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

Project: Research project

Project Details


Alzheimer’s disease (AD) and related dementias are a major global public health problem, predicted to increase dramatically over the next decades as the world population ages. There are no effective therapies available to prevent, cure, or slow the disease progression. New therapeutic strategies are urgently needed. Key to addressing the crisis is a diversified portfolio of therapeutic approaches that test discrete hypotheses and deliver drug candidates with discrete but complementary pharmacological function. Our approach is to target a particular feature of neuroinflammation, dysregulated cytokine production. This aspect of pathophysiology progression, driven by abnormally activated glia, is a contributor to synaptic dysfunction, neurodegeneration and cognitive decline in diverse neurodegenerative diseases. Our clinical drug candidate MW189 is a CNS-penetrant, small molecule that selectively attenuates stressor-induced proinflammatory cytokine overproduction and can enhance anti-inflammatory cytokine production. MW189 has outstanding physical properties and has no liabilities in IND-enabling preclinical safety pharmacology and toxicology following FDA guidelines. Importantly, MW189 has successfully completed three first-in-human, phase 1 clinical studies of safety, tolerability, pharmacokinetics and pharmacodynamic end point engagement. Currently, MW189 is entering phase 2a clinical trials for acute use in critical care medicine for hemorrhagic stroke. MW189’s excellent pharmacological profile in FDA guided preclinical and clinical studies provides a strong biological foundation for continued MW189 clinical development in other disease areas. Our hypothesis is that MW189 is a viable candidate for extended daily oral treatment of individuals with dementia. The proposed studies will remove the remaining technical barriers to MW189 entry into a future phase 2a safety and tolerability study in early AD patients: Aim 1: Produce GMP clinical drug substance, drug product, reference standard and internal standard. This aim involves GMP production of MW189 drug for oral administration that is compliant with requirements for phase 2 trials and recent FDA guidances on enhanced drug quality. Aim 2: Perform extended toxicology studies in rats (6 mo) and dogs (9 mo) with recovery phase and toxicokinetics. Extended toxicity studies are required for future extended daily administration to AD patients compliance and allows refinement of dosing for longer term administration. Aim 3: Obtain a phase 2a IND for a future clinical trial in early AD patients. This will be the final milestone, and will position us to immediately proceed to the future phase 2a proof-of-concept clinical study in early AD. Successful outcomes from the proposed investigations and the follow-on clinical trials will impact a number of CNS disorders where cytokine dysregulation is part of the disease progression mechanism.
Effective start/end date6/1/225/31/26


  • National Institute on Aging (1U01AG076480-01)


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