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

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.NARRATIVE The ongoing clinical campaign addresses the urgent and critical need to develop effective disease- modifying therapeutics to prevent, delay, and treat AD, through a promising drug candidate that in multiple animal models attenuates cognitive dysfunction and disease progression. The aims of this proposal are focused on developing a commercial scale production lot of GMP clinical drug substance and an initial lot of commercial GMP drug product (drug substance in gelatin capsule) for quality analyses. Completion of these aims allows immediate preparation of the phase 2 investigational new drug quality (CMC) section and immediate initiation of extended toxicology studies that are also a required milestone before initiation of FIP trials