EPICERTIN for Mucosal Healing in Ulcerative Colitis

表菌素用于溃疡性结肠炎粘膜愈合

• 批准号: 10602120
• 负责人: Daniel Tuse
• 金额: $ 27.36万
• 依托单位: GROW BIOMEDICINE LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10602120
• 关键词: Acute; Address; Affinity; Animal Model; Animals; Anti-Inflammatory Agents; Binding; Biological; Biological Response Modifier Therapy; Businesses; C-terminal; Canis familiaris; Cholera; Cholera Toxin Protomer B; Chronic; Clinic; Clinical; Clinical Research; Colitis; Collaborations; Colon; Colorectal; Communication; Complex; Consult; Data; Data Set; Development; Development Plans; Disease; Distal; Documentation; Dosage Forms; Dose; Drug Kinetics; Endoplasmic Reticulum; Enteral; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Epithelial; Epithelial Cells; Etiology; Exhibits; Exposure to; Feedback; Formulation; Frequencies; Future; Ganglioside GM1; Gastrointestinal tract structure; Genetic; Goals; Histopathology; Immunohistochemistry; Immunologic Surveillance; Immunosuppressive Agents; Impairment; Incidence; Inflammation; Inflammatory Bowel Diseases; Institution; Intellectual Property; Intracolonic; Lead; Malignant Neoplasms; Methods; Modeling; Modification; Molecular; Monoclonal Antibodies; Mucosal Immune Responses; Mucous Membrane; Mus; Natural regeneration; Operative Surgical Procedures; Oral; Patients; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phosphate Buffer; Plasma; Preventive therapy; Process; Property; Proteins; Protocols documentation; Quality of life; Rattus; Recombinant Proteins; Recommendation; Recovery; Rectum; Relapse; Research Personnel; Risk; Rodent; Safety; Sampling; Schedule; Signal Transduction; Small Business Technology Transfer Research; Sodium Dextran Sulfate; Therapeutic; Therapeutic Agents; Therapeutic Effect; Toxic effect; Treatment Efficacy; Trinitrobenzenesulfonic Acid; Ulcerative Colitis; United States National Institutes of Health; Universities; Variant; absorption; analytical method; base; clinical development; clinical remission; colitis associated cancer; conventional therapy; curative treatments; design; dextran sulfate sodium induced colitis; drug candidate; enema administration; epithelial repair; epithelial wound; first-in-human; gastrointestinal; healing; holotoxins; human study; improved; in vivo; indexing; infection risk; intestinal barrier; intestinal epithelium; murine colitis; non-Native; novel; novel therapeutics; pre-clinical; preclinical development; preclinical study; product development; rectal; repaired; residence; response; restoration; retrograde transport; tissue repair; virtual; wound healing

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.

项目摘要 我们已经开发了一种候选产品，该产品可诱导溃疡性结肠炎（UC）模型中的结肠上皮修复。 UC 包括主要类型的炎症性肠病，其特征是慢性和继电器 胃肠道（GI）的炎症。 UC在远端胃肠道的最内向粘膜层中发展 以连续的方式，通常从直肠开始，然后扩散到结肠中。 UC的病因仍然存在 难以捉摸遗传和环境因素似乎引发了失调的粘膜免疫反应，导致 为了慢性炎症，结肠中肠道屏障功能和上皮损伤受到干扰。缺乏 明确的原因，未开发针对UC的预防疗法或治愈疗法。常规治疗 旨在钝化炎症，建立和维持临床缓解，粘膜愈合，降低 并发症并改善生活质量。实现粘膜愈合被认为是重要的临床 UC治疗的终点，因为它与持续的临床缓解密切相关，改善生活质量， 如临床研究所示，较少的手术干预和癌症发病率。但是，当前的UC药物确实 不能有效诱导粘膜愈合，因为仅抑制感染不一定会促进组织 维修，这是一个复杂而动态的过程，必须涉及恢复肠壁功能 加上减轻有害感染的减轻。那就是上皮伤口修复剂的发展 填补对UC管理的重要空白。 我们的铅产物Epicertin是一种源自霍乱毒素B亚基的重组蛋白 用含有KDEL内质网保留信号的C末端肽的C末端肽进行了修饰。这 简单的修饰将结肠上皮伤口愈合活性灌输。 Epicertin是我们的领导 通过上皮屏障恢复来管理UC的主动药物诱导。路易斯维尔大学（UOFL） 研究人员发明了Epicertin，并广泛地表征了其生物学作用方式（MOA）和 结肠炎的急性和慢性动物模型的治疗作用。 MOA涉及展开的蛋白质 反应，所有初步研究都强调了口服或结肠上的高安全性和耐受性 对动物的管理。我们已经与FDA进行了预先讨论，并收到了初始代理商 指导大大降低了监管风险。遵循FDA和NIH审稿人的 建议，UOFL及其商业合作伙伴种植生物医学LLC是以产品为中心的 通过此阶段I STTR项目开发Epicertin的目标：（1）进一步探索剂量效应 UC大鼠模型中的体内关系，以支持未来的药效学和毒性研究，（2） 扩展我们的生物分析方法的应用范围，以量化犬血浆中的药物，并使用 这两个旨在修改我们的非临床发展计划的结果，并寻求进一步的代理意见以支持 未来的IND提交是人类临床研究的一项。