Document text
Principal Investigator: Edward Burgard
Organization: DIGNIFY THERAPEUTICS, LLC
Fiscal Year: 2024
Award: $1,473,895
Funding agency: National Institute of Neurological Disorders and Stroke
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.
Terms: <Acute><Aging><Agonist><Anal Incontinence><Apoplexy><Assay><Award><Bioassay><Biological Assay><Bladder><Bladder Urinary System><Blood Plasma><Bowel incontinence><Brain Vascular Accident><CNS Nervous System><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Catheterization><Central Nervous System><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Clinical><Clinical Research><Clinical Study><Colon><Colon or Rectum><Colorectal><Common Rat Strains><Crab-Eating Macaque><Crab-Eating Monkey><Cynomolgus Monkey><Cynomolgus macaque><Cytochrome P-450><Cytochrome P-450 Enzyme System><Cytochrome P450><Cytochrome P450 Family Gene><Defecation><Diabetes Mellitus><Disease><Disorder><Disseminated Sclerosis><Dose><Drug Interactions><Drug Kinetics><Drug Targeting><Drugs><Electronics><Electrophysiology><Electrophysiology (science)><Enzyme Gene><Enzymes><Ethers><Fecal Incontinence><Funding><Future><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Good Manufacturing Process><Good manufacturing practice><Grant><Guidelines><Heart Vascular><Human><In Vitro><Incontinence><Intestinal><Intestines><Intramuscular><Intramuscular Injections><Intravenous><Investigational New Drug Application><Involuntary Muscle><M fascicularis><M. fascicularis><Macaca fascicularis><Measurement><Measures><Mediating><Medication><Miniature Swine><Minipigs><Modern Man><Monitor><Multiple Sclerosis><Mutation><NINDS><NK-2 Receptor Site><NK-2 Receptors><National Institute of Neurological Diseases and Stroke><National Institute of Neurological Disorders and Stroke><Nervous System Diseases><Nervous System Disorder><Neuraxis><Neurokinin A Receptors><Neurokinin-2 Receptors><Neurologic Disorders><Neurological Disorders><Neurophysiology / Electrophysiology><P450><Paralysis Agitans><Parkinson><Parkinson Disease><Pathway interactions><Patients><Peptide Receptor><Persons><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacodynamics><Pharmacokinetics><Pharmacologic Substance><Pharmacological Substance><Phase><Plasma><Plasma Serum><Preparation><Primary Parkinsonism><Rat><Rats Mammals><Rattus><Recommendation><Recovery><Regulation><Reticuloendothelial System, Serum, Plasma><Route><SP-K Receptors><Safety><Sampling><Schistorrhachis><Site><Smooth Muscle><Spina Bifida><Spinal Cord Trauma><Spinal Dysraphia><Spinal Dysraphism><Spinal Trauma><Spinal cord injured><Spinal cord injury><Sterility><Stroke><Substance K Receptor><Therapeutic><Toxic effect><Toxicities><Toxicokinetics><Toxicology><Traumatic Myelopathy><Urinary Incontinence><Urinary Retention><Urination><Validation><analytical method><bowel><bowel movement><brain attack><cerebral vascular accident><cerebrovascular accident><circulatory system><cleft spine><clinical development><colorectum><diabetes><digital><drug/agent><electronic><electronic device><electrophysiological><genome mutation><good laboratory practice><healthy volunteer><human tissue><hydrocele spinalis><in vivo><insular sclerosis><intramuscular drug administration><manufacture><manufacturing test><meeting><meetings><micronucleus><micturition><mini pig><mini-swine><miniswine><neurological disease><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><non-human primate><nonhuman primate><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathway><patient population><pharmaceutical><phase 2 study><phase II study><pre-clinical><pre-clinical development><pre-clinical efficacy><pre-clinical study><preclinical><preclinical development><preclinical efficacy><preclinical study><preparations><pressure><programs><rachischisis posterior><respiratory><safety assessment><safety practice><safety study><stability testing><sterile><stroked><strokes><subcutaneous><subdermal><urinary bladder><validations>