Grants and Contracts Details
We seek three years of U01 support to attain an oral drug IND for use in phase 1 safety and phase 2 studies of progressive cognitive diseases such as Alzheimer's disease (AD). The anticipation is that after successful attainment of an oral drug IND as a result of U01 funding, future phase 1 first-in-human studies will be done at the Duke Clinical Research Unit (DCRU) and the phase 2a clinical feasibility studies will be done at the University of Kentucky Alzheimer's Disease Center. Background: Up-regulation of proinflammatory cytokine production is a common mechanism of pathology progression among diverse CNS diseases and injuries, and also contributes to tumor growth and metastasis. Modulation of this disease progression mechanism via therapeutic intervention during appropriate time windows after clinical presentation would address major unmet medical needs across multiple disease and trauma indications. Novel small molecule candidates with this clinical potential have been developed in previous NIA supported research. Intellectual property filings protect the candidates for development. One candidate, MW01-6-189WH (=MW189), was taken though IND and into phase 1a SAD first-in- human studies with no reported adverse events. The formulation was for intravenous use in critical care indications, and the indication being pursued in phase 1b MAD and phase 2a pharmacodynamic clinical studies is closed head traumatic brain injury. We have published extensively on the efficacy, pharmacological mechanism of action and dosing time windows for another of the candidates, MW01-2-151SRM (=MW151). MW151's potential for CNS penetrance, metabolic stability and safety pharmacology and toxicology have also been probed. MW151 remains an attractive candidate for development as an oral formulation for use in cognitive function disorder progression, such as mild cognitive impairment (MCI) to AD. Our published work on the pharmacological mechanism of action end point, attenuation of stress-induced proinflammatory cytokine overproduction that contributes to synaptic dysfunction, shows that earlier stage intervention provides better pharmacodynamics and efficacy outcomes compared to later disease stage intervention, although there is an effect at the disease stage also. A GMP compatible production scheme has been developed. However, MW151 has not progressed into final GLP preclinical development, and neither candidate (MW151 or MW189) is being pursued for dementia indications. Discovery: The discovery process began with a validated drug discovery engine and a mouse model with defined time windows for proinflammatory cytokine production, onset of synaptic dysfunction and late stage cognitive behavior deficits. The screen involved oral treatment after start of injury, monitoring of pharmacodynamics related to pharmacological mechanism of action, and assessment of downstream neurologic outcomes. Novel small molecules were designed using pharmacoinformatics and a curated database of stable CNS penetrant drugs in conjunction with the scaffold hopping medicinal chemistry approach. The strict exclusion criteria of the database and leveraging a scaffold used in prior CNS drugs resulted in less than two dozen novel small molecules being synthesized to find viable hits. Focused refinement was then done to improve ADMET related features. Of the five candidate compounds generated for consideration, the best of class were MW151 and MW189. These candidates for development restore A?- induced proinflammatory cytokine levels back towards normal and attenuate the associated synaptic and behavioral deficits in mice. Efficacy in additional models of other neurologic disorders that are characterized by cytokine overproduction as a pathophysiology progression mechanism increased confidence in the pharmacological mechanism of action. Summary Characteristics: MW151 is a novel, water-soluble, orally bioavailable, CNS-penetrant, small molecule with outstanding chemical stability and good potential for metabolic stability. MW151 has a documented disease-modifying efficacy in diverse animal models in which cognitive dysfunction is brought about by injury- or disease-induced overproduction of proinflammatory cytokines. Competitive Landscape: There are no approved small molecule therapies in this class. Approved macromolecular drugs that inhibit proinflammatory cytokine action constitute a similar class in terms of mechanism of action, attenuation of excessive proinflammatory cytokine activity. Some approved small molecule drugs have off-target activities that alter proinflammatory cytokine action; however, they have liabilities related to adverse events which limit utility and they face limited intellectual property status.
|Effective start/end date||8/1/15 → 8/1/15|
- National Institute on Aging
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