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.

抽象的脊髓损伤、多发性硬化症、帕金森病、脊柱裂、中风以及并发症由于衰老和糖尿病，可能会失去对肠道和膀胱功能的自主控制，从而导致同一患者的大便失禁和尿失禁以及尿潴留的情况。应用程序将使 Dignify Therapeutics 能够完成按需、快速的临床前开发起效（< 5 分钟）、短时（< 10 分钟）、药物诱导、排尿疗法，以恢复肠道自主控制以及上述患者群体的膀胱功能。该项目最终将提交一份报告。 DTI-117 的研究性新药申请 (IND) 并完成 I 期临床研究。神经激肽 2 受体 (NK2R) 位于排便和排尿途径的多个位点，特别是结直肠和膀胱平滑肌的临床前体外和体内研究。包括人体组织在内的多个物种已表明 NK2R 的激活会产生强大的结肠和我们之前的临床前研究表明，当通过肌肉注射给药时，静脉内、皮下、鼻内或舌下途径，NK2R激动剂，包括DTI-117，可迅速引起结直肠和膀胱压力短暂增加，从而产生排尿和排便。 DTI-117 目前由 Dignify Therapeutics 进行临床前开发，由 NINDS CREATE Bio 负责。 Optimization Track 奖 U44NS106685，DTI-117 的功效、选择性和初步安全性已获得建立了符合 GMP 的合成路线、理化表征、分析方法， NK2R 与多种常见的生物分析测定、体外表征和靶标选择性药物靶点均已确定，通过快速排便和排便来衡量。排尿，已被证明，体内药代动力学特征模拟体内药效学迄今为止完成的一般毒性研究表明 DTI-117 既安全又有效。 DTI-117临床前开发的最后一步是提交新药研究申请（IND） FDA 指南要求在开始临床研究之前提供可接受的毒理学和安全性资料。在良好实验室规范 (GLP) 条件下进行的临床前研究证明了同时，原料药和药品必须按照严格的规定进行生产。 FDA 规定完成本申请中描述的这些活动将使 IND 申请成为可能。 DTI-117。