Alzheimer’s disease (AD) is one of the largest global public health crises facing us today, yet there are no effective therapies available to prevent, delay, or slow disease progression. The majority of AD clinical trials have tested drug candidates that target beta-amyloid, the major component of the amyloid plaque pathology observed in the AD brain. These experimental drugs have been disappointingly ineffective. Therefore, there is a major need for testing novel and alternative pathways distinct from those pursued over the past two decades. Our strategy is to target a particular form of dysregulated inflammation in the brain, injurious proinflammatory cytokine overproduction, that is a key contributor to synaptic dysfunction, neurodegeneration and cognitive decline in diverse neurodegenerative diseases. We have developed a novel, brain-penetrant, orally active, small molecule drug candidate, called MW151, that selectively suppresses stressor-induced proinflammatory cytokine overproduction. MW151 ameliorates nerve cell damage and cognitive impairment at low doses in many different animal models where proinflammatory cytokine dysregulation is established as a contributor to disease progression. MW151 is chemically and metabolically stabile, and shows an excellent safety profile in FDA-required preclinical tests. Further, a MW151 analog developed for the more demanding intravenous route of administration has been shown to be safe in phase 1 clinical trials. Overall, MW151 is a highly de-risked and promising candidate for clinical development as an oral formulation for the treatment of AD and related disorders.

We propose in this ADDF application to move to the required next step, first-in-human (FIH) phase 1 safety clinical trials. We will conduct a phase 1a single ascending dose study (aim 1) and a phase 1b multiple ascending dose study (aim 2) of MW151 in healthy adult volunteers. We also propose (aim 3) to conduct long-term toxicity studies in rats (6-months) and dogs (9-month), so that we will be able to move into phase 2 trials in patients as quickly as possible after the phase 1a/1b studies are completed. 

Overall, this project will advance clinical development of a promising drug candidate that could have disease-modifying effects not only in AD but also in a number of other CNS disorders where proinflammatory cytokine dysregulation is part of the disease progression mechanism.