Preclinical and Early Clinical Development of a Novel Drug for On-Demand Voiding

ABSTRACT
Spinal cord injury, multiple sclerosis, Parkinson’s disease, spina bifida, and stroke, as well as complications
due to aging and diabetes, can produce a loss of voluntary control over bowel and bladder function resulting
in both fecal and urinary incontinence as well as retention in the same patient. The activities proposed in this
application will enable Dignify Therapeutics to complete preclinical development of an on-demand, rapid-
onset (< 5 min), short-duration (< 10 min), drug-induced, voiding therapy to restore voluntary control of bowel
and bladder function for the patient populations listed above. This project will culminate in the filing of an
Investigational New Drug Application (IND) for DTI-117 and completion of a Phase I clinical study.
Neurokinin 2 receptors (NK2Rs) are located at several sites in the defecation and micturition pathways,
particularly the colorectal and urinary bladder smooth muscles. Preclinical in vitro and in vivo studies in
several species, including human tissue, have shown that activation of NK2Rs produces forceful colonic and
bladder contractions. Our previous preclinical studies showed that when administered via intramuscular,
intravenous, subcutaneous, intranasal, or sublingual routes, NK2R agonists, including DTI-117, rapidly
induced transient increases in colorectal and bladder pressures that produced urination and defecation.
DTI-117 is currently in preclinical development by Dignify Therapeutics. Under NINDS CREATE Bio
Optimization Track award U44NS106685, efficacy, selectivity, and preliminary safety of DTI-117 has been
established. A GMP-compliant synthetic route, physicochemical characterization, analytical methods,
bioanalytical assays, in vitro characterization, and target selectivity for NK2Rs versus multiple common
drug targets have all been established. Preclinical efficacy, measured as rapid-onset defecation and
urination, has been demonstrated, and in vivo pharmacokinetic profiles mimic in vivo pharmacodynamic
profiles. General toxicity studies completed to-date indicate that DTI-117 is both safe and effective.
The final step for preclinical development of DTI-117 is to file an Investigational New Drug application (IND)
prior to initiation of clinical studies. FDA guidelines require that acceptable toxicological and safety profiles
are demonstrated in preclinical studies conducted under Good Laboratory Practice (GLP) conditions for
inclusion in the IND. In parallel, drug substance and drug product must be manufactured according to strict
FDA regulations. Completion of these activities as described in this application will enable an IND filing for
DTI-117.

Grant Number: 5U44NS129628-03
NIH Institute/Center: NIH
Principal Investigator: Edward Burgard