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IND-enabling studies for a potent and efficient neuroprotective drug

Award Number: R44NS120427
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/24/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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IND-enabling studies for a potent and efficient neuroprotective drug - Project Summary/Abstract Global Cerebral Ischemia (GCI) afflicts over 700,000 Americans each year and often results in permanent cognitive impairment or death. Here, we will complete IND-enabling studies for a therapeutic strategy for GCI. Our optimized peptide inhibitor of CaMKII, tatCN19o, shows effective and potent neuroprotection in animal models of GCI that closely mimic the most relevant human conditions: cardiopulmonary resuscitation (CPR) after cardiac arrest in mice or after ventricular fibrillation in pigs. When our CaMKII inhibitors were injected i.v. at a clinically relevant timepoint after GCI, they provided dramatic improvement over therapeutic hypothermia alone (the current standard of care); after combination with therapeutic hypothermia, only residual and barely detectable neuronal cell death was seen. Neuroprotection manifested on the anatomical, synaptic, and behavioral level. Target validation has been done using mutant mice with impaired CaMKII signaling. Target engagement has been characterized by biochemical and structural studies. This current lead compound has been optimized for potency (ki of 0.1 nM) and selectivity (>100,000x compared to the most closely related kinases). Intellectual property protection for tatCN19o is in place. The tatCN19o peptide is a tight-binding active kinase inhibitor that only engages the CaMKII fraction that remains hyperactivated after ischemic insult. These features enable optimal efficacy at an extremely low dose (0.01 mg/kg i.v.). TatCN19o is a cell- and blood-brain- barrier –penetrating 30mer peptide that is readily soluble in water or saline and highly stable in lyophilized or solubilized formulation (to be further characterized here). Current data suggest a favorable safety profile (also to be further characterized here), including lack effects on memory. These characteristics enable straightforward preparation of an injectable for clinical use in humans. Notably, tatCN19o inhibits rodent and human CaMKII equally well. Phase I of this project achieved the proposed key preclinical milestones for tatCN19o, including: characterize binding kinetics of dissociation from target, establish a quantitative method for detection in plasma, and evaluate pharmacokinetics in safety species. To enable testing in humans, this SBIR project will conduct studies required for a successful IND application, including (1) an in vivo extension of our in vitro characterization from Phase I, (2) formulation development, (3) pivotal safety studies, and (4) regulatory document preparation. The results of this proposal will serve as critical components of an IND application to the FDA, in preparation for a Phase I clinical trial and ultimately commercialization. Our Pre-IND meeting is planned for the end of year 1. The clinical/market potential for tatCN19o as a GCI therapeutic is detailed in the Commercialization Plan.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $1,833,347 )
2025	2025	NEUREXIS THERAPEUTICS, INC.	12635 E MONTVIEW BLVD	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/15/2025	NON-COMPETING CONTINUATION	$1,833,347
														Subtotal = $1,833,347

Issue Date FY: 2024 ( Subtotal = $938,239 )
2024	2024	NEUREXIS THERAPEUTICS, INC.	12635 E MONTVIEW BLVD	AURORA	CO	80045	ADAMS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	9/10/2024	COMPETING CONTINUATION	$938,239
														Subtotal = $938,239

Grand Total All Awards = $2,771,586

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IND-enabling studies for a potent and efficient neuroprotective drug

Award Number: R44NS120427

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/24/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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