Research Project
8905338
? DESCRIPTION (provided by applicant): Neurological conditions, such as multiple sclerosis, Parkinson's disease, dementia, spina bifida, diabetes, stroke, and 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 urinary tract infections, sepsis, isolation, depression and hospitalization. An 'on demand', saf 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 'quality of life' 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 efficacy, safety, and pharmacodynamic (PD) profiles in various dog and rat models (spinal intact, SCI, and diabetes) following IV administration. Presently, the overarching objective of its development program is to discover a formulation that is more convenient for people with neurological conditions but maintains the therapeutic benefit of the IV formulation. The specific aims of the current Phase I application are to examine the suitability of an intranasal (IN) formulation and an orally- dissolving film (ODF) formulation. Based on previous work with systemic delivery of similar peptides from each of the formulations, it is anticipated that either may provide a stable dosage that provides rapid release, systemic absorption, and PD activity. The specific aims of this Phase I application are to compare stability and release rates of each formulation containing various media and to compare the in vivo activity of the most optimized formulations using a simple, but clinically relevant, anesthetized, acute spinal rat cystometry model. If positive results are obtained, detailed pharmacokinetic studies and testing in additional species and neuropathological models are proposed for Phase II studies.
