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

迫切需要疾病改变阿尔茨海默病的治疗方法，阿尔茨海默病是一种主要的健康 缺乏疾病修正疗法的危机。Neurokine Treateutics(NKT)具有独特的2期临床准备 ASSET，MW01-18-150SRM(=MW150)，这代表着从该领域的主导重点转向 淀粉样蛋白通路靶向治疗候选药物。MW150拥有独特的目标识别和 参与度、临床前和临床安全性以及口服生物利用药暴露。该产品组合提供 合理解释某些非靶向效应、不良药理学和临床挑战 在同一治疗类中与现有技术相遇，其中只有一种显示出脑暴露。 因此，NKT寻求通过以下方式迅速填补临床开发和未来商业化的关键空白 利用NIA SBIR计划。即使新冠肺炎大流行推迟，NKT预计也会出现异常 在NIA的Fast Track SBIR投资的潜在开始日期之前，阶段2a准备好投资组合。MW150 发展的基础是阿尔茨海默氏症和相关疾病是 进行性突触功能障碍伴常见的神经炎症成分。因此，我们的小说 疾病修正治疗干预的方法是以病理生理进展路径为目标， 神经炎症-突触功能障碍轴是多种疾病的潜在因素。 可药物的丝氨酸/苏氨酸蛋白激酶p38alphaMAPK的活性在神经元和 胶质细胞，通过一种新的多效性药理机制提高疗效潜力，在这种机制中，单一的 分子靶向药物在不同的细胞病理生理过程中受到调节。我们的具体目标是：目标1， 生产、鉴定药物产品和安慰剂胶囊，并将其转移到哥伦比亚大学(CU)网站。 商业规模的药材在手，GMP药品批量生产流程建立，CU已 经验丰富且合格的研究药房；目标2a，准备、招募和实施2a期临床 MW150的研究。我们将研究24名阿尔茨海默氏症患者，随机每天服用一次测试品 (MW150：42和84 mg)或安慰剂(3：1比例)；目标2B。评估安全性和药代动力学并进行监测 反应生物标记物。SBIR的关键里程碑第一部分涉及交付足够的有效药物产品以 临床现场研究药房。第二部分涉及临床治疗和评估的关键里程碑 安全和PK。结果将填补MW150的S商业和临床开发组合中的一个关键空白 并为阿尔茨海默病的后续2b期研究提供所需的坚实基础。潜力 更长期的影响将是填补一系列相关神经学的安全、疾病改善疗法的空白 精神错乱。

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.