GMP Production and Extended Toxicology of an Oral Formulation Drug for Alzheimer's Disease

ABSTRACT Alzheimer’s disease (AD) and related dementias are major neurodegenerative diseases that cause considerable mortality and morbidity in older Americans. Despite hundreds of clinical trials testing potential interventions, there are still no effective therapies available to prevent, delay, or slow disease progression. We developed MW189, a CNS-penetrant, small molecule that selectively suppresses stressor-induced proinflammatory cytokine overproduction. Proinflammatory cytokine overproduction from abnormally activated glia is a key contributor to synaptic dysfunction, neurodegeneration and cognitive decline in diverse neurodegenerative diseases, including Alzheimer’s. The mechanistic linkage of proinflammatory cytokine overproduction to pathophysiology progression provides a rational therapeutic approach to disease intervention and attenuation. MW189 is entering phase 2a clinical trials for acute use (i.v.) in critical care medicine for hemorrhagic stroke. MW189’s excellent safety, tolerability, pharmacokinetics and pharmacodynamics in human phase 1 clinical studies provide a strong biological foundation for continued MW189 clinical development in other disease areas. Our hypothesis is that MW189 is a viable candidate for potential oral treatment of individuals with dementia. There are two FDA technical barriers for MW189 use in future phase 2 trials in AD patients: 1) GMP clinical drug substance (API) that is compliant with quality (CMC) guidance for phase 2 clinical studies in patients (21 CFR 312.22 and 312.23; Section 312.23(a)(7)(i)); and 2) GLP extended toxicology analyses in two distinct species (rat and dog) for FDA approval of extended daily drug administration. We propose to remove these technical barriers to MW189 entry into future phase 2a safety and tolerability studies in early AD patients. Specifically, we propose: Specific Aim 1: GMP production of MW189 clinical drug for oral administration that is compliant with requirements for phase 2 trials and more recent FDA guidances on drug quality. We have developed a more streamlined GMP production scheme that addresses FDA quality (CMC) requirements for patient clinical trials requiring daily oral administration for years. Specific Aim 2: Extended toxicology studies in rats (6 mo) and dogs (9 mo) with recovery phase and toxicokinetics as a required foundation for future extended administration for chronic disease. The longest toxicology studies done with MW189 to date are 28-day tox studies. As a prelude to future studies in AD, extended toxicity studies are required for compliance and to establish dosing for longer term administration. Successful outcomes from the proposed investigations and the follow-on clinical trials will have a scientific impact on a number of CNS disorders where proinflammatory cytokine dysregulation is part of the disease progression mechanism.