EPICERTIN for Mucosal Healing in Ulcerative Colitis

项目摘要 我们已经开发了一种候选产品，可以在溃疡性结肠炎(UC)模型中诱导结肠上皮修复。加州大学 由一种主要类型的炎症性肠病组成，以慢性和复发为特征 胃肠道(GI)的炎症。UC发生在远端胃肠道最内侧的粘膜层 以一种连续的方式，通常从直肠开始并扩散到结肠。溃疡性结肠炎残存的病因学 难以捉摸；遗传和环境因素似乎触发了失调的粘膜免疫反应，导致 导致慢性炎症、肠屏障功能紊乱和结肠上皮损伤。缺少一个 确切的原因是，目前还没有针对UC的预防或根治疗法。常规治疗 目的是钝化炎症，建立和维持临床缓解，粘膜愈合，降低发病风险 并发症和改善生活质量。实现粘膜愈合是公认的一个重要的临床 UC治疗的终点，因为它与持续的临床缓解、改善的生活质量、 临床研究表明，手术干预和癌症发病率较少。然而，目前的UC药物可以 不能有效地诱导粘膜愈合，因为仅仅抑制炎症并不一定会促进组织 修复，这是一个复杂和动态的过程，必须涉及肠道屏障功能的恢复 同时减轻有害的炎症。因此，开发一种上皮伤口修复剂将 填补了UC管理的一个重要空白。 我们的主要产品EPICERTIN是一种来自霍乱毒素B亚单位的重组蛋白，它已经被 用含有KDEL内质网滞留信号的C-末端多肽进行基因修饰。这 外源性简单修饰对结肠上皮损伤愈合活性的影响。EPICERTIN是我们的领头羊 通过上皮屏障修复治疗UC的有效药物成分。路易斯维尔大学(UofL) 研究人员发明了EPICERTIN并广泛表征了其生物学作用模式(MOA)和 对急、慢性结肠炎动物模型的治疗作用。MOA涉及一种未折叠的蛋白质 所有的初步研究都强调了口服或结肠的高度安全性和耐受性 对动物的管理。我们已经开始与FDA进行IND前的讨论，并已收到首批代理 指导意见，大大降低了监管风险。遵循FDA和NIH审查员的 建议，UofL及其商业合作伙伴Growth Biomedicine LLC正在启动以产品为重点的计划 通过这一第一阶段STTR项目开发EPICERTIN，目标是：(1)进一步探索剂量效应 UC大鼠模型的体内关系以支持未来的药效学和毒性研究，以及(2) 扩大我们生物分析方法的应用范围，以定量犬血浆中的药物，并使用 这两项研究的结果旨在修订我们的非临床开发计划，并寻求机构的进一步投入以支持 未来IND提交的首个人类临床研究报告。

Project Summary We have developed a candidate product that induces colon epithelial repair in ulcerative colitis (UC) models. UC comprises a major type of inflammatory bowel disease and is characterized by chronic and relapsing inflammation in the gastrointestinal (GI) tract. UC develops in the innermost mucosal layer of the distal GI tract in a continuous manner, usually starting at the rectum and spreading into the colon. The etiology of UC remains elusive; genetic and environmental factors appear to trigger dysregulated mucosal immune responses, leading to chronic inflammation, disrupted intestinal barrier function and epithelial damage in the colon. Lacking a definitive cause, no preventative or curative therapies have been developed for UC. Conventional treatments aim to blunt inflammation, establish and maintain clinical remission, mucosal healing, decrease the risk of complications and improve quality of life. Achieving mucosal healing is recognized as an important clinical endpoint in UC treatment, as it is closely associated with sustained clinical remission, improved quality of life, fewer surgical interventions and cancer incidence, as shown in clinical studies. However, current UC drugs do not effectively induce mucosal healing because merely inhibiting inflammation will not necessarily facilitate tissue repair, which is a complex and dynamic process that must involve the restoration of the intestinal barrier function along with alleviation of detrimental inflammation. Thus, development of an epithelial wound repair agent will fill an important gap for the management of UC. Our lead product, EPICERTIN, is a recombinant protein derived from cholera toxin B subunit that has been modified genetically with a C-terminal peptide containing the KDEL endoplasmic reticulum retention signal. This simple modification instills in EPICERTIN the colon epithelial wound healing activity. EPICERTIN is our lead active pharmaceutical ingredient for managing UC via epithelial barrier recovery. University of Louisville (UofL) researchers invented EPICERTIN and extensively characterized its biological mode of action (MOA) and therapeutic effects in acute and chronic animal models of colitis. The MOA involves an unfolded protein response, and all preliminary studies have underscored high safety and tolerability upon oral or colonic administrations to animals. We have initiated pre-IND discussions with FDA and have received initial Agency guidance, which has substantially reduced regulatory risk. Following FDA’s and NIH reviewers’ recommendations, UofL and its commercial partner GROW Biomedicine LLC are initiating product-focused development of EPICERTIN through this Phase I STTR project with the goals of: (1) further exploring dose-effect relationships in vivo in a rat model of UC to support future pharmacodynamic and toxicity studies, and (2) expanding the range of applications of our bioanalytical method to quantify the drug in canine plasma, and using the results of the two aims to revise our nonclinical development plan and seek further Agency input to support a future IND submission for a first-in-human clinical study.