Delivery of Nanoencapsulated TGFbeta and ATRA for the Treatment of IBD

描述（由申请人提供）：I期研究确立了口服缓释TGF？1（TPX-6001）和ATRA（TPX-7001）纳米颗粒在鼠过继性T细胞转移模型中治疗IBD中的作用。具体而言，口服TPX-6001和TPX-7001的两周方案实现了患有晚期IBD的小鼠中多种疾病指标的严重程度降低50- 90%。重要的是，共同管理的ATRA与TGF？1是实现最大治疗效果的关键，疾病的改善与结肠中T调节细胞活性的增强有关。II期工作旨在进一步优化临床前小鼠IBD模型中的治疗方案，建立规模化生产工艺，并完成导致IND申报的毒理学研究。在目标1中，完成临床前优化工作。为此，结合TGF？1和ATRA剂量进行优化。然后，该组合用于确定最佳治疗方案，确定治疗长期维持疾病缓解的能力并监测副作用。在目标2中，确定了规模放大工艺参数，以实现原料药生产。确定了放大产品的批间均匀度和有效期。目的完成2种哺乳动物的毒理学研究。这些研究是与Charles River Laboratories的Navigators毒理学组合作进行的。目标1-3中获得的数据随后用于准备向FDA提交的研究性新药（IND）申请（目标4）。II期研究的成功完成将促进TPX-6001/7001进入IBD患者的I期临床试验。 公共卫生相关性：目前用于炎症性肠病（IBD）如克罗恩病和溃疡性结肠炎的治疗由于无效或治疗限制性副作用而使相当大比例的患者失败。TherapyX公司正在开发一种更先进的药物输送系统，目标是转化生长因子？1和视黄酸的肠道炎症部位，从而减少全身副作用。这种疗法有可能显着改善IBD患者的发病率和生活质量。

DESCRIPTION (provided by applicant): Phase I studies established proof-of-principle for the efficacy of oral sustained-release TGF?1 (TPX-6001) and ATRA (TPX-7001) nanoparticles in the treatment of IBD in a murine adoptive T-cell transfer model. Specifically, a two-week regimen of oral TPX-6001 and TPX-7001 achieved a 50-90 % reduction in the severity of multiple disease indicators in mice with advanced IBD. Importantly, co-administration of ATRA with TGF?1 was essential to achieving maximal therapeutic efficacy and disease amelioration was associated with enhanced T-regulatory cell activity in the colon. Phase II work is designed to further optimize therapy protocol in the pre-clinical murine IBD model, establish scale-up manufacturing process and complete toxicology studies leading up to IND filing. In Aim 1, pre-clinical optimization work is completed. To this end, combination TGF?1 and ATRA dosages are optimized first. This combination is then used to identify the optimal therapeutic regimen, determine the ability of treatment to maintain disease remission in the long-term and monitor side-effects. In Aim 2, scale-up process parameters are established to achieve bulk drug production. Batch-to-batch uniformity and shelf-life are determined for the scaled-up product. Aim 3 studies are designed to complete toxicokinetics in 2 mammalian species. These studies are performed in collaboration with the Navigators Toxicology Group at Charles River Laboratories. The data obtained in Aims 1-3 are then utilized in the preparation of an Investigational New Drug (IND) application to the FDA (Aim 4). Successful completion of Phase II studies will facilitate the advancement of TPX-6001/7001 to a Phase I clinical trial in IBD patients. PUBLIC HEALTH RELEVANCE: Current therapies for inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis fail a considerable percentage of patients due to ineffectiveness or therapy limiting side effects. TherapyX, Inc. is developing a more advanced drug delivery system that targets Transforming Growth Factor ?-1 and Retinoic Acid to the site of inflammation in the gut thereby reducing systemic side effects. This therapy has the potential to significantly improve morbidity and quality of life of those suffering with IBD.