PNA5 for treatment of vascular cognitive impairment and dementia (vcid) and alzheimer's disease related dementias (adrd): a phase 1A safety and tolerability study - research summary/abstract…

The National Institute on Aging awarded the University of Arizona a cooperative agreement totaling $6,348,351 on September 1, 2026, under the Aging Research program (CFDA 93.866) to conduct a first-in-human Phase 1A randomized, placebo-controlled safety and tolerability study of PNA5, a novel glycosylated angiotensin-(1-7) peptide and selective MAS receptor agonist designed to treat vascular cognitive impairment and dementia (VCID) and Alzheimer's disease-related dementias (ADRD).

The study will include both single ascending dose (SAD) and multiple ascending dose (MAD) components in healthy adults. PNA5 targets two key mechanisms of VCID: neuroinflammation and impaired cerebral blood flow. Preclinical VCID models demonstrated that PNA5 improved cerebral perfusion, reduced neuroinflammatory signaling, and restored cognitive performance. The FDA has granted Investigational New Drug (IND) clearance (IND #160089), and clinical-grade drug product is available for the trial. All IND-enabling studies, including GLP toxicology studies, pharmacokinetics, dose formulation, and GMP manufacturing, were completed under two prior NIA-funded U01 awards.

The award period extends from September 1, 2026, through August 31, 2027, with place of performance in Tucson, Arizona. The University of Arizona operates as the Arizona Board of Regents in receiving this award.

PNA5 for treatment of vascular cognitive impairment and dementia (vcid) and alzheimer's disease related dementias (adrd): a phase 1A safety and tolerability study - research summary/abstract vascular contributions to cognitive impairment and dementia (vcid) are now recognized as a leading cause of alzheimer's disease-related dementias (adrds), particularly among older adults with hypertension, diabetes, or cardiovascular DISEASE1,2 ,3 ,4 ,5 ,6 ,7 ,8 ,9. Vcid is progressive, underdiagnosed, and often coexists with alzheimer's pathology. Longitudinal studies report that up to 45% of individuals with vascular cognitive impairment (VCI) progress to dementia within five YEARS10,11. Despite the high prevalence and impact of vcid, there are currently no FDA-approved therapies to treat or prevent its progression. Our team has developed PNA5, a novel glycosylated angiotensin-(1-7) peptide and selective MAS receptor agonist that targets two key mechanisms of vcid: neuroinflammation and impaired cerebral blood flow. In preclinical vcid models, PNA5 improved cerebral perfusion, reduced neuroinflammatory signaling, and restored cognitive PERFORMANCE12,13 ,14 ,15. The present UG3/UH3 proposal supports a first-in-human phase 1A clinical trial of PNA5. All IND-enabling studies have been completed under two NIA-funded U01 awards (U01AG066623, U01AG082617), including GLP toxicology studies in rats and dogs, PK, dose formulation, and GMP manufacturing. The FDA has granted IND clearance (IND #160089), and clinical-grade drug product is release-tested and available for the present studies. For this UG3/UH3, we will complete a randomized, placebo-controlled phase 1A safety study of PNA5 including both single ascending dose (SAD) and multiple ascending dose (MAD) components in healthy adults. The program is structured around clear specific aims and milestone-driven decision points: specific aim 1 (UG3 phase): single ascending dose study (SAD): establish safety, tolerability, and PK following single SC doses. Milestones: 1) demonstrate an acceptable safety profile with no dose-limiting toxicities, 2) characterize single-dose PK, 3) establish dose proportionality and identify any unexpected non- linearities in PK, and 4) identify safe starting doses for the MAD study. Specific aim 2 (UH3 phase): multiple ascending dose study (MAD): evaluate repeat-dose safety, tolerability, and steady-state PK. Milestones: 1) demonstrate safety with repeat dosing, 2) define accumulation and steady-state kinetics, 3) confirm dose proportionality under repeat dosing, 4) submit an IND amendment with SAD/MAD results, 5) identify safe, pharmacologically justified doses and regimens for the planned phase 2 vcid study. This integrated UG3/UH3 design ensures a seamless transition from SAD to MAD and establishes the foundation for phase 2 proof-of-concept evaluation in patients with vcid.