Alzheimer's disease and epilepsy are common age-related CNS disorders. Both Alzheimer's disease andepilepsy are more frequent in the elderly compared to any other age groups, and a history of epilepsy is a riskfactor for development of Alzheimer's and related dementias. Further, patients with Alzheimer's disease haveunprovoked seizures and epilepsy at a significantly higher rate than non-demented elderly. These public healthcorrelations are seen at the level of pathophysiology and manifested symptoms. For example, cognitiveimpairment is a definitive aspect of Alzheimer's disease, and recurrent epileptic seizures are associated withcognitive impairment. Clearly, the increase in aging of the world's population makes this comorbidity a majorconcern. This proposal is focused on addressing a common pathophysiological mechanism in Alzheimer's andepilepsy - dysregulated proinflammatory cytokine production. Proinflammatory cytokine overproduction fromabnormally activated glia is a contributor to subsequent neurological damage and cognitive deficits in bothepilepsy/seizure disorders and in Alzheimer's and related dementias. Despite advances in our understandingof these molecular neuroinflammatory mechanisms underlying adverse neuronal sequelae in CNS disorders,approved therapeutics that target this pathological process are lacking. ImmunoChem Therapeutics (ICT)proposes to advance MW189, a novel small molecule candidate already in early phase clinical development,having successfully completed phase 1a and phase 1b clinical trials. MW189 is a selective suppressor ofinjury- and disease-induced proinflammatory cytokine overproduction associated with destructive gliainflammation/synaptic dysfunction cycles and their long-term neurotoxic effects. This proposed Fast-TrackSBIR will deliver a phase 2a trial-ready portfolio for future first-in-patient (FIP) epilepsy treatment trials.Specifically, we will: 1. Develop a commercial-scale version of a validated GMP clinical grade drug productionapproach, produce a multi-Kg drug substance lot, and obtain its release for future patient clinical trials,2. Obtain preclinical efficacy data for dosing information and the biological rationale required to support futurephase 2a proof-of-concept studies in patients with drug-resistant epilepsy, 3. Prepare required documents andsubmit a phase 2 IND for a future clinical trial in patients with drug-resistant epilepsy.Our milestones and their associated key tasks are organized as SBIR Phase I activities (year 01) and SBIRPhase II activities (years 02-03). The Fast-Track structure will allow us to immediately move to SBIR Phase IIactivities that flow seamlessly from preparation and technology transfer to essential milestones for a future FIPsafety trial including pharmacokinetics and a pharmacodynamic arm. Success will also further de-risk MW189for future phase 2 trials in Alzheimer's disease or other age-related disorders that involve dysregulatedneuroinflammation as a driver of disease progression.
Public Health Relevance Statement: NARRATIVE
Alzheimer's disease and epilepsy have an age-related association as well as shared disease
progression features, including brain inflammation and cognitive impairment. We developed a small
molecule experimental therapeutic, MW189, with potential to alter disease progression. This SBIR
project will facilitate progression to future first-in-patient clinical trials for MW189 which has exhibited
exceptional safety in recently completed first-in-human safety trials.
Project Terms: cognitive performance ; phase II trial ; phase 2 trial ; non-demented ; nondemented ; clinical development ; first-in-human ; first in man ; Alzheimer's disease related dementia ; AD related dementia ; ADRD ; Alzheimer related dementia ; dementia risk ; risk factor for dementia ; risk for dementia ; dose information ; Phase Ib Clinical Trial ; Phase 1b Clinical Trial ; Affect ; Elderly ; advanced age ; elders ; geriatric ; late life ; later life ; older adult ; older person ; senior citizen ; Aging ; 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 ; Brain ; Brain Nervous System ; Encephalon ; Central Nervous System Diseases ; CNS Diseases ; CNS disorder ; Central Nervous System Disorders ; Clinical Trials ; comorbidity ; co-morbid ; co-morbidity ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Encephalitis ; Brain Inflammation ; Epilepsy ; Epileptic Seizures ; Epileptics ; Seizure Disorder ; epilepsia ; epileptiform ; epileptogenic ; Exhibits ; Future ; Recording of previous events ; History ; Incidence ; Inflammation ; Mus ; Mice ; Mice Mammals ; Murine ; 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 ; Pathologic Processes ; Pathological Processes ; Patients ; Drug Kinetics ; Pharmacokinetics ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Production ; Public Health ; Recurrence ; Recurrent ; Risk ; Risk Factors ; Safety ; Seizures ; Synapses ; Synaptic ; synapse ; Time ; cytokine ; Injury ; injuries ; improved ; Clinical ; Phase ; Biological ; Link ; Individual ; Disease Progression ; Technology Transfer ; analog ; Funding ; Functional disorder ; Dysfunction ; Physiopathology ; pathophysiology ; Therapeutic ; Attenuated ; Cognitive Disturbance ; Cognitive Impairment ; Cognitive decline ; Cognitive function abnormal ; Disturbance in cognition ; cognitive dysfunction ; cognitive loss ; Impaired cognition ; Frequencies ; Severities ; Oral ; Amentia ; Dementia ; age group ; success ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; Structure ; cognitive defects ; Cognitive deficits ; novel ; Nervous System Injuries ; Nervous System damage ; Neurological Damage ; Neurological Injury ; Neurological trauma ; neurotrauma ; Nervous System Trauma ; Pharmacodynamics ; Modeling ; drug production ; Experimental Therapies ; Investigational Treatments ; experimental therapeutic agents ; experimental therapeutics ; Investigational Therapies ; Refractory epilepsy ; drug-resistant epilepsy ; Intractable Epilepsy ; patient safety ; Causality ; causation ; disease causation ; Etiology ; small molecule ; Address ; Dose ; Symptoms ; Data ; Clinical Treatment ; trial regimen ; trial treatment ; Scheme ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Preparation ; Molecular ; Development ; developmental ; treatment trial ; age related ; age dependent ; neuroinflammation ; neuroinflammatory ; Population ; Prevalence ; neurotoxic ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; Alzheimer's disease risk ; Alzheimer risk factor ; alzheimer risk ; therapeutic target ; high risk ; preclinical efficacy ; pre-clinical efficacy ; GMP lots ; good manufacturing practice lot ; arm ;
