Development of small molecule drug candidates that target dysregulated neuroinflammation in acute brain injuries
- Martin Watterson, Linda Van Eldik
Introduction: A critical mechanism driving neurodegenerative disease progression is dysregulated brain inflammation. Neuroinflammatory repair processes are fundamental to CNS homeostasis, but inefficient, excessive, or prolonged inflammation can contribute to neurodegeneration. In acute brain injuries, such as traumatic brain injury (TBI) and intracerebral hemorrhage (ICH), injury-induced overproduction of proinflammatory cytokines from activated glia that occurs in the first several hours to days after insult has been linked to subsequent cerebral edema, long term neuronal dysfunction and cognitive impairment.
Objective: We postulate that the acute proinflammatory cytokine surge is a rational therapeutic target for intervention in the acute care setting.
Methods: We developed novel, brain-penetrant, orally active, small molecule drug candidates that selectively suppress injury- or disease-induced overproduction of proinflammatory cytokines and ameliorate synaptic damage and cognitive impairment in multiple animal models of CNS disorders.
Results: One compound, named MW189, is a phase 2a-ready drug candidate developed as an intravenous formulation for acute injury/critical care indications. MW189 has successfully completed phase 1a/1b clinical trials in healthy volunteers, and a clinical plan has been established for a phase 2a trial in ICH or TBI with pharmacodynamic endpoints. Another compound, named MW151, was developed as an oral formulation for repeat administration and is currently entering a first-in-human phase 1a trial. MW189 and MW151 are chemically and metabolically stable and efficacious at low doses, with no general immunosuppression and no suppression of basal cytokine levels.
Conclusions: Overall, our compounds are highly de-risked and promising candidates for continued clinical development as disease-modifying drugs for CNS disorders.