A Ph2 Randomized, Placebo-controlled, Multiple Dose Study to Determine the Safety, Pharmacokinetics and Efficacy of Oral Ifetroban in Subjects with Duchenne Musculary Dystrophy IND136895 (10/10/2018)

项目总结/摘要 杜氏肌营养不良症（DMD）是一种罕见的致命性疾病，每3,500例患者中约有1例 所有种族和文化的男性出生都无法治愈。DMD会导致心律失常，呼吸衰竭， 心肌病（CM）和过早死亡。CM现在是DMD死亡的主要原因。有限 DMD患者中的amplitudine往往掩盖了心力衰竭的典型症状， 进展在DMD中没有积极的筛查，CM的第一个表现可能是不可逆的心脏 衰竭或心脏性猝死。我们的小组和其他人已经显示了血栓素前列腺素类的激活 位于血小板、免疫细胞、平滑肌和心肌细胞上的TPr受体有助于 对心脏的有害影响。此外，用有效的和选择性的TPr拮抗剂伊非曲班阻断TPr， 在DMD CM的多种动物模型中预防心脏纤维化，改善心脏功能和死亡率。 异前列腺素（IP）激活TPr，并在DMD中升高。它们不仅是最可靠的标记 评估氧化应激，IP是血管功能障碍的介质。他们延续了煽动性的 对氧化损伤的反应，这可能在DMD CM发病机制中起关键作用。我们的总体目标是 确定伊非曲班的安全性和有效性，以支持其批准用于治疗DMD CM，一种罕见的 目前不存在治疗方法的情况，从而直接服务于孤儿产品开发 使命。该临床研究旨在确定口服给药的安全性、药代动力学和有效性。 伊非曲班在DMD CM患者中的应用除了定量的心脏和呼吸结果外， 将研究口服伊非曲班对肌肉力量、日常活动和生活质量的可测量的作用， DMD患者这项随机、安慰剂对照、多中心II期试验旨在检测 TPr信号转导促进心脏炎症并驱动IP过度产生导致DMD的假设 CM，从而使导致心脏纤维化和血管功能障碍的炎症反应持续存在。 目的1：确定口服TPr拮抗剂伊非曲班治疗DMD的安全性和有效性 厘米在美国最大的DMD中心拥有DMD和心脏成像专业知识的儿科心脏病专家网络 国家将加快对这种罕见疾病的登记。相同的成像设备和标准化 心脏成像方案将用于比较各中心的心脏成像数据。目标2将决定 TPr阻断对蛋白表达和CMR结构的影响。标本和成像将 用于确定TPr阻断对骨骼肌和CM疾病进展的影响。成功 该2期试验的完成将有助于支持伊非曲班用于治疗DMD CM的批准。研究 结果将为关键III期研究的设计提供必要的信息， 对减少DMD患者死亡和残疾的影响。

PROJECT SUMMARY/ABSTRACT Duchenne muscular dystrophy (DMD) is a rare and fatal disease affecting approximately 1 in every 3,500 live male births across all races and cultures with no cure. DMD results in loss of ambulation, respiratory failure, cardiomyopathy (CM), and premature death. CM is now the leading cause of death in DMD. Limited ambulation in DMD patients often masks typical symptoms of heart failure, allowing unchecked CM disease progression. Without aggressive screening in DMD, the first manifestation of CM can be irreversible heart failure or sudden cardiac death. Our group and others have shown activation of the thromboxane prostanoid receptor (TPr) located on platelets, immune cells, smooth muscle and cardiomyocytes contributes to deleterious effects in the heart. Further, TPr blockade with the potent and selective TPr antagonist, ifetroban, prevents cardiac fibrosis, improves cardiac function and mortality in multiple animal models of DMD CM. Isoprostanes (IP) activate the TPr and are elevated in DMD. Not only are they the most reliable marker for assessing oxidative stress, IP are mediators of vascular dysfunction. They perpetuate the inflammatory response to oxidant injury, which may play a key role in DMD CM pathogenesis. Our overall goal is to determine the safety and efficacy of ifetroban to support its approval for the treatment of DMD CM, a rare condition where no current therapy exists thereby directly serving the Orphan Products Development’s mission. The proposed clinical study aims to determine the safety, pharmacokinetics and efficacy of oral ifetroban in patients with DMD CM. In addition to quantitative cardiac and respiratory outcomes, the measurable effect of oral ifetroban on muscle strength, daily activity and quality-of-life will be investigated in DMD patients. This randomized, placebo-controlled, multicenter phase 2 trial is designed to test the central hypothesis that TPr signaling promotes cardiac inflammation and drives IP overproduction contributing to DMD CM, thereby perpetuating the inflammatory response which leads to cardiac fibrosis and vascular dysfunction. Aim 1 will determine the safety and efficacy of ifetroban, an oral TPr antagonist, as treatment for DMD CM. A network of pediatric cardiologists with DMD and cardiac imaging expertise at the largest DMD centers in the country will expedite enrollment for this rare disease. The same imaging equipment and standardized cardiac imaging protocol will be used to compare cardiac imaging data across centers. Aim 2 will determine the effect of TPr blockade on protein expression and CMR structures. Specimens and imaging will be used to determine the effects of TPr blockade on skeletal muscle and CM disease progression. Successful completion of this phase 2 trial will help support the approval of ifetroban for treatment of DMD CM. Study outcomes will provide the necessary information for design of the pivotal phase 3 study to have the greatest impact on reducing death and disability in patients with DMD.