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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的溃疡性结肠炎 (UC) 是一种慢性、复发性炎症性肠病 (IBD)，其特征是由结肠和直肠的炎症和溃疡引起。不受控制的 UC 可能导致严重的并发症，包括中毒性巨结肠和结直肠癌。这种疾病影响了美国约 70 万人，高达 25% 的患者在 20 岁之前被诊断出来。年轻的 UC 患者通常会出现更严重的症状症状，承受沉重的心理社会负担，并遭受生长和发育问题。此外，已批准疗法的副作用在儿童中通常更为严重，从而限制了治疗的效果。针对这一弱势群体的治疗方法。特别是，需要新颖、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。为了满足这一未满足的医疗需求，Thetis 提议开发溶二碳五酸镁，或者 TP-252，一种创新的新分子实体（NME），作为一种安全的口服疗法，可维持症状缓解患有 UC 的儿童和青少年。 TP-252 提供二十碳五烯酸 (EPA)，一种 Omega-3 多不饱和脂肪酸（PUFA）已被证明对治疗 UC 具有临床疗效。 TP-252克服了 EPA 本身固有的物理化学和商业缺陷，使其能够作为一种药物进行开发和注册用于维持儿科 UC 患者缓解的处方药。重要的是，在一个 Thetis 之前进行的临床前研究表明，TP-252 能够：(i) 向患者提供治疗水平的 EPA 结肠组织和（ii）有利地改变结肠组织中调节关键类二十烷酸介质的水平炎。基于这些生物学发现，以及技术、制药和知识产权优势 TP-252，Thetis 计划进行 TP-252 的开发，以维持儿科 UC 患者的缓解。在这个 SBIR Fast Track 项目中，Thetis 将完成 IND 所需的临床前活动提交并启动临床研究。这一目标将通过三个具体目标来实现。第一阶段将包括使用葡聚糖硫酸钠 (DSS) 小鼠模型进行的功效研究（具体目标#1)。 TP-252的功效将单独评估（子目标#1a）并结合当前的治疗（子目标#1b）。在第二阶段，我们将确定 TP-252 的青少年安全概况，以支持治疗儿科 UC 患者（具体目标 #2）。一旦疗效和可接受的毒性特征 TP-252得到论证，Thetis将进行GMP原料药（具体目标#3），其本身涉及两个子目标，包括原型药物产品开发（子目标#3a），然后是临床药品的生产放大、测试、包装和发布供应（子目标#3b）。该项目完成后，Thetis 将能够准备并提交 IND 备案作为启动 I 期临床研究的先决条件。该 SBIR 项目对于实现 SBIR 的开发至关重要 TP-252 计划旨在解决这一弱势儿科人群未得到满足的医疗需求。