Phase 2 studies of MW151, a selective small molecule suppressor of neuroinflammation for Alzheimer's disease

SPECIFIC AIMS Alzheimer’s disease (AD) is one of the largest global public health crises facing us today, and is predicted to increase dramatically over the next decades. There are no effective therapies available to prevent, cure, or slow the progression of disease. The prevailing perspectives on disease modification approaches have failed, making urgent the need to get alternative approaches tested for feasibility in patients. First-in-patient (FIP) studies for AD require prior completion of first-in-human (FIH) studies in volunteers. A priority, therefore, is to take potential new chemical entities developed explicitly as novel therapeutic approaches through FIH trials in order to test hypotheses about alternative approaches in subsequent FIP trials. The facilitation of rapid FIH qualification trials is especially relevant if the novel candidate has an attractive safety portfolio based on ICH/FDA guided preclinical qualification. MW01-2-151SRM (= MW151) is such a novel candidate – both in terms of unique chemical entity and in terms of its potential as a new therapeutic approach. A multi-Kg GMP clinical drug lot is available under GMP storage (release CoA, 2017) and exhibits excellent storage stability. MW151 is a water soluble, chemically stable drug with outstanding physical properties that portend well for future use in phase 2 and 3 clinical trials. Further derisking is provided by prior art in a phase 1b clinical trial with a MW151 analog, developed for the more demanding i.v. route of administration. A phase 1 clinical trial synopsis for MW151 is available, as well as a protocol for the required extended toxicology. A potential start date of July, 2018 is feasible. This application seeks funding for the required FIH phase 1 clinical studies and extended preclinical toxicology, both essential to start of future FIP trials. MW151 selectively suppresses stressor-induced proinflammatory cytokine (PIC) overproduction with resultant amelioration of synaptic damage and cognitive impairment. The efficacy and pharmacodynamics (PD) of MW151 is evident across a dozen diverse animal studies where PIC overproduction is a contributor to pathophysiology progression. These diverse models include two different AD-relevant animal models as well as susceptibility studies in an AD model. MW151 exhibits efficacy, at low doses. It does not bring about immunosuppression or a non-selective anti-inflammatory action. There is no evidence of suppression of basal cytokine levels characteristic of homeostasis. Function at efficacy doses involves restoration to homeostasis after disease or injury induced increases. MW151 is chemically and metabolically stabile, has no liabilities in respiratory and cardiovascular safety pharmacology screens, and exhibits no significant toxicology liabilities in rat and dog 28-day repeat administration studies, genotoxicity analyses, or CNS studies. Our hypothesis is that MW151 will be a successful candidate for development as an oral formulation for the future treatment of individuals with AD. MW151 preclinical development was funded by a NIA U01 award. We propose in this ADDF application to move to the required next step, FIH phase 1 safety clinical trials. We also propose 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. Specifically, our aims for this proposal are: Aim 1: FIH phase 1a single ascending dose (SAD) study of MW151. This study will determine safety and tolerability, maximum tolerated dose, and pharmacokinetics (PK) in a SAD paradigm in healthy adult volunteers. Plasma cytokine levels will be measured to provide baseline data for a future exploratory pharmacodynamic (PD) endpoint in phase 2 clinical trials. Aim 2: Phase 1b multiple ascending dose (MAD) study of MW151. This study will determine safety and tolerability, maximum tolerated dose and PK in a MAD paradigm in healthy adult volunteers. In addition, a cohort of elderly healthy subjects and exploratory PD cytokine endpoints in CSF will be included. Aim 3: Long-term toxicity studies in rats and dogs. As a prelude to future FIP phase 2 studies, extended toxicity will be done in rat and dog (6 and 9 months, respectively), including recovery groups and toxicokinetics. MW151 is uniquely positioned to become a first-in-class disease-modifying therapy. MW151’s efficacy, safety profile and low risk for drug-drug interactions make it an attractive candidate for preventative use by the elderly and asymptomatic at-risk patients with mild cognitive decline and memory loss. Efficacy in other disease models expands MW151 market potential well beyond AD and neurodegenerative disorders.