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

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

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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，帕金森氏病，脊柱裂和中风以及并发症由于衰老和糖尿病，可能会导致对肠和膀胱功能的自愿控制丧失在粪便和尿失禁以及同一患者的保留率中。提出的活动应用将使尊严的治疗学能够完成按需快速的临床前开发发作（<5分钟），短期（<10分钟），药物诱导的，排尿的治疗，以恢复碗的自愿控制上面列出的患者人群的膀胱功能。该项目将在提交 DTI-117的研究新药应用（IND）和I期临床研究的完成。 Neurokinin 2受体（NK2R）位于定义和排尿途径的几个位置，尤其是结直肠和膀胱光滑肌肉。临床前体外和体内研究包括人体组织在内的几种物种表明，NK2RS的激活会产生有力的结肠和膀胱收缩。我们以前的临床前研究表明，当通过肌肉内施用时静脉注射，皮下，鼻内或舌下路线，NK2R激动剂，包括DTI-117，迅速诱导的瞬态增加了结直肠和膀胱压力，产生了排尿和定义。 DTI-117目前通过尊严的治疗剂正在临床前开发。在Ninds下创建生物 DTI-117的优化轨道奖U44NS106685，效率，选择性和初步安全性已确立的。符合GMP的合成途径，物理表征，分析方法，生物分析测定，体外表征以及NK2RS的目标选择性与多个常见都建立了药物靶标。临床前效率，以快速发作的排便和排尿已被证明，体内药代动力学特征模仿体内药效学概况。一般毒性研究完成了迄今为止，表明DTI-117既安全有效又有效。 DTI-117临床前开发的最后一步是提交研究新药应用（IND）在开始临床研究之前。 FDA指南要求可接受的毒理学和安全概况在良好的实验室实践（GLP）条件下进行的临床前研究证明了包含在印度。同时，必须根据严格制造药物和药物产品 FDA法规。如本申请中所述完成这些活动的完成将使IND提交 DTI-117。