Production and quality analysis of clinical drug for a novel CNS protein kinase inhibitor therapeutic candidate

新型中枢神经系统蛋白激酶抑制剂治疗候选药物的生产和临床质量分析

• 批准号: 9902252
• 负责人: Daniel Martin Watterson
• 金额: $ 201.87万
• 依托单位: NEUROKINE THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902252
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease related dementia; Amyloid; Animal Model; Arts; Attenuated; Canis familiaris; Central Nervous System Diseases; Clinical; Clinical Research; Clinical Trials; Cognition Disorders; Complex; Development; Disease; Disease Progression; Drug Targeting; Drug effect disorder; Foundations; Frontotemporal Dementia; Functional disorder; Funding; GMP lots; Gelatin; Generations; Goals; Heat shock proteins; Impaired cognition; Investigation; Investigational Drugs; Neurodegenerative Disorders; Neuroglia; Neurons; Outcome; Parkinson Disease; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase; Phase II Clinical Trials; Preparation; Production; Progressive Disease; Protein Isoforms; Protein-Serine-Threonine Kinases; Rattus; Scheme; Specificity; Stress; Synapses; Testing; Therapeutic; Toxicology; Treatment Efficacy; Validation; Work; capsule; clinical development; drug candidate; drug production; drug quality; first-in-human; improved; insight; large scale production; lot production; neglect; neuroinflammation; novel; novel therapeutic intervention; prevent; protein kinase inhibitor; therapeutic candidate; therapeutic development; virtual

ABSTRACT Alzheimer’s disease (AD) and related dementias are increasing rapidly yet, remarkably, there are no approved disease modifying drugs. Virtually all trials targeting amyloid related pathways have failed over the last 10 years. Regrettably, few alternative targets or pathways have been explored. Therefore, there is an urgent need to explore alternative pathways as monotherapies or as constituents of a multi-drug armamentarium for a complex disease. An alternative view of progressive neurodegenerative disorders such as AD, frontotemporal dementia, and Parkinson’s disease is diseases of progressive synaptic dysfunction. Protein kinase inhibitors (PKI) are logical candidates to explore as potential attenuators of such progressive synaptic dysfunction and cognitive decline. However, PKI drug candidates are under explored as a foundation for CNS disease- modifying therapeutic development and there are currently no approved CNS PKI drugs for any indication. This proposal is a discrete component of a clinical development campaign for a novel stress PKI drug candidate, MW01-18-150SRM (= MW150) that represents a paradigm change for CNS targeted diseases such as AD. MW150 is distinct from past or current drug candidates in AD clinical trials. MW150 ameliorates cognitive dysfunction in discrete AD-relevant animal models. MW150 has a unique profile of target recognition, pharmacological features, and efficacy outcomes. A GMP production scheme was developed and provided the first released clinical drug supply for first-in-human (FIH) trials. This prior art provides a firm foundation for a commercial scale production of GMP drug substance (API) and drug product (drug-in-capsule). There is an immediate need for multi-Kg scale production of drug substance and validation of commercial drug product in order to move into first-in-patient (FIP) status without untoward delays. In this regard, our specific aims are: aim 1, develop and validate a large-scale production lot for GMP clinical drug substance (API); aim 2, generate a pilot lot of. Completion of aim 1 is required immediately for the extended toxicology studies. Completion of aims 1 and 2 allows immediate generation of the phase 2 IND quality (CMC) section and initiation of planning for phase 2 FIP trials. The FIP trials will provide alternative therapeutic approaches to AD and related dementia. The clinical campaign is directly testing the hypothesis that an isoform selective PKI drug can address the synaptic dysfunction and injurious neuroinflammation that characterize diverse neurodegenerative diseases. Further, attenuating the disease relevant pathways associated with increased p38aMAPK activity in both neurons and glia tests the hypothesis that improved efficacy can be obtained with a single target drug that works via pleiotropic drug action.

摘要 阿尔茨海默病（AD）和相关痴呆正在迅速增加，然而，值得注意的是， 改善疾病的药物在过去的10年里，几乎所有针对淀粉样蛋白相关通路的试验都失败了。 年令人遗憾的是，几乎没有探讨其他目标或途径。因此，迫切需要 探索替代途径作为单一疗法或作为多种药物医疗设备的组成部分， 复杂的疾病进行性神经退行性疾病（如AD、额颞叶疾病）的另一种观点 痴呆和帕金森病是进行性突触功能障碍的疾病。蛋白激酶抑制剂 (PKI)是探索作为这种进行性突触功能障碍的潜在衰减剂的合乎逻辑的候选者， 认知能力下降然而，PKI候选药物作为CNS疾病的基础正在探索中- 这改变了治疗的发展，目前还没有批准用于任何适应症的CNS PKI药物。这 该提案是一种新型压力PKI候选药物临床开发活动的独立组成部分， MW 01 -18- 150 SRM（= MW 150）代表了CNS靶向疾病（如AD）的范式变化。 MW 150与AD临床试验中过去或当前的候选药物不同。MW 150改善认知功能 在离散的AD相关动物模型中的功能障碍。MW 150具有独特的目标识别特征， 药理学特征和功效结果。制定了GMP生产方案， 首次发布用于首次人体试验（FIH）的临床药物供应。该现有技术为本发明提供了坚实的基础。 GMP原料药（API）和制剂（胶囊剂）的商业规模生产。有一个 迫切需要多Kg规模原料药生产和商业制剂验证 为了进入第一个病人（FIP）的地位，没有不利的延误。在这方面，我们的具体目标是： 目的1，开发和验证GMP临床原料药（API）的大规模生产批次;目的2，生成 很多飞行员。扩展毒理学研究要求立即完成目标1。完成 目标1和2允许立即生成2期IND质量（CMC）部分并启动计划 用于第二阶段FIP试验。FIP试验将为AD和相关疾病提供替代治疗方法。 痴呆临床活动是直接测试的假设，异构体选择性PKI药物可以 解决突触功能障碍和损伤性神经炎症，这些是各种神经退行性疾病的特征。 疾病此外，减弱与p38 aMAPK活性增加相关的疾病相关途径， 神经元和神经胶质都检验了这样的假设，即用单一靶向药物可以获得改善的功效， 通过多效性药物作用起作用。