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：
10157610
负责人：
Wayne F Anderson
金额：
$ 50万
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 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10157610
关键词：
Academic Medical Centers Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amyloid Animal Model Anti-Inflammatory Agents Arts Attenuated Bioavailable Biological Markers Brain COVID-19 pandemic Canis familiaris Clinical Clinical Research Clinical Treatment Clinical Trials Clinical Trials Data Monitoring Committees Cognition Disorders Development Disease Disease Progression Dose Double-Blind Method Drug Exposure Drug Kinetics Drug usage Elements Event Exhibits Exposure to Foundations Frontotemporal Dementia Functional disorder Funding Future Guidelines Hand Health Human Impaired cognition Inflammation Investments Modeling Molecular Target Monitor Neuroglia Neurologic Dysfunctions Neurons Observational Study Oral Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacology Pharmacology and Toxicology Pharmacy facility Phase Placebos Plasma Predisposition Process Property Protein-Serine-Threonine Kinases Public Health Publishing Randomized Rattus Reporting Research Safety Site Small Business Innovation Research Grant Synapses Testing Therapeutic Therapeutic Intervention Time Toxicology United States National Institutes of Health Universities base capsule clinical development clinical material clinical research site commercialization cytokine drug candidate efficacy clinical trial experience inhibitor/antagonist kinase inhibitor molecular drug target nervous system disorder neuroinflammation novel novel strategies pharmacodynamic biomarker phase I trial pre-clinical preclinical safety prevent programs recruit research clinical testing response biomarker stress kinase targeted treatment therapeutic candidate tissue injury trend

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重大健康问题，迫切需要针对疾病的治疗方法缺乏疾病缓解疗法的危机神经因子疗法 (NKT) 拥有独特的 2 期临床准备。资产 MW01-18-150SRM (= MW150)，代表了该领域的主导焦点的范式转变 MW150 具有独特的靶标识别和靶向治疗候选药物组合。该产品组合提供了参与度、临床前和临床安全性以及口服生物可利用药物的暴露。对一些脱靶效应、不良药理学和临床挑战的合理解释在同一治疗类别中遇到了现有技术，其中只有一种表现出脑部暴露。因此，NKT寻求通过以下方式快速填补临床开发和未来商业化的关键空白：即使 covid-19 大流行造成延误，NKT 仍预计会出现异常情况。在 NIA MW150 快速通道 SBIR 投资的潜在开始日期之前，第 2a 阶段已准备好投资组合。开发基于这样的观点：阿尔茨海默病和相关疾病是一种疾病进行性突触功能障碍与常见的神经炎症成分因此，我们的小说。疾病改变治疗干预的方法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。可药物化的丝氨酸/苏氨酸蛋白激酶 p38alphaMAPK 的活性在神经元和神经胶质细胞，通过一种新颖的多效性药理学机制提高疗效的潜力，其中单个分子靶标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、鉴定并传输至哥伦比亚大学 (CU) 站点药品和安慰剂胶囊。商业规模原料药已到位，GMP药品批次工艺已建立，CU已经验丰富且合格的研究药房；目标 2A，准备、招募和进行 2a 期临床；我们将研究 24 名阿尔茨海默病患者，随机每天服用一次测试品。（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。 SBIR 第一部分的关键里程碑涉及向患者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和评估。安全性和 PK 的结果将填补 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 期研究提供所需的坚实基础。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失调。