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.
Public Health Relevance Statement: NARRATIVE The ongoing clinical campaign addresses the urgent and critical need to develop effective disease modifying therapeutics to prevent, delay, and treat Alzheimer's disease, through a promising drug candidate that in multiple animal models attenuates cognitive dysfunction and disease progression. The aims of this proposal are focused on performing a Phase 2a clinical trial on patients affected by the disease. Completion of these aims allows progression to a future phase 2b Alzheimer's disease trial.
Project Terms: Academic Medical Centers; University Medical Centers; Affect; Alzheimer's Disease; AD dementia; Alzheimer; Alzheimer Type Dementia; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's disease dementia; Alzheimers Dementia; Alzheimers disease; Primary Senile Degenerative Dementia; dementia of the Alzheimer type; primary degenerative dementia; senile dementia of the Alzheimer type; Amyloid; Amyloid Substance; inhibitor/antagonist; inhibitor; Anti-Inflammatory Agents; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Arts; Brain; Brain Nervous System; Encephalon; capsule; Capsules; Clinical Research; Clinical Study; Clinical Trials; Cognition Disorders; cognitive disease; cognitive disorder; cognitive syndrome; Disease; Disorder; Canis familiaris; Canine Species; Dogs; Dogs Mammals; canine; domestic dog; Double-Blind Method; Double-Blind Study; Double-Blinded; Double-Masked Method; Double-Masked Study; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Elements; Exhibits; Foundations; Future; Hand; Health; Human; Modern Man; Inflammation; Investments; United States National Institutes of Health; NIH; National Institutes of Health; nervous system disorder; Nervous System Diseases; Neurologic Disorders; Neurological Disorders; neurological disease; Neuroglia; Glia; Glial Cells; Kolliker's reticulum; Neuroglial Cells; Non-neuronal cell; Nonneuronal cell; nerve cement; Neurons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Patients; Pharmacy facility; Pharmacies; Drug Kinetics; Pharmacokinetics; Pharmacology; Placebos; Sham Treatment; sham therapy; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Public Health; Publishing; Rattus; Common Rat Strains; Rat; Rats Mammals; Research; Safety; Synapses; Synaptic; synapse; Testing; Time; Toxicology; Universities; Protein-Serine-Threonine Kinases; Protein-Serine Kinase; Protein-Threonine Kinase; Serine Kinase; Serine-Threonine Kinases; Serine/Threonine Protein Kinase Gene; Threonine Kinase; cytokine; Guidelines; base; Site; Clinical; Phase; Susceptibility; Predisposition; drug use; Drug usage; Disease Progression; Funding; Dysfunction; Physiopathology; pathophysiology; Functional disorder; Therapeutic; Exposure to; Attenuated; Frontal Temporal Dementia; front temporal dementia; frontal lobe dementia; fronto-temporal dementia; fronto-temporal lobar dementia; frontotemporal lobar dementia; frontotemporal lobe degeneration associated with dementia; Frontotemporal Dementia; Cognitive Disturbance; Cognitive Impairment; Cognitive decline; Cognitive function abnormal; Disturbance in cognition; cognitive dysfunction; cognitive loss; Impaired cognition; programs; Event; Oral; experience; Animal Models and Related Studies; model of animal; model organism; Animal Model; Pharmacology and Toxicology; novel; Reporting; Drug Exposure; neurological dysfunction; Neurologic Dysfunctions; intervention therapy; Therapeutic Intervention; Modeling; Property; Bioavailable; Data Monitoring Committees; Data and Safety Monitoring Boards; Safety Monitoring Boards; Clinical Trials Data Monitoring Committees; kinase inhibitor; preventing; prevent; Address; Dose; Molecular Target; randomisation; randomization; randomly assigned; Randomized; Clinical Evaluation; Clinical Testing; clinical test; research clinical testing; trial regimen; trial treatment; Clinical Treatment; Observation research; Observation study; Observational research; Observational Study; SBIR; Small Business Innovation Research; Small Business Innovation Research Grant; Monitor; trend; Process; developmental; Development; pathway; Pathway interactions; preclinical; pre-clinical; neuroinflammatory; neuroinflammation; new approaches; novel approaches; novel strategy; novel strategies; clinical site; clinical research site; Outcome; commercialization; bio-markers; biologic marker; biomarker; Biological Markers; pre-clinical safety; preclinical safety; clinical material; drug candidate; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; targeted treatment; phase 1 trial; phase I trial; pharmacodynamic marker; pharmacodynamic biomarker; response markers; response biomarker; molecular pharmacotherapy target; molecular drug target; clinical development; therapeutic candidate; recruit; AD related dementia; ADRD; Alzheimer related dementia; Alzheimer's disease related dementia; stress kinase; injury to tissue; tissue injury; Alzheimer's patient; Alzheimer's disease patient; efficacy clinical trial; COVID-19 epidemic; COVID19 epidemic; COVID19 pandemic; corona virus disease 2019 epidemic; corona virus disease 2019 pandemic; coronavirus disease 2019 epidemic; coronavirus disease 2019 pandemic; COVID-19 pandemic
