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.
