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

ABSTRACT Alzheimer s diseaseADand related dementias are increasing rapidly yetremarkablythere are no approved disease modifying drugsVirtually all trials targeting amyloid related pathways have failed over the lastyearsRegrettablyfew alternative targets or pathways have been exploredThereforethere is an urgent need to explore alternative pathways as monotherapies or as constituents of a multi drug armamentarium for a complex diseaseAn alternative view of progressive neurodegenerative disorders such as ADfrontotemporal dementiaand Parkinson s disease is diseases of progressive synaptic dysfunctionProtein kinase inhibitorsPKIare logical candidates to explore as potential attenuators of such progressive synaptic dysfunction and cognitive declineHoweverPKI drug candidates are under explored as a foundation for CNS diseasemodifying therapeutic development and there are currently no approved CNS PKI drugs for any indicationThis proposal is a discrete component of a clinical development campaign for a novel stress PKI drug candidateMWSRMMWthat represents a paradigm change for CNS targeted diseases such as ADMWis distinct from past or current drug candidates in AD clinical trialsMWameliorates cognitive dysfunction in discrete AD relevant animal modelsMWhas a unique profile of target recognitionpharmacological featuresand efficacy outcomesA GMP production scheme was developed and provided the first released clinical drug supply for first in humanFIHtrialsThis prior art provides a firm foundation for a commercial scale production of GMP drug substanceAPIand drug productdrug in capsuleThere 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 patientFIPstatus without untoward delaysIn this regardour specific aims areaimdevelop and validate a large scale production lot for GMP clinical drug substanceAPIaimgenerate a pilot lot ofCompletion of aimis required immediately for the extended toxicology studiesCompletion of aimsandallows immediate generation of the phaseIND qualityCMCsection and initiation of planning for phaseFIP trialsThe FIP trials will provide alternative therapeutic approaches to AD and related dementiaThe 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 diseasesFurtherattenuating the disease relevant pathways associated with increased paMAPK 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 diseasemodifying therapeutics to preventdelayand treat ADthrough a promising drug candidate that in multiple animal models attenuates cognitive dysfunction and disease progressionThe 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 productdrug substance in gelatin capsulefor quality analysesCompletion of these aims allows immediate preparation of the phaseinvestigational new drug qualityCMCsection and immediate initiation of extended toxicology studies that are also a required milestone before initiation of FIP trials