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.

迫切需要修改阿尔茨海默氏病的治疗方法，这是一种缺乏修改疗法疾病的重大健康危机。 Neurokine Therapeutics（NKT）具有独特的2期现成临床资产，MW01-18-150SRM（= MW150），这代表了从该领域对淀粉样蛋白途径靶向治疗候选者的主要关注的范式转变。 MW150具有目标识别和参与，临床前和临床安全以及口服生物利用药物暴露的独特组合。该投资组合为某些脱离目标效应，不良药理学和临床挑战提供了合理的解释，在同一治疗类别中遇到的先前ART遇到的临床挑战，其中只有一种暴露了大脑暴露。因此，NKT试图通过利用NIA SBIR计划来快速填补临床开发和未来商业化的关键空白。即使有19日的大流行延迟，NKT也预计，在NIA快速赛道SBIR投资的潜在开始日期之前，2A阶段的Ready投资组合也有非凡的阶段。 MW150的开发是基于以下观点：阿尔茨海默氏病和相关疾病是具有常见神经炎症成分的渐进性突触功能障碍的疾病。因此，我们对修饰治疗干预的疾病的新方法是靶向病理生理进展途径，神经炎症突触功能障碍轴是多种疾病的潜在元素。在神经元和神经胶质中，可吸毒丝氨酸/苏氨酸蛋白激酶p38alphamapk的活性增加，通过一种新型的多效性药物机制提高了有效的潜力，在这种机制中，单个分子靶标在不同的细胞病理生理学过程中被单个分子靶标被调制。我们的具体目的是：AIM 1，生成，资格并转移到哥伦比亚大学（CU）场地药品和安慰剂胶囊。商业规模的药物有目的地，GMP药物批处理工艺已建立，CU具有经验和合格的研究药房； AIM 2A，准备，招募和进行MW150的2A期临床研究。我们将研究24例阿尔茨海默氏症患者，随机分配一次测试文章（MW150：42和84 mg）或安慰剂（3：1比率）；目标2B。评估安全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处理临床现场研究药房的足够验证的药物。第二部分的关键里程碑涉及临床治疗和安全和PK的评估。成果将填补MW150的商业和临床开发产品组合中的关键空白，并为阿尔茨海默氏病的后续2b研究提供了坚定的基础。潜在的长期影响将填补一组相关神经系统疾病的安全，疾病修饰疗法的空隙。