ABSTRACT Alzheimer’s disease and epilepsy are common age-related CNS disorders. Both Alzheimer’s disease and epilepsy are more frequent in the elderly compared to any other age groups, and a history of epilepsy is a risk factor for development of Alzheimer’s and related dementias. Further, patients with Alzheimer’s disease have unprovoked seizures and epilepsy at a significantly higher rate than non-demented elderly. These public health correlations are seen at the level of pathophysiology and manifested symptoms. For example, cognitive impairment is a definitive aspect of Alzheimer’s disease, and recurrent epileptic seizures are associated with cognitive impairment. Clearly, the increase in aging of the world’s population makes this comorbidity a major concern. This proposal is focused on addressing a common pathophysiological mechanism in Alzheimer’s and epilepsy – dysregulated proinflammatory cytokine production. Proinflammatory cytokine overproduction from abnormally activated glia is a contributor to subsequent neurological damage and cognitive deficits in both epilepsy/seizure disorders and in Alzheimer’s and related dementias. Despite advances in our understanding of 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 of injury- and disease-induced proinflammatory cytokine overproduction associated with destructive glia inflammation/synaptic dysfunction cycles and their long-term neurotoxic effects. This proposed Fast-Track SBIR 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 production approach, 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 future phase 2a proof-of-concept studies in patients with drug-resistant epilepsy, 3. Prepare required documents and submit 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 SBIR Phase II activities (years 02-03). The Fast-Track structure will allow us to immediately move to SBIR Phase II activities that flow seamlessly from preparation and technology transfer to essential milestones for a future FIP safety trial including pharmacokinetics and a pharmacodynamic arm. Success will also further de-risk MW189 for future phase 2 trials in Alzheimer’s disease or other age-related disorders that involve dysregulated neuroinflammation as a driver of disease progression.

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.