Preclinical characterization of a novel neuropeptide for inducing "on-demand" voiding

用于诱导“按需”排尿的新型神经肽的临床前表征

基本信息

批准号：
10080913
负责人：
Edward Burgard
金额：
$ 182.36万
依托单位：
DIGNIFY THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10080913
关键词：
Acute Affect Agonist American Animal Model Beds Binding Binding Proteins Biological Assay Biological Availability Bladder Blood Vessels Canis familiaris Cardiovascular system Caregivers Catheterization Chinese Hamster Ovary Cell Chronic Climacteric Clinical Conscious Consumption Data Defecation Detection Development Dose Drug Kinetics Evaluation Exhibits Feces Fluorescence Functional disorder Future G-Protein-Coupled Receptors Grant Half-Life Health Health Care Costs Histopathology Hospitalization Human In Vitro Incontinence Individual Intestines Ion Channel Lead Life Manuals Measurement Measures Mediating Mesentery Methods Miniature Swine Molecular Target Nerve Neurokinin A Neuropeptides No-Observed-Adverse-Effect Level Oryctolagus cuniculus Patients Peptides Persons Pharmaceutical Preparations Pharmacologic Substance Phase Plasma Powder dose form Primates Program Development Property Quality of life Rattus Reproducibility Risk Series Spinal Cord Spinal cord injury Stigmatization Substance K Receptor TACR1 gene Telemetry Therapeutic Therapeutic Index Time Toxic effect Toxicology Urinary tract infection Urination Urine Validation active method base digital efficacy study hemodynamics improved in vivo meetings next generation novel peptide analog phase 1 testing pre-clinical preclinical development programs prototype release of sequestered calcium ion into cytoplasm safety assessment safety study side effect standard of care subcutaneous success treatment optimization vascular injury

项目摘要

PROJECT SUMMARY (ABSTRACT) Spinal cord injury (SCI) affects an estimated 285,000 Americans. Damage to nerves in the spinal cord can result in a loss of voluntary control over bladder and bowel function that often produces both incontinence and retention of urine and stools in the same patient. The standard of care for urine retention is bladder catheterization to void urine, which may produce urinary tract infections (UTIs) and hospitalization. Retention of feces requires manual extraction bowel programs, which are extremely time consuming, can contribute to UTIs, and are stigmatizing for patients and caregivers. Because bladder and bowel dysfunction are among the top concerns of people with SCI, a convenient and safe “on-demand, rapid-onset, short-duration, drug-induced, voiding therapy” would be a life-changing paradigm shift in treating bladder and bowel dysfunction for those who currently rely on life-long multiple daily catheterizations and daily digital bowel programs. Dignify Therapeutics is developing next-generation potent and selective neurokinin 2 receptor (NK2R) agonists to produce “on-demand” voiding in people with SCI. In a series of proof-of-concept studies, the prototype NK2R agonist, DTI-100, rapidly induced bladder and bowel voiding in multiple animal models. A next- generation NK2R agonist, DTI-117, has been identified that has optimized selectivity and, potentially, an improved pharmacokinetic (PK) profile for subcutaneous administration. Like DTI-100, DTI-117 exhibits properties that support a target product profile of rapid-onset, short-duration, drug-induced voiding. In addition, due to its greater target selectivity, DTI-117 potentially has a greater therapeutic index than DTI-100. Dignify is now advancing DTI-117 through preclinical development as its lead NK2R agonist. This Fast-Track CREATE Bio Optimization Track U44 application is focused on extensive preclinical characterization of DTI- 117 for subsequent IND-enabling studies and future support from the CREATE Bio Development program. Phase I activities will establish successful synthesis, stability, and bioanalytical measurement of DTI-117, and determine the therapeutic index (TI) for DTI-117 in dog. Phase II activities will complete preclinical characterization of DTI-117 and provide additional toxicity and safety assessments prior to the initiation of IND- enabling studies. The proposed project will allow Dignify Therapeutics to develop an optimized “on-demand, rapid-onset, short- duration, drug-induced, voiding therapy” to treat bladder and bowel dysfunction in people with SCI. This therapy would greatly improve quality of life for people with SCI, reduce UTIs and associated health risks, and decrease overall healthcare costs.

项目概要（摘要）脊髓损伤 (SCI) 影响了大约 285,000 名美国人脊髓神经受损。导致膀胱和肠道功能失去自主控制，常常导致失禁和同一患者出现尿潴留和粪便潴留尿潴留的标准治疗是膀胱治疗。导尿管排尿，这可能会导致尿路感染 (UTI) 和滞留。粪便需要手动提取，肠道程序非常耗时，可能会导致尿路感染对患者和护理人员来说是一种耻辱，因为膀胱和肠道功能障碍是其中之一。一种方便、安全的“按需、起效快、持续时间短、药物诱导、排尿疗法”将是治疗膀胱和肠道功能障碍的改变生活的范式转变目前，他们终生依赖于每日多次导尿和每日数字肠道计划。 Dignify Therapeutics 正在开发下一代强效选择性神经激肽 2 受体 (NK2R) 激动剂在一系列概念验证研究中，该原型可以让 SCI 患者产生“按需”排尿。 NK2R 激动剂 DTI-100 在多种动物模型中快速诱导膀胱和肠道排空。新一代 NK2R 激动剂 DTI-117 已被确定具有优化的选择性，并且有可能与 DTI-100 一样，DTI-117 具有改善的皮下给药药代动力学 (PK) 特性。支持快速起效、持续时间短、药物诱导排尿的目标产品特性。由于其更高的靶点选择性，DTI-117 可能比 DTI-100 具有更高的治疗指数。 Dignify 目前正在通过临床前开发推进 DTI-117 作为其领先的 NK2R 激动剂。 CREATE Bio Optimization Track U44 应用程序专注于 DTI 的广泛临床前表征 117 用于后续 IND 支持研究以及 CREATE Bio Development 计划的未来支持。第一阶段活动将建立 DTI-117 的成功合成、稳定性和生物分析测量，以及确定 DTI-117 在狗中的治疗指数 (TI) 将完成临床前研究。 DTI-117 的表征并在 IND 启动之前提供额外的毒性和安全性评估赋能研究。拟议的项目将使 Dignify Therapeutics 能够开发一种优化的“按需、快速起效、短期治疗” 持续时间、药物诱导、排尿疗法”来治疗 SCI 患者的膀胱和肠道功能障碍。治疗将大大改善 SCI 患者的生活质量，减少尿路感染和相关的健康风险，并且降低总体医疗费用。