IND Enabling Studies for RASRx 1902, a novel Mas receptor agonist, for treatment of cognitive impairment in patients at risk for Alzheimer's disease.

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Activation of brain inflammatory pathways contributes to amyloid accumulation, neuronal dysfunction, cognitive impairment, and memory loss which are the main pathological features of Alzheimer's disease (AD). There are few treatments for AD and those available have limited utility. As a result, there is a desperate need for therapies involving novel targets for the treatment of AD. Part of the difficulty in the development of therapeutics for AD is the heterogeneity of the population and etiology as well as the insensitivity of the endpoints, particularly in early- stage clinical trials. For these early trials, outcome measures focused on target engagement or biological pathway analysis might improve trial outcomes and better support the drug development process. Based upon these compelling data, we have chosen RASRx1902 as our clinical candidate for AD. Based on conversations with key AD opinion leaders, it is crucial that we have biomarkers of target engagement and efficacy for use in clinical trials. This proposal requests support to identify blood biomarkers of RASRx1902 target engagement to facilitate dose optimization and patient enrollment during the clinical study of RASRx1902 in AD patients. Using the known mechanisms by which Mas agonists reduced neurodegeneration, we hypothesize that Mas agonism will reduce markers of neuronal death, astrogliosis, inflammation and oxidative stress. Amendment Aim 1. Classically, the biomarkers used to monitor the degree of neurological injury include those that reflect direct neuronal damage (phosphorylated Tau, p-Tau) and astrogliosis as well as blood-based biomarkers such as neurofilament light, S100 calcium binding protein B, and ubiquitin carboxyl-terminal hydrolase isoenzyme L1. Therefore, in Aim 1, we assess the effects of RASRx1902 treatment on these classic neurodegenerative biomarkers. Amendment Aim 2. To take an unbiased approach to biomarker discovery, we will use SomaScan (an aptamer- based system that measures 7,000 proteins in the plasma) and Metabolon’s Global Metabolomics™ (an LC-MS global metabolomics platform) to identify pathways both altered in AD and by RASRx1902. We will analyze and correlate the data acquired by SomaScan with cognition and neurological changes. Comprehensive metabolomic and lipidomic analyses will be conducted at Metabolon using their Global Metabolomics (>1000 metabolites involved in amino acid, carbohydrate, energy, lipid and nucleotide metabolism). Amendment Aim 3. In Aim 3, we will seek to correlate the peripheral markers — the neurodegenerative biomarkers (Aim 1) and the unbiased biomarkers (Aim 2) — with cognitive function and brain pathology, microglial activation, astrogliosis and amyloid burden. Exploratory analyses will include pathway enrichment analyses, multivariable visualization. Statistical hypothesis will be generated based on analyte differences between the RASRx1902 and vehicle treated 5xFAD and WT at multiple time points. From these analyses, biomarker discovery will be conducted.