Preclinical characterization of a novel neuropeptide for inducing "on-demand" voiding

PROJECT SUMMARY (ABSTRACT) Spinal cord injury (SCI) affects an estimated 285,000 Americans. Damage to nerves in the spinal cord can result in a loss of voluntary control over bladder and bowel function that often produces both incontinence and retention of urine and stools in the same patient. The standard of care for urine retention is bladder catheterization to void urine, which may produce urinary tract infections (UTIs) and hospitalization. Retention of feces requires manual extraction bowel programs, which are extremely time consuming, can contribute to UTIs, and are stigmatizing for patients and caregivers. Because bladder and bowel dysfunction are among the top concerns of people with SCI, a convenient and safe “on-demand, rapid-onset, short-duration, drug-induced, voiding therapy” would be a life-changing paradigm shift in treating bladder and bowel dysfunction for those who currently rely on life-long multiple daily catheterizations and daily digital bowel programs. Dignify Therapeutics is developing next-generation potent and selective neurokinin 2 receptor (NK2R) agonists to produce “on-demand” voiding in people with SCI. In a series of proof-of-concept studies, the prototype NK2R agonist, DTI-100, rapidly induced bladder and bowel voiding in multiple animal models. A next- generation NK2R agonist, DTI-117, has been identified that has optimized selectivity and, potentially, an improved pharmacokinetic (PK) profile for subcutaneous administration. Like DTI-100, DTI-117 exhibits properties that support a target product profile of rapid-onset, short-duration, drug-induced voiding. In addition, due to its greater target selectivity, DTI-117 potentially has a greater therapeutic index than DTI-100. Dignify is now advancing DTI-117 through preclinical development as its lead NK2R agonist. This Fast-Track CREATE Bio Optimization Track U44 application is focused on extensive preclinical characterization of DTI- 117 for subsequent IND-enabling studies and future support from the CREATE Bio Development program. Phase I activities will establish successful synthesis, stability, and bioanalytical measurement of DTI-117, and determine the therapeutic index (TI) for DTI-117 in dog. Phase II activities will complete preclinical characterization of DTI-117 and provide additional toxicity and safety assessments prior to the initiation of IND- enabling studies. The proposed project will allow Dignify Therapeutics to develop an optimized “on-demand, rapid-onset, short- duration, drug-induced, voiding therapy” to treat bladder and bowel dysfunction in people with SCI. This therapy would greatly improve quality of life for people with SCI, reduce UTIs and associated health risks, and decrease overall healthcare costs.PROJECT NARRATIVE The ultimate aim of this project is to provide a novel pharmaceutical treatment that will produce convenient, efficient, and safe on-demand voiding of bladder and bowel in people with spinal cord injury (SCI). Many people with SCI currently rely on life-long, multiple daily catheterizations and life-long, daily, digital bowel programs to void urine and feces, respectively. This grant will enable the advancement of an optimized therapy with reduced risk of side-effects. Success of our project will restore individual dignity, improve daily quality of life and health, and reduce associated health care costs for individuals who have diminished voluntary bladder and bowel control.