Developing Novel REV-ERB Agonists for the Treatment of Neuroinflammation in Alzheimer's Disease

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Alzheimer’s Disease (AD) is a progressive neurodegenerative disease with clinical hallmarks such as memory loss, cognitive impairment, and dementia. AD affects over 5 million American and is the 6th leading cause of death; these numbers will rise dramatically as the US aging population increases. Given the continued failures and controversies of AD drugs in clinical trials, it is critical to identify novel targets to develop effective therapies for AD. One novel potential therapeutic approach that is supported by the literature is to correct the aberrant glial activation and neuroinflammation that contribute to neuronal degeneration and AD progression. Pelagos Pharma aims to reduce neuroinflammation by targeting the nuclear receptor and transcriptional repressor REV-ERB, a novel target has been extensively studied by Pelagos co-founder and nuclear receptor expert Thomas Burris, PhD. REV-ERB is highly expressed in the brain and functions as a transcriptional repressor to negatively regulate expression of multiple inflammatory components in microglia, particularly the NLRP3 inflammasome and pro-inflammatory cytokines such as IL-6, IL-1, and IL-18. In multiple in vitro and in vivo AD models, REV- ERB agonism with tool compounds reduces neuroinflammation and protects against memory loss. Pelagos is now developing the first clinically-viable small molecule agonists that target REV-ERB to suppress neuroinflammation and treat AD. Targeting REV-ERB to suppress neuroinflammation by inhibiting NLRP3 inflammasome expression and subsequent formation is an innovative approach that has tremendous potential to reduce symptoms and effectively reduce the burdens associated with AD. Our approach is unique - competitors are targeting individual inflammasome components, an approach that may result in impartial suppression, limited efficacy, and increased potential for negative rebound effects. By targeting the upstream regulator of inflammasome and cytokine expression in microglia, we may return expression of inflammatory components to a basal level and limit chronic inflammation for a prolonged period. The goal of this Phase I SBIR is to select a lead candidate from a shortlist of compounds derived from our proprietary scaffold (Aim 1) and establish safety and efficacy proof-of-concept in multiple in vitro and in vivo neuroinflammation and AD models (Aim 2). We will take a systematic cost- and time-effective approach to selecting the optimal compound based on DMPK properties and efficacy results in well-established models, starting with high-throughput assays to screen multiple compounds and ending with long-term transgenic animal models to assess the best 1 compound. The product of this Phase I proposal will be an orally bioavailable small molecule REV-ERB agonist with favorable PK/PD that can cross the blood brain barrier to reduce neuroinflammation in AD models. Successful completion of this phase I will position Pelagos to raise the necessary capital to complete long-term safety and efficacy assays and initiate IND-enabling studies.