A Phase II/III randomized, placebo controlled, double blind study to evaluate the effects of up to 24 weeks of low dose pazopanib on HHT related epistaxis and anemia. IND#144808 June 25, 2020

项目摘要/摘要 HHT国际基金会(d/b/a Cure HHT)，遗传性出血性疾病患者权益倡导组织 毛细血管扩张症(HHT)正在研究帕佐帕尼的开发和注册，以改善鼻出血和贫血。 HHT(1：5000，在美国约为50K，全球为150万)是一种基于ICM代码的罕见疾病(在 FDA孤儿疾病名称)，尽管其总体上报告不足。这是一种血管发育的紊乱， 其中常见的细小动脉-静脉相互作用异常，导致黏膜破裂病变。病人 患有这种疾病的人有频繁和严重的鼻子和胃肠道出血，贫血，通常需要静脉注射铁或 输血。通常，他们的生活质量很差，使他们与社会互动隔绝，并且 影响睡眠、亲密关系等。这种疾病的遗传缺陷已经被发现，他们有 已发现可导致旺盛的生长因子表达(VEGF)。没有注册的治疗剂。一个 抗血管生成癌症药物帕佐帕尼(Votrient)，它减少血管生成信号，包括血管内皮生长因子-1。 受体，被重新用于这种罕见的疾病。一种临床前小鼠HHT模型显示了 帕佐帕尼-治疗胃肠道出血的类似产品。此外，一项小型先导性临床研究显示了令人鼓舞的结果(一些 改变生活)，就像在一组严重依赖输血的HHT患者的标签外使用一样。这些后一种临床 案例的结果是FDA提供了我们的计划突破称号。 一项双盲、安慰剂对照研究(n=40 Rx和n=20 pBO)在两个严重程度的分级内被提出 水平的患者表型，“重度”和“中度”。严重组将提供亚肿瘤剂量(100 Mg/d)，疗程6个月。中度组每天服用两剂，50毫克和100毫克。功效 将通过显示鼻出血持续时间减少50%和/或血清中2gm/dl的升高来证明 血红蛋白。 拥有HHT基金会的10,000人数据库，以及我们10个人中每个人的庞大患者网络 在北美预期的学习地点，招聘这项工作将是可行的。除了临床指标之外 将评估患者的生活质量、疲劳感和鼻出血日记。如果成功 开发出来的帕佐帕尼将成为治疗这种疾病的第一个注册药物。

Project Summary/Abstract HHT Foundation International, Inc. (d/b/a Cure HHT), a patient advocacy group for hereditary hemorrhagic telangiectasia (HHT) is pursuing the development and registration of pazopanib to improve epistaxis and anemia. HHT (1:5000, or about 50K in the US, 1.5M globally) is a rare disorder based on ICM codes (operating under FDA orphan disease designation), despite its general under-reporting. It is a disorder of vascular development, in which common small artery: vein interactions are abnormal leading to rupturable mucosal lesions. Patients with this disorder have frequent and severe nose and GI bleeds, are anemic and commonly require IV iron or blood transfusions. Often, their quality of life is quite poor, isolating them from social interactions, and compromising sleep, intimacy etc. The genetic defects of this disorder have been discovered, and they have been found to lead to exuberant growth factor expression (VEGF). There is no registered therapeutic agent. An anti-angiogenic cancer drug, pazopanib (Votrient), which reduces angiogenic signaling, including the VEGF- receptors, was repurposed for this rare disorder. One preclinical mouse HHT model revealed benefit with a pazopanib-similar product for GI bleeds. Further, a small pilot clinical study revealed encouraging results (some life-altering), as has off-label use in a group of severe transfusion dependent HHT patients. These latter clinical cases have resulted in the FDA providing our program Breakthrough designation. A double-blind, placebo-controlled study (n=40 Rx and n=20 pbo) is proposed within a hierarchy of two severity level patient phenotypes, “severe” and “moderate”. The severe group will be provided a sub-oncologic dose (100 mg daily) for 6 months. The moderate group will be allocated to two doses, 50 mg and 100 mg daily. Efficacy would be demonstrated by revealing a 50% reduction in the duration of epistaxis, and/or a 2 gm/dl rise in serum hemoglobin. With the HHT Foundation's >10,000 person database, and vast network of patients from each of our 10 anticipated study sites in North America, recruitment for this work will be feasible. In addition to the clinical metrics of epistaxis and serum hemoglobin; quality of life, fatigue and epistaxis diaries will be evaluated. If successfully developed, pazopanib would be the first registered agent for this disease.