Evaluation of a dual PPAR agonist for treatment of Alzheimer's disease

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SUMMARY Alzheimer’s disease (AD) is the sixth leading cause of death in United States, affecting 5M people, yet this indication lacks effective therapeutics. The lead co-investigator at the academic performance site has developed a novel dual peroxisomal proliferator activating receptor delta/gamma (PPARδ/γ) agonist called OL-003 (previously AU9). The Phase I SBIR project demonstrated that OL-003 reduced AD-related pathologies, including amyloid accumulation, tau phosphorylation and neuroinflammation, and improved insulin signaling, neuronal plasticity and behavioral deficits, while exhibiting no heart or liver toxicity in 3xTg-AD mice. The company is a private preclinical biotechnology company developing novel therapies for mitigating AD. The company has in-licensed the patent for OL-003 from our academic partner. Studies outlined in this Phase II application are designed to test efficacy in two additional animal models and assess pharmacology and toxicology in GLP and non-GLP studies. If successful, this information will position OL-003 for additional IND-enabling studies (CMC in particular) to submit an IND application and begin first-in- human clinical trials. Three aims are proposed. In aim 1, research will be performed using the TE4 mouse model to test the effectiveness of OL-003 against tau-driven neuropathology in the context of APOE4, the strongest genetic risk factor for late-onset AD. Studies will include measuring the impact of OL-003 on phosphorylated tau levels, gliosis and neurodegeneration. In aim 2, the impact of OL-003 on glucose utilization, mitochondrial function and neurometabolism in the brains of mice will be studied. Current research supports the hypothesis that AD progression is driven by energy dysregulation, mitochondrial defects, and brain insulin resistance and the 5xFAD model is suitable for these studies. In aim 3, research performed under GLP conditions will determine if OL-003 is safe in acute and 6-month repeat dose toxicity studies as well as genotoxicity and carcinogenicity studies. Toxicokinetic analysis as well as neurologic, cardiovascular, and pulmonary parameters will be evaluated. Additional in vitro studies will address drug-drug interaction potential, including effects on drug transporter activity and expression, as well as target selectivity assays against off-target nuclear receptors and metabolite identification. Upon successful completion of this project, the company will possess a data package of IND-enabling research that should be attractive for a license deal or partnership with a pharmaceutical company.