Lead Optimization of a Therapeutic Candidate for Alzheimer’s Disease

Summary. Overactivation of the hypothalamic-pituitary-adrenal (HPA) axis occurs in Alzheimer's disease (AD) and dysregulation of the stress system plays a mechanistic role in the pathophysiology of AD progression. This Phase I SBIR proposal will set the groundwork for the clinical development of a first-in-class treatment for the long-term management for AD and other conditions characterized by excessive activation of the HPA. While the stress response is essential for survival, it can become dysregulated. Excessive activation of the HPA axis results in increased glucocorticoids release, which has detrimental actions on the central nervous system, causing hippocampal and prefrontal cortex functional impairments, and contributes to AD progression. Therapeutics to modulate the HPA axis have been under research for decades. While glucocorticoid receptor antagonists have shown some potential in the treatment of depression, they can be counterproductive when used long-term. CRF receptor type 1 (CRF1) antagonists have also been studied extensively but have generally been unsatisfactory due to side effects and limited efficacy on the HPA. Brain-penetrant CRF1 antagonists can induce fear and aversion in humans, which may represent class side effects. Thus, there is a considerable unmet medical need for identification of novel therapeutics to normalize HPA hyperactivity that are effective and tolerable for long-term use. HPA hyperactivity is believed to be a key pathogenic driver of AD and a validated therapeutic target. The present Phase I SBIR seeks to advance the development of a novel therapeutic to reduce HPA hyperactivity and will lay the foundations for the clinical development of a first-in-class therapeutic by optimizing a lead candidate therapeutic for the long-term management of chronic hyperactivity of the hypothalamic pituitary adrenal axis (HPA) for AD and other degenerative conditions.