Loss of voluntary control over bladder and bowel function as a result of spinal cord injury (SCI) has profound impact on the mental and physical health status and quality of life of patients. It is estimated that 270,000 people in the USA have SCI ((www.nscisc.uab.edu/PublicDocuments/fact_figures_docs/.pdf). Urinary retention as a result of SCI is irreversible and can be life threatening. The only available pharmacotherapy consists of cholinergic agonists, which have minimal efficacy and severe side effects. Consequently, patients catheterize multiple times daily to empty their bladder. Catheter use is associated with increased incidence of health problems, predominately repeated urinary tract infections, sepsis, isolation, depression and hospitalization. An "on demand", safe and effective, pharmaceutical alternative to catheterization would be a life-changing improvement in the daily routine of bladder management for SCI patients, not to mention a significant reduction in individual and community health care costs. Dignify Therapeutics is a drug development company focused on advancing novel bladder - drug therapies for patients with SCI, multiple sclerosis and similar diseases that result in voiding dysfunction. By combining novel pharmaceutical, smooth muscle prokinetics with novel drug delivery technology, Dignify Therapeutics hopes to redefine treatment of voiding disorders and restore the dignity of voluntary excretory function for these patients in a way that mimics normal micturition. Phase I studies are proposed in spinally intact and SCI rats to confirm in vivo proof of concept (POC), provide intravenous (iv) dose ranges, and reveal any SCI-induced changes in drug sensitivity. Establishing a positive POC and iv dose ranges will serve as the basis for subsequent Phase II studies, which will use the iv "effective doses" data to establish therapeutic plasma concentrations and baseline PK and ADMET criteria to provide insight regarding the best mode(s) of clinical drug delivery. Although iv delivery might be acceptable in emergency situations, transdermal and/or transmucosal delivery would be preferable and are a primary aim of our SBIR Phase II grant. The SBIR Phase II grant will establish the final formulation for clinical studies (i.e. transdermal and/or transmucosal) which will be tested in a translational, chronic SCI, rat model to mimic administration in our phase 2 clinical trials. Differences in sensitivity between acute SCI versus control rats will set PK criteria that must be obtained in control rats in our SBIR phase II studies, as well as provide insight regarding differences between clinical phase 1 volunteers and clinical phase 2 SCI patients to account for potential differences in drug sensitivity.
The ultimate aim of this project is to provide paraplegic patients a pharmaceutical alternative to multiple daily catheterization of their bladder to void urine. Passage of a catheter into the urethra and bladder can be discomforting and stigmatized, and is associated with urinary tract infections and various other complications. Success of our project will restore patients'dignity and improve their daily quality of life and health, as well s reducing individual and community health care costs. This grant will provide proof of concept animal data for a novel drug to produce efficient voiding and hence provide an alternative to catheterization in patients with spinal cord injury (SCI).