PNA5: A Novel Mas Receptor Agonist for Treatment of Cognitive Impairment in Patients at Risk for Vascular Dementia and Alzheimer's Disease Related Dementia: an FDA required Toxicology Study - PROJECT SUMMARY Vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's disease related dementias (ADRD) significantly contribute to the 55 million people world-wide who suffer with dementia. This number is estimated to increase to over 139 million people by 2050 (WHO). A number of studies have shown that VCID and conversion to ADRD are strongly correlated with vascular disease, inflammation and decreased cerebral brain blood flow 1,2,3, 4,5,6, 7,8. The relationship between vascular disease, cognitive function and progression to dementia and possible AD have been recently reviewed 9. These authors successfully make the case for a close relationship between cardiovascular risk factors and risk for VCID and ADRD. Furthermore, conversion rates of VCI to dementia has been reported to be within 40-46% within 5 years of diagnosis of VCI 10,11. There is an urgent unmet medical need for therapeutics to prevent cognitive decline in individuals at risk for VCID. The goal of this proposed late-stage NIA U01 ADDP program is to complete FDA-required long-term toxicology and safety studies required to advance to a Phase 2 clinical trial of the anti-inflammatory peptide, PNA5, for treatment of persons with MCI and are at risk for VCID/ADRD. The peptide PNA5 is a novel pleotropic anti- inflammatory Angiotensin-(1-7)/MasR agonist that has outstanding brain penetration, enhanced bioavailability, decreases brain and cerebrovascular inflammation, improves cerebral blood flow and restores cognitive function in our preclinical VCID model 12,13,14,15. None of the other published studies with oral formulations of Ang-(1-7) related peptides or small molecules 18,19,20 have exhibited the excellent brain penetration that we have observed with our glycosylated peptides, which will be key for developing an effective CNS anti-inflammatory, cognitive protective therapeutic. With support from the NIA, we are completing our early stage ADDP program, have successfully completed our FDA pre-IND meeting, and will have our new FDA IND for PNA5 by Q3 2023. By the time of this review, we will have completed our formal initial 28-day toxicology and safety work for PNA5 required for Phase 1a first-in-human safety studies. In this application we are requesting support for 1) additional long- term exposure safety analysis,2) expanded GMP manufacturing and final formulation and packaging for a Phase 2 trial, and 3) FDA regulatory documentation and design of the Phase 2 trial required to advance to Phase 2 clinical trials in persons with MCI at risk for VCID/ADRD. Specific Aim I: Conduct six-month chronic toxicology studies in two species to determine the toxicokinetic and safety profiles for subcutaneously administered PNA5. Specific Aim II. Expanded GMP manufacturing and final fill and finish of PNA5 for Phase 2 trials in VCID. Specific Aim III: Complete regulatory assessments and documentation for submission to FDA and to generate Phase 2 clinical trial design and plan.
