研究。从对年龄的研究- 遗忘型MCI患者与啮齿动物记忆障碍相关的临床研究 内侧颞叶/海马区的关键回路和记忆表现已被证明 通过低剂量的左乙拉西坦治疗来减少海马区的过度活动。健壮的海马体 GABA-Aα5受体的定位及其控制紧张性抑制的作用使GABA-Aα5 PAM 非常适合于减少AD引起的MCI中海马区的过度活动。 BPN-27473已被很好地表征，是一种高效、高选择性和口服活性的GABA-Aα5 PAM 这符合体外和体内发现的标准。BPN-27473在体内显示良好的受体占有率和 对与年龄相关的记忆丧失的大鼠(一种显示海马区过度活动的模型)的研究表明 BPN-27473在急性和慢性给药后都能有效地改善记忆表现。一个 大鼠剂量范围发现研究表明，剂量是MED的15倍没有有限的安全性或毒性 负债。一种能够制造大量材料的适当的放大工艺已经被 演示了。 目前的提案将扩大BPN-27473生产的非GMP和GMP规模，以实现 为完成对大鼠和狗/猴子的安全研究提供了足够的供应品。配方和 药物产品开发将完成，以拥有适合第一阶段研究的剂型。A前IND 将要求FDA召开会议，并提交IND。一期单次递增剂量研究 在健康的老年志愿者中将完成。这些研究将使我们能够彻底了解 BPN-27473的安全性和耐受性及其在进一步临床开发中的应用。

The overall objective of this UO1 application is to advance the development of BPN-27473, a potent, selective and orally active GABA-A α5 Positive Allosteric Modulator (PAM) for the treatment of Mild Cognitive Impairment due to Alzheimer’s Disease (MCI due to AD). As yet, no treatment has shown significant and reliable therapeutic efficacy on the progression of AD in patients making this an area of extremely high unmet need. There is strong support from preclinical AD models and human patients, particularly in this early stage of AD, that neuronal circuits in the hippocampus become excessively active contributing to neuronal pathology and brain dysfunction. AgeneBio’s GABA-A α5 PAM program represents a novel approach to addressing the excess hippocampal activity in this patient population at high risk for dementia. The concept that reduction of hippocampal overactivity is therapeutically beneficial is supported by recent preclinical and clinical studies using the atypical antiepileptic levetiracetam. Ranging from research on age- associated memory impairment in rodents to clinical studies in patients with amnestic MCI, beneficial effects on key circuits in the medial temporal lobe/hippocampus and on memory performance have been demonstrated by treatment at low doses of levetiracetam that reduce hippocampal overactivity. The strong hippocampal localization of GABA-A α5 receptors coupled with its role to control tonic inhibition make GABA-A α5 PAMs well suited to reduce the excess hippocampal activity in MCI due to AD. BPN-27473 has been well characterized and is a potent, highly selective and orally active GABA-A α5 PAM that meets discovery in vitro and in vivo criteria. BPN-27473 shows good in vivo receptor occupancy and studies in rats with age-associated memory loss (a model which shows hippocampal overactivity) demonstrate that BPN-27473 is effective on improving memory performance after both acute and chronic administration. A rat dose-range finding study has shown that doses > 15-fold the MED do not have limiting safety or toxicity liabilities. A suitable scaleup process to enable manufacture large quantities of material has been demonstrated. The current proposal will expand both non-GMP and GMP scale up of BPN-27473 manufacture to enable sufficient supplies for the completion IND-enabling safety studies in rats and dogs/monkeys. Formulation and drug product development will be completed to have a suitable dosage form for Phase I studies. A pre-IND meeting will be requested from the FDA and the IND will be submitted. A Phase 1 single ascending dose study in healthy elderly volunteers will be completed. These studies will enable a thorough understanding of the safety and tolerability of BPN-27473 and its utility for further clinical development.