Development of potential delivery methods for treating voiding dysfunction associated with SCI

 描述（由申请人提供）：脊髓损伤（SCI）可导致对膀胱和肠功能的自主控制丧失，通常在同一患者中产生尿失禁和尿便潴留。这对患者的身心健康状况和生活质量产生了深远的影响，对医疗保健费用也产生了很大的影响。例如，尿潴留通常是不可逆的，并且可能危及生命。唯一可用的药物治疗包括胆碱能激动剂，其具有最小的功效和严重的副作用。因此，患者每天多次导尿以排空膀胱。导尿管的使用与健康问题的发生率增加有关，主要是反复尿路感染、败血症、隔离、抑郁和住院。 一个“按需”，安全有效，药物替代导尿管将是一个改变生活的改善日常膀胱管理的患者，更不用说显着减少个人和社区的医疗保健费用。类似地，“按需”排便控制将为神经源性肠道患者的生活质量提供实质性改善。Dignify Therapeutics正在开发一种“按需，快速起效，持续时间短，药物诱导的排尿”疗法，使用神经激肽A - [Lys 5，MeLeu 9，Nle 10]-NKA（4-10）-（又名DTI-100）的类似物。DTI-100是NK 2受体的强效和选择性激动剂，其在体外诱导人膀胱和直肠的强力收缩，并在静脉内（IV）给药后在各种犬和大鼠模型中提供非常有希望的体内排尿功效、安全性和药效学（PD）特征。目前，其开发计划的首要目标是发现一种比IV制剂更方便的SCI患者制剂，但保持其治疗益处。因此，该I期申请旨在使用简单的（但临床相关的）麻醉的急性脊髓大鼠膀胱测压模型，比较IV递送的DTI-100与以下3种替代途径的起效时间、作用持续时间、效力和功效：皮下（SC）、肌内（IM）和鼻内（IN）。重要的是量化和理解这些不同递送途径在功效、效力、起效和作用持续时间方面的差异， 因为这些因素会影响患者的疗效、耐受性、便利性和产品成本。因此，关于配方的谨慎决定对于最大化商业和卫生保健益处至关重要。我们的II期申请将在平移慢性SCI动物模型中测试优选的给药途径，检查DTI-100对尿道活动的影响，确定DTI-100的药代动力学特征，并进行临床前安全性/毒理学研究以建立用于临床研究的最终制剂。

 DESCRIPTION (provided by applicant): Spinal cord injury (SCI) can result in loss of voluntary control over bladder and bowel function, often producing both incontinence and retention of urine and stools in the same patient. This has a profound impact on the mental and physical health status and quality of life of patients as well as a large impact on health care costs. For example, urinary retention is generally irreversible and can be life threatening. The only available pharmacotherapy consists of cholinergic agonists, which have minimal efficacy and severe side effects. Consequently, patients catheterize themselves multiple times daily to empty their bladder. Catheter use is associated with increased incidence of health problems, predominately repeated urinary tract infections, sepsis, isolation, depression and hospitalization. An "on demand", safe and effective, pharmaceutical alternative to catheterization would be a life-changing improvement in the daily routine of bladder management for patients, not to mention a significant reduction in individual and community health care costs. Similarly, "on-demand" bowel control would provide substantial improvement in QOL for people with neurogenic bowel. Dignify Therapeutics is developing an "on-demand, rapid-onset, short-duration, drug-induced voiding" therapy using an analogue of neurokinin A - [Lys5,MeLeu9,Nle10]-NKA(4-10) - (aka DTI-100). DTI-100 is a potent and selective agonist of the NK2 receptor, which induces powerful contractions of the human bladder and rectum in vitro and provides highly promising in vivo voiding efficacy, safety, and pharmacodynamic (PD) profiles in various dog and rat models following intravenous (IV) administration. Presently, the overarching objective of its development program is to discover a formulation that is more convenient than the IV formulation for people with SCI but maintains its therapeutic benefit. Thus, this Phase I application aims to compare - onset of action, duration of action, potency, and efficacy - of DTI-100 delivered IV with the following 3 alternative routes: subcutaneous (SC), intramuscular (IM), and intranasal (IN); using a simple (but clinically relevant) anesthetized, acute spinal rat cystometry model. It is important to quantify and understand the differences in efficacy, potency, onset and duration of action of these various routes of delivery, because these factors will impact efficacy, tolerability, convenience, and cost of product for the patient. Thus a careful decision regarding formulation is critical to maximizing commercial and health care benefits. Our Phase II application will test the preferred route(s) of administration i a translational chronic SCI animal model, examine the effects of DTI-100 on urethral activity, determine the pharmacokinetic profile of DTI-100, and conduct preclinical safety/toxicology studies to establish the final formulation for clinical studies.