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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：
10686404
负责人：
Sharon Rosenzweig-Lipson
金额：
$ 110万
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 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686404
关键词：
Acute Address Adult Advanced Development Age Age-associated memory impairment Alzheimer&apos s Disease Alzheimer&apos s disease model Amendment Antiepileptic Agents Area Canis familiaris Caregivers Chemicals Chronic Clinical Clinical Protocols Clinical Research Coupled Cyclic GMP Dosage Forms Dose Dose Limiting Dryness Elderly Formulation Goals Half-Life Healthcare Systems Hippocampus Human In Vitro Levetiracetam Medial Memory Memory Loss Methods Modeling Monitor Monkeys Neurons Oral Pathology Patients Performance Pharmaceutical Preparations Pharmacology Phase Phase I Clinical Trials Preparation Process Program Development Protocols documentation Published Comment Rattus Research Rodent Role Safety Temporal Lobe Therapeutic Toxic effect Toxicology 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UO 1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阳性别构调节剂（PAM），用于治疗轻度认知障碍阿尔茨海默氏病（AD导致的MCI）。到目前为止，没有治疗显示出显著的，对AD患者的进展具有可靠的治疗效果，使其成为极高未满足的领域需要的有来自临床前AD模型和人类患者的强有力的支持，特别是在这个早期阶段在AD中，海马中的神经元回路变得过度活跃，从而导致神经元病理学和脑功能障碍AgeneBio的GABA-A α5 PAM计划代表了一种解决在痴呆症高危人群中海马活动过度。最近的研究支持了减少海马过度活跃在治疗上是有益的这一概念。使用非典型抗癫痫药物左乙拉西坦的临床前和临床研究。从对年龄的研究- 与遗忘型MCI患者的临床研究相关的啮齿动物记忆障碍，内侧颞叶/海马中的关键回路和记忆性能已被证明通过低剂量的左乙拉西坦治疗来减少海马体的过度活跃。强大的海马 GABA-A α5受体的定位及其控制紧张性抑制的作用使GABA-A α5 PAM 非常适合于减少AD引起的MCI中的过度海马活动。 BPN-27473已被充分表征，是一种强效、高选择性和口服活性的GABA-A α5 PAM 符合体外和体内发现标准。BPN-27473显示出良好的体内受体结合率，对与年龄相关的记忆丧失大鼠的研究（显示海马过度活跃的模型）表明， BPN-27473在急性和慢性给药后均可有效改善记忆表现。一大鼠剂量范围探索研究表明，> 15倍MED的剂量没有限制安全性或毒性负债一种能够制造大量材料的合适的放大方法已经被提出。演示。当前提案将扩大BPN-27473生产的非GMP和GMP规模，用于完成大鼠和犬/猴IND启用安全性研究的充足供应。制定和将完成药物产品开发，以获得适合I期研究的剂型。IND前 FDA将要求召开会议，并提交IND。一项I期单次给药剂量递增研究在健康的老年志愿者将完成。这些研究将使我们能够全面了解 BPN-27473的安全性和耐受性及其用于进一步临床开发的效用。