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

GABA-A a5 PAM 的临床前和早期临床开发

基本信息

批准号：
10810466
负责人：
Sharon Rosenzweig-Lipson
金额：
$ 27.5万
依托单位：
AGENEBIO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2026-08-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10810466
关键词：
Acute Address Advanced Development Age Age-associated memory impairment Alzheimer&apos s Disease Alzheimer&apos s disease model Antiepileptic Agents Area Canis familiaris Caregivers Chemicals Chronic Clinical Clinical Research Coupled Dosage Forms Dose Elderly Formulation Goals Healthcare Systems Hippocampus Human In Vitro Levetiracetam Medial Memory Memory Loss Modeling Monkeys Neurons Oral Pathology Patients Performance Pharmaceutical Preparations Phase Process Program Development Rattus Research Rodent Role Safety Temporal Lobe Therapeutic Toxic effect Treatment Efficacy brain dysfunction clinical development dementia risk gamma-Aminobutyric Acid high risk improved in vivo manufacture mild cognitive impairment neuronal circuitry novel novel strategies patient population phase 1 study positive allosteric modulator pre-Investigational New Drug meeting pre-clinical preclinical study product development programs receptor safety study scale up therapeutic biomarker volunteer

项目摘要

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.

该 UO1 申请的总体目标是推进 BPN-27473 的开发，BPN-27473 是一种有效的、选择性的和口服活性 GABA-A α5 正变构调节剂 (PAM)，用于治疗轻度认知障碍阿尔茨海默病（AD 引起的 MCI）造成的损伤迄今为止，尚无治疗方法显示出显着且有效的效果。对 AD 患者的进展具有可靠的治疗效果，这使得该领域成为一个极其未满足的领域临床前 AD 模型和人类患者的大力支持，特别是在这个早期阶段。 AD 中，海马体中的神经元回路变得过度活跃，导致神经元病理学 AgeneBio 的 GABA-A α5 PAM 项目代表了一种解决这些问题的新方法。该患者群体的海马活动过度，是痴呆症的高危人群。最近的研究支持了减少海马过度活动对治疗有益的概念使用非典型抗癫痫左乙拉西坦的临床前和临床研究啮齿类动物的记忆障碍与遗忘性 MCI 患者的临床研究相关，对记忆的有益影响内侧颞叶/海马体和记忆表现的关键回路已被证明通过低剂量左乙拉西坦治疗可减少海马过度活动。 GABA-A α5 受体的定位及其控制强直抑制的作用使得 GABA-A α5 PAM 非常适合减少 AD 引起的 MCI 中过度的海马活动。 BPN-27473 已得到充分表征，是一种有效、高选择性和口服活性的 GABA-A α5 PAM BPN-27473 符合体外和体内发现标准，显示出良好的体内受体占有率和对与年龄相关的记忆丧失的大鼠（显示海马过度活跃的模型）进行的研究表明 BPN-27473 在急性和慢性给药后均可有效改善记忆能力。大鼠剂量范围研究表明，> 15 倍 MED 的剂量不会限制安全性或毒性合适的放大工艺已经能够制造大量材料。证明了。目前的提案将扩大 BPN-27473 生产的非 GMP 和 GMP 规模，以实现为完成大鼠和狗/猴子制剂的 IND 安全性研究提供足够的供应。药品开发将完成，以获得适合 I 期临床试验前研究的剂型。 FDA 将要求召开会议，并提交 1 期单剂量递增研究。在健康的老年志愿者中完成这些研究将使人们能够彻底了解。 BPN-27473 的安全性和耐受性及其进一步临床开发的实用性。