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

按需排尿新药的临床前和早期临床开发

基本信息

批准号：
10569279
负责人：
Edward Burgard
金额：
$ 49.94万
依托单位：
DIGNIFY THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10569279
关键词：
Acute Aging Agonist Award Biological Assay Bladder Cardiovascular system Catheterization Central Nervous System Clinical Clinical Research Colon Colorectal Cytochrome P450 Defecation Diabetes Mellitus Disease Dose Drug Interactions Drug Kinetics Drug Targeting Electronics Electrophysiology (science)Enzymes Ethers Fecal Incontinence Funding Future Genes Genetic Good Manufacturing Process Grant Guidelines Human In Vitro Incontinence Intestines Intramuscular Intramuscular Injections Intravenous Investigational New Drug Application Macaca fascicularis Measurement Measures Mediating Miniature Swine Monitor Multiple Sclerosis Mutation National Institute of Neurological Disorders and Stroke Parkinson Disease Pathway interactions Patients Peptide Receptor Persons Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Plasma Preparation Rattus Recommendation Recovery Regulation Route Safety Sampling Site Smooth Muscle Spinal Dysraphism Spinal cord injury Sterility Stroke Substance K Receptor Therapeutic Toxic effect Toxicokinetics Toxicology Urinary Incontinence Urinary Retention Urination Validation analytical method clinical development digital good laboratory practice healthy volunteer human tissue in vivo manufacture manufacturing test meetings micronucleus nervous system disorder nonhuman primate novel novel therapeutics patient population phase 2 study pre-clinical preclinical development preclinical efficacy preclinical study pressure programs respiratory safety assessment safety practice safety study stability testing subcutaneous

项目摘要

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.

摘要