Development of TP-252 for the Maintenance of Remission in Pediatric Ulcerative Colitis Patients

开发 TP-252 用于维持小儿溃疡性结肠炎患者的缓解

• 批准号: 9923650
• 负责人: Frank Sciavolino
• 金额: $ 49.84万
• 依托单位: THETIS PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923650
• 关键词: Address; Adolescent; Affect; Age; Appearance; Biological; Biological Assay; C57BL/6 Mouse; Child; Childhood; Chronic; Clinical; Clinical Research; Clinical Trials; Colitis; Colon; Colorectal Cancer; Data; Development; Diagnosis; Disease; Disease remission; Dose; Drug Prescriptions; Eicosanoids; Eicosapentaenoic Acid; Enteral; Evaluation; Formulation; Future; Goals; Growth and Development function; Inflammation; Inflammatory Bowel Diseases; Laboratories; Lead; Magnesium; Maintenance; Mediator of activation protein; Medical; Modeling; Molecular; Monitor; Nonesterified Fatty Acids; Omega-3 Fatty Acids; Oral; Patients; Pediatric ulcerative colitis; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Population; Program Development; Rectum; Relapse; Research; Rivers; Safety; Severities; Small Business Innovation Research Grant; Sodium Dextran Sulfate; Specific qualifier value; Symptoms; Tablets; Testing; Therapeutic; Tissues; Toxic Megacolon; Toxic effect; Toxicokinetics; Toxicology; Treatment Efficacy; Ulcer; Ulcerative Colitis; Validation; Vulnerable Populations; analytical method; base; clinical development; clinical efficacy; efficacy study; innovation; juvenile animal; manufacturing scale-up; method development; mouse model; novel; pre-clinical; preclinical study; product development; programs; protocol development; prototype; psychosocial; scale up; side effect; tablet formulation; treatment group

ABSTRACT Ulcerative colitis (UC) is a chronic, relapsing form of Inflammatory Bowel Disease (IBD) characterized by inflammation and ulceration of the colon and rectum. Uncontrolled UC can lead to serious complications, including toxic megacolon and colorectal cancer. The disease affects approximately 700,000 people in the US, with up to 25% of patients diagnosed before age 20. Young UC patients typically present with more severe symptoms, are subject to heavy psycho-social burden, and suffer from growth and development issues. Moreover, the side effect profiles of approved therapies are frequently more severe in children, limiting the therapies available for this vulnerable population. In particular, there is a need for novel, safe therapeutic options suitable for chronic administration in pediatric and adolescent UC patients. To answer this unmet medical need, Thetis proposes to develop magnesium lysicosapentate, or TP-252, an innovative new molecular entity (NME) as a safe, oral therapy to maintain remission of symptoms in children and adolescents with UC. TP-252 delivers eicosapentaenoic acid, (EPA), an Omega-3 polyunsaturated fatty acid (PUFA) shown to have clinical efficacy for treatment of UC. TP-252 overcomes the physico-chemical and commercial deficits inherent in EPA itself to enable development and registration as a prescription drug with an indication for maintenance of remission in pediatric UC patients. Importantly, in a previous preclinical study conducted by Thetis, TP-252 was shown to: (i) deliver therapeutic levels of EPA to colonic tissue and (ii) favorably change colon tissue levels of key eicosanoid mediators that regulate inflammation. Based on these biological findings, along with technical, pharmaceutical and IP advantages of TP-252, Thetis plans to undertake the development of TP-252 to maintain remission in pediatric UC patients. In this SBIR Fast Track project, Thetis will complete the preclinical activities required for IND submission and initiation of clinical studies. This goal will be achieved through three Specific Aims. Phase I will include an efficacy study performed using a dextran sulfate sodium (DSS) mouse model of UC (Specific Aim #1). The efficacy of TP-252 will be evaluated alone (Sub-aim #1a) and in combination with current treatment (Sub-aim #1b). In Phase II, we will determine the juvenile safety profile of TP-252 in support of treatment of pediatric UC patients (Specific Aim #2). Once the efficacy and acceptable toxicity profile of TP-252 are demonstrated, Thetis will conduct the manufacture and testing of GMP Drug Substance (Specific Aim #3), which itself involves two sub-aims including prototype drug product development (Sub-aim #3a), followed by manufacturing scale-up, testing, packaging and release of drug product for clinical supplies (Sub-aim #3b). Upon completion of this project, Thetis will be able to prepare and submit an IND filing as a prerequisite to initiate Phase I clinical studies. This SBIR project is critical to enabling development of the TP-252 program to address the unmet medical need in this vulnerable pediatric population.

摘要 溃疡性结肠炎（UC）是一种慢性、复发性炎症性肠病（IBD）， 结肠和直肠的炎症和溃疡不受控制的UC可导致严重的并发症， 包括中毒性巨结肠和结肠直肠癌。这种疾病影响了美国大约70万人， 高达25%的患者在20岁之前确诊。年轻的UC患者通常表现出更严重的 这些儿童有严重的社会心理负担，并患有生长和发育问题。 此外，批准的治疗的副作用特征在儿童中通常更严重，限制了治疗的有效性。 为这些弱势群体提供的治疗方法。特别地，需要一种新颖、安全的治疗方法， 适合儿童和青少年UC患者长期给药的选择。 为了解决这一未满足的医疗需求，Thetis提出开发赖氨酸五齿镁，或 TP-252，一种创新的新分子实体（NME），作为一种安全的口服疗法，可维持症状缓解 儿童和青少年UC。TP-252提供二十碳五烯酸（EPA），一种欧米茄-3 多不饱和脂肪酸（PUFA）显示出治疗UC的临床疗效。TP-252克服了 环保署本身固有的物理化学和商业缺陷，使发展和登记作为一个 适应症为维持儿童UC患者缓解的处方药。重要的是，在A 先前由Thetis进行的临床前研究显示，TP-252：（i）递送治疗水平的EPA至 结肠组织和（ii）有利地改变结肠组织中关键类花生酸介质的水平，所述关键类花生酸介质调节 炎症基于这些生物学发现，沿着技术、制药和知识产权优势， TP-252，Thetis计划开发TP-252以维持儿童UC患者的缓解。 在此SBIR快速通道项目中，Thetis将完成IND所需的临床前活动 提交和启动临床研究。这一目标将通过三个具体目标来实现。一期将 包括使用UC葡聚糖硫酸钠（DSS）小鼠模型（特异性 目标1）。将评价TP-252单独给药（子目标1a）和与当前药物联合给药的疗效 治疗（子目标#1b）。在第二阶段，我们将确定TP-252的青少年安全性特征，以支持 儿童UC患者的治疗（具体目标#2）。一旦疗效和可接受的毒性特征， TP-252得到证明，Thetis将进行GMP原料药（特定）的生产和检测 目标#3），其本身涉及两个子目标，包括原型制剂开发 （子目标#3a），然后是临床用制剂的生产规模扩大、检测、包装和放行 供应（次级目标3b）。完成本项目后，Thetis将能够准备并提交IND申请 作为启动I期临床研究的先决条件。该SBIR项目对于开发 TP-252计划，以解决这一弱势儿科人群未满足的医疗需求。