First-in-human SAD & MAD Trials for MW151, a Novel Alzheimer's Disease Drug Candidate that Attenuates Proinflammatory Cytokine Dysregulation

The medical and socioeconomic impact of Alzheimer’s disease (AD) and related dementias is increasing rapidly, yet there are no approved disease-modifying drugs to prevent, delay, or slow disease progression. The majority of AD clinical trials have targeted beta-amyloid, and 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 seek funding for phase 1 clinical studies of MW01-2-151SRM (=MW151), a novel, CNS-penetrant, orally bioavailable, small molecule drug candidate that selectively suppresses stressor-induced proinflammatory cytokine overproduction. MW151 ameliorates synaptic 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 has no liabilities in investigational new drug (IND)-enabling safety pharmacology and toxicology tests, including respiratory and cardiovascular safety pharmacology screens, rat and dog 28-day repeat administration toxicology studies, and genotoxicity analyses. Further, a MW151 analog developed for the more demanding intravenous route of administration has been substantially de-risked in phase 1 clinical trials. Our hypothesis is that MW151 will be a successful candidate for development as an oral formulation for the future treatment of individuals with Alzheimer’s disease. We propose in this application to move to the required next step, first-in-human (FIH) phase 1 safety clinical trials. Our specific aims are: Aim 1: Conduct a first-in-human (FIH) phase 1a single ascending dose (SAD) study of MW151. This study will determine safety and tolerability, maximum tolerated dose, and pharmacokinetics (PK) of MW151 in healthy adult volunteers. Plasma cytokine levels will be measured to provide baseline data for a future exploratory pharmacodynamic (PD) endpoint in phase 2a clinical trials. Aim 2: Conduct a phase 1b multiple ascending dose (MAD) study of MW151. This study will determine safety and tolerability, maximum tolerated dose, and PK of MW151 in healthy adult volunteers. In addition, a cohort of elderly healthy subjects and exploratory PD inflammatory cytokine endpoints in CSF will be included. Aim 3: Prepare clinical protocol and investigators brochure for a future phase 2a clinical trial of MW151 in early AD. Based on the outcomes of the proposed phase 1 studies, we will design a phase 2a trial and prepare the documents required. This will allow immediate progress to future FIP studies for AD. Overall, MW151 is uniquely positioned for development as a first-in-class stand-alone disease-modifying AD therapeutic or as part of an armamentarium of therapeutic approaches to alter disease progression in AD.