Development of a stress kinase inhibitor therapeutic candidate for Alzheimer's Disease and related dementia

开发治疗阿尔茨海默病和相关痴呆症的应激激酶抑制剂候选药物

基本信息

批准号：
10394169
负责人：
LAWRENCE S HONIG
金额：
$ 117.52万
依托单位：
NEUROKINE THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394169
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amyloid Arts Bioavailable Brain COVID-19 pandemic Clinical Clinical Research Clinical Treatment Development Disease Drug Exposure Drug Kinetics Elements Exhibits Foundations Functional disorder Future Hand Health Investments Monitor Neuroglia Neurons Oral Outcome Pathway interactions Pharmaceutical Preparations Pharmacology Pharmacy facility Phase Placebos Process Protein-Serine-Threonine Kinases Randomized Research Safety Site Small Business Innovation Research Grant Synapses Testing Therapeutic Therapeutic Intervention Universities base capsule clinical development clinical research site commercialization experience kinase inhibitor molecular drug target nervous system disorder neuroinflammation novel novel strategies pre-clinical programs recruit research clinical testing response biomarker stress kinase targeted treatment therapeutic candidate

项目摘要

There is an urgent need for disease modifying therapeutic approaches to Alzheimer’s disease, a major health crisis that lacks disease modifying therapies. Neurokine Therapeutics (NKT) has a unique phase 2 ready clinical asset, MW01-18-150SRM (= MW150), that represents a paradigm shift from the field’s dominant focus on amyloid pathway targeted therapeutic candidates. MW150 has a unique portfolio of target recognition and engagement, preclinical and clinical safety, and orally bioavailable drug exposure. The portfolio provides rational explanations for some of the off-target effects, adverse pharmacology, and clinical challenges encountered with prior art in the same therapeutic class, only one of which exhibited brain exposure. Therefore, NKT seeks to rapidly fill a key gap for clinical development and future commercialization through leveraging of the NIA SBIR program. Even with covid-19 pandemic delays, NKT anticipates an exceptional phase 2a ready portfolio before the potential start date of a Fast Track SBIR investment by NIA. MW150 development was based on the perspective that Alzheimer’s and related diseases are disorders of progressive synaptic dysfunction with a common neuroinflammation component. Therefore, our novel approach to disease modifying therapeutic intervention was to target pathophysiology progression pathways, with the neuroinflammation-synaptic dysfunction axis being an underlying element across multiple diseases. The activity of the druggable serine/threonine protein kinase, p38alphaMAPK is increased in both neurons and glia, raising the potential for efficacy through a novel pleiotropic pharmacological mechanism in which a single molecular target drug is modulated in distinct cellular pathophysiology processes. Our specific aims are: Aim 1, Generate, qualify and transfer to the Columbia University (CU) site drug product and placebo capsules. Commercial scale drug substance is on hand, GMP drug product batch processes are established and CU has an experienced and qualified Research Pharmacy; Aim 2A, Prepare, recruit, and conduct a phase 2a clinical study of MW150. We will study 24 Alzheimer’s patients, randomized to once daily administration of test article (MW150: 42 and 84 mg) or placebo (3:1 ratio); Aim 2B. Evaluate safety and pharmacokinetics and monitor response biomarkers. Key milestones for SBIR part I deal with delivery of sufficient validated drug product to the clinical site research pharmacy. Key milestones for part II deal with clinical treatment and evaluations of safety and PK. Outcomes will fill a critical gap in MW150’s commercial and clinical development portfolio as well as provide a firm foundation required for follow-on phase 2b studies in Alzheimer’s Disease. The potential longer-term impact would be filling a void in safe, disease modifying therapeutics for a set of related neurologic disorders.

阿尔茨海默病是一种缺乏疾病修饰疗法的重大健康危机，迫切需要疾病修饰治疗方法。 Neurokine Therapeutics (NKT) 拥有独特的 2 期临床资产 MW01-18-150SRM (= MW150)，它代表了阿尔茨海默氏病。 MW150 是该领域主要关注淀粉样蛋白通路靶向治疗候选药物的范式转变，具有独特的靶标识别和参与、临床前和临床安全性组合。该组合为相同治疗类别中现有技术遇到的一些脱靶效应、不良药理学和临床挑战提供了合理的解释，其中只有一种表现出脑暴露。因此，NKT 寻求通过利用 NIA SBIR 计划快速填补临床开发和未来商业化的关键空白，即使在 covid-19 大流行延迟的情况下，NKT 预计在快速通道 SBIR 的潜在开始日期之前将有一个特殊的 2a 期产品组合。 MW150 的开发基于这样的观点：阿尔茨海默病和相关疾病是具有常见神经炎症成分的进行性突触功能障碍，因此，我们的疾病修饰治疗新方法。干预的目的是针对病理生理学进展途径，神经炎症-突触功能障碍轴是多种疾病的潜在因素。可药物丝氨酸/苏氨酸蛋白激酶 p38alphaMAPK 的活性在神经元和神经胶质细胞中均增加，从而通过以下方式提高疗效的潜力。新颖的多效药理学机制，其中单分子靶药物在不同的细胞病理生理学过程中受到调节。我们的具体目标是：目标 1，生成、鉴定和转移到。哥伦比亚大学 (CU) 网站药品和安慰剂胶囊。商业规模的原料药已到位，GMP药品批次流程已建立，并且CU拥有经验丰富且合格的研究药房；目标2A，准备、招募并进行MW150的2a期临床研究我们将随机研究24名阿尔茨海默病患者。每日一次施用测试品（MW150：42 和 84 mg）或安慰剂（3:1 比例）；评估安全性和药代动力学并监测反应生物标志物。 SBIR 第一部分的关键里程碑涉及向临床研究药房提供足够的经过验证的药物产品，第二部分的关键里程碑涉及临床治疗以及安全性和 PK 的结果评估，这将填补 MW150 商业和临床开发组合的关键空白。并为阿尔茨海默病的后续 2b 期研究提供坚实的基础，潜在的长期影响将填补一系列相关神经系统疾病的安全、疾病缓解疗法的空白。