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，在溃疡性结肠炎（UC）模型中诱导结肠上皮修复。UC 包括一种主要类型的炎性肠病， 胃肠道（GI）炎症。UC发生在远端胃肠道的最内层粘膜层 以连续的方式，通常从直肠开始并扩散到结肠。UC的病因仍然是 难以捉摸;遗传和环境因素似乎触发失调的粘膜免疫反应，导致 慢性炎症，破坏肠道屏障功能和结肠上皮损伤。缺乏 由于病因不明，尚未开发出UC的预防性或治愈性疗法。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 并发症，提高生活质量。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、生活质量的改善密切相关， 临床研究表明，手术干预和癌症发病率更低。然而，目前的UC药物 不能有效诱导粘膜愈合，因为仅仅抑制炎症并不一定会促进组织愈合 修复，这是一个复杂的动态过程，必须涉及肠道屏障功能的恢复 沿着有害炎症的减轻。因此，上皮创伤修复剂的开发将 填补了UC管理的重要空白。 我们的主要产品Epicertin是一种重组蛋白，来源于霍乱毒素B亚单位， 用含有KDEL内质网滞留信号的C末端肽进行遗传修饰。这 通过简单的修饰使EPICERTIN具有结肠上皮伤口愈合活性。EPICERTIN是我们的领导者 用于通过上皮屏障恢复管理UC的活性药物成分。路易斯维尔大学（UofL） 研究人员发明了Epicertin，并对其生物学作用模式（MOA）进行了广泛表征， 在急性和慢性结肠炎动物模型中的治疗效果。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给药的高安全性和耐受性。 给动物施用。我们已与FDA启动了IND前讨论，并已收到FDA的初步批准。 这大大降低了监管风险。根据FDA和NIH的审查人员的意见， 建议，UofL及其商业合作伙伴GROW Biomedicine LLC正在启动以产品为重点的 通过该I期STTR项目开发Epicertin，目的是：（1）进一步探索剂量效应 在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，以及（2） 扩大我们的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，并寻求进一步的机构投入，以支持 首次人体临床研究的未来IND提交。