Preclinical and Early Clinical Development of a Novel Drug for On-Demand Voiding

摘要 脊髓损伤、多发性硬化症、帕金森病、脊柱裂和中风以及并发症 由于衰老和糖尿病，可以产生对肠和膀胱功能的自主控制的丧失， 大便失禁和尿失禁以及尿潴留在同一个病人。本报告中提出的活动 应用程序将使Dignify Therapeutics能够完成按需，快速， 起效时间（< 5分钟）、持续时间短（< 10分钟）、药物诱导、排尿治疗，以恢复自主排便控制 和膀胱功能。该项目将最终在一个文件的 DTI-117的研究性新药申请（IND）和I期临床研究的完成。 神经激肽2受体（NK 2 R）位于排便和排尿途径中的几个位点， 特别是结肠直肠和膀胱平滑肌。临床前体外和体内研究 包括人类组织在内的几个物种已经表明，NK 2 R的激活产生强有力的结肠和结肠炎， 膀胱收缩我们以前的临床前研究表明，当通过肌肉注射时， 静脉内、皮下、鼻内或舌下途径，NK 2 R激动剂，包括DTI-117， 引起结肠直肠和膀胱压力的短暂增加，引起排尿和排便。 DTI-117目前正由Dignify Therapeutics进行临床前开发。在NINDS CREATE Bio 优化跟踪奖U44 NS 106685，DTI-117的有效性，选择性和初步安全性已被 确立了习符合GMP的合成路线、理化表征、分析方法， 生物分析测定、体外表征和NK 2 R与多种常见 药物靶点都已确定。临床前疗效，以快速排便和 排尿，已被证明，体内药代动力学特征模拟体内药效学 数据区.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研究性新药申请（IND） 在临床研究开始之前。FDA指南要求可接受的毒理学和安全性特征 在药物非临床研究质量管理规范（GLP）条件下进行的临床前研究中证明， 同时，原料药和制剂必须按照严格的标准生产。 FDA法规。完成本申请中所述的这些活动将使IND申请成为可能， DTI-117。

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.