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、帕金森氏病、脊柱裂、中风以及并发症 由于衰老和糖尿病，会产生自主控制大便和膀胱功能的丧失而导致 在同一患者的大小便失禁和尿失禁中。本报告中提议的活动 应用将使Digitify Treateutics能够完成按需、快速- 起病(&lt；5分钟)、持续时间短(&lt；10分钟)、药物诱导、排尿治疗以恢复自主排便 以及上述患者群体的膀胱功能。这个项目的最终结果是提交一份 DTI-117的研究性新药申请(IND)和完成I期临床研究。 神经激肽2受体(NK2Rs)位于排尿和排尿途径的多个部位， 尤其是结直肠和膀胱的平滑肌肉。临床前的体外和体内研究 包括人类组织在内的几个物种已经表明，NK2Rs的激活会产生强大的结肠和 膀胱收缩。我们之前的临床前研究表明，当通过肌肉注射给药时， 静脉、皮下、鼻腔或舌下途径，NK2R激动剂，包括DTI-117，迅速 引起一过性结直肠和膀胱压力升高，导致排尿和排便。 DTI-117目前正由Diguify Treeutics进行临床前开发。在NINDS Create Bio下 优化跟踪奖U44NS106685，DTI-117的有效性、选择性和初步安全性已被 已经成立了。符合GMP的合成路线、物理化学表征、分析方法、 NK2Rs与多种常见受体的生物分析分析、体外表征和靶向选择性 毒品目标都已确定。临床前疗效，以快速排便和 排尿，已被证实，体内药代动力学曲线模拟体内药效学 配置文件。到目前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新药研究申请(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性描述 在良好实验室操作规范(GLP)条件下进行的临床前研究证明 包含在IND中。同时，药材和药品必须严格按规定生产 FDA的规定。完成本申请中描述的这些活动将使IND申请 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.