Development of potential delivery methods for treating voiding dysfunction associated with SCI

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 DESCRIPTION (provided by applicant): Spinal cord injury (SCI) can result in loss of voluntary control over bladder and bowel function, often producing both incontinence and retention of urine and stools in the same patient. This has a profound impact on the mental and physical health status and quality of life of patients as well as a large impact on health care costs. For example, urinary retention is generally 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 themselves 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 patients, not to mention a significant reduction in individual and community health care costs. Similarly, "on-demand" bowel control would provide substantial improvement in QOL for people with neurogenic bowel. Dignify Therapeutics is developing an "on-demand, rapid-onset, short-duration, drug-induced voiding" therapy using an analogue of neurokinin A - [Lys5,MeLeu9,Nle10]-NKA(4-10) - (aka DTI-100). DTI-100 is a potent and selective agonist of the NK2 receptor, which induces powerful contractions of the human bladder and rectum in vitro and provides highly promising in vivo voiding efficacy, safety, and pharmacodynamic (PD) profiles in various dog and rat models following intravenous (IV) administration. Presently, the overarching objective of its development program is to discover a formulation that is more convenient than the IV formulation for people with SCI but maintains its therapeutic benefit. Thus, this Phase I application aims to compare - onset of action, duration of action, potency, and efficacy - of DTI-100 delivered IV with the following 3 alternative routes: subcutaneous (SC), intramuscular (IM), and intranasal (IN); using a simple (but clinically relevant) anesthetized, acute spinal rat cystometry model. It is important to quantify and understand the differences in efficacy, potency, onset and duration of action of these various routes of delivery, because these factors will impact efficacy, tolerability, convenience, and cost of product for the patient. Thus a careful decision regarding formulation is critical to maximizing commercial and health care benefits. Our Phase II application will test the preferred route(s) of administration i a translational chronic SCI animal model, examine the effects of DTI-100 on urethral activity, determine the pharmacokinetic profile of DTI-100, and conduct preclinical safety/toxicology studies to establish the final formulation for clinical studies.