An optimized NK2R agonist for 'on-demand' voiding

项目摘要 膀胱活动不足（UAB）是一个重要的临床问题，在老年人。UAB的特点是弱 膀胱收缩和不完全膀胱排空导致排尿频率，排尿困难， 和尿失禁，并可能导致严重的并发症，如永久性膀胱和肾脏损伤。 年龄相关的UAB可能会影响近25%的60岁以上的美国人，以及近三分之二的失禁护理 居民展示了UAB。在全球范围内，预期寿命的增加预计将增加患者数量 UAB和下尿路症状目前的标准治疗，以实现完全膀胱 UAB患者的排空是间歇性导管插入。虽然药物治疗有时被用来 管理较温和形式的UAB，目前可用的那些疗效和耐受性较差， 由于多种副作用，适合老年患者使用。一种安全有效的产品， 有效、完全的排泄将为UAB的管理提供范式转变。 Dignify Therapeutics正在开发下一代强效和选择性NK2R激动剂，以按需生产 排尿作为UAB的治疗方法。药物引起的副作用，如低血压是一个特别关注的问题， 老年人，因为他们可能导致精神混乱，流动性差，和衰弱的福尔斯。因此，一个选择性的，短暂的 持续性NK2R激动剂将是用于该群体所希望。在第一阶段，两个下一代NK2R 已经鉴定了具有优化的选择性、改善的药代动力学（PK）曲线和改善的药物代谢的激动剂。 治疗指标在该第二阶段项目中， 一天将开发和测试的有效性和改善的副作用概况，在成人和老年人临床前 动物模型优化的NK2R的原型鼻内（IN）和口腔崩解片剂（ODT）制剂 激动剂将被开发和制造用于临床前研究。经确认的血浆生物分析方法 还将开发检测。治疗指数、药效学（PD）和PK特征将被 在老年大鼠中进行急性和重复长期IN给药后， 制剂将在麻醉和清醒的狗中表征。 拟议的第二阶段项目将允许Dignify Therapeutics开发一种优化的“按需， 快速起效、持续时间短、药物诱导的排尿疗法”来治疗老年人的UAB。这种优化疗法 将通过提供更大的靶选择性和减少的 行动上这种疗法将大大改善UAB老年人的日常生活，减少UTI， 相关的健康风险，并降低整体医疗成本。

PROJECT SUMMARY Underactive bladder (UAB) is a clinically important problem in the elderly. UAB is characterized by weak bladder contractions and incomplete bladder emptying that result in symptoms of voiding frequency, nocturia, and incontinence, and it can lead to serious complications such as permanent bladder and kidney damage. Aging-related UAB may affect almost 25% of Americans over 60, and nearly two-thirds of incontinent nursing home residents exhibit UAB. Globally, increased life expectancy is expected to increase the number of patients with UAB and lower urinary tract symptoms. The current standard treatment to achieve complete bladder emptying in UAB patients is intermittent catheterization. Although drug therapies are sometimes used to manage milder forms of UAB, those currently available have poor efficacy and tolerability and may not be suitable for use in elderly patients due to multiple side effects. A safe and effective product that facilitates efficient, complete voiding would provide a paradigm shift in the management of UAB. Dignify Therapeutics is developing next-generation potent and selective NK2R agonists to produce on-demand voiding as a treatment for UAB. Drug-induced side effects such as hypotension are a particular concern in the elderly as they can lead to mental confusion, poor mobility, and debilitating falls. Thus, a selective, short duration NK2R agonist would be desirable for use in this population. In Phase I, two next-generation NK2R agonists were identified that have optimized selectivity, improved pharmacokinetic (PK) profiles, and improved therapeutic indices. In this Phase II project, prototype formulations for convenient administration several times a day will be developed and tested for efficacy and improved side effect profiles in adult and aged preclinical animal models. Prototype intranasal (IN) and orally disintegrating tablet (ODT) formulations of optimized NK2R agonists will be developed and manufactured for preclinical studies. Qualified bioanalytical methods for plasma detection will also be developed. The therapeutic index, pharmacodynamic (PD), and PK profiles will be characterized following acute and repeated long-term IN dosing in aged rats and optimized ODT and IN formulations will be characterized in anesthetized and awake dogs. The proposed Phase II project will allow Dignify Therapeutics to develop an optimized “on-demand, rapid-onset, short-duration, drug-induced, voiding therapy” to treat UAB in the elderly. This optimized therapy will reduce the risk of deleterious side effects by providing greater target selectivity and a reduced duration of action. This therapy would greatly improve the daily routine of elderly individuals with UAB, reduce UTIs and associated health risks, and decrease overall healthcare costs.