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

项目总结/摘要 HHT国际基金会（d/B/a Cure HHT），一个遗传性出血性疾病的患者倡导组织 毛细血管扩张症（HHT）正在开发和注册帕唑帕尼以改善鼻出血和贫血。 HHT（1：5000，在美国约为50 K，全球约为150万）是一种基于ICM代码的罕见疾病（在ICM代码下运行）。 FDA孤儿病认定），尽管其普遍报告不足。它是一种血管发育障碍， 其中常见的小动脉：静脉相互作用是异常的，导致可破裂的粘膜损伤。患者 患有这种疾病的患者经常和严重的鼻子和胃肠道出血，贫血，通常需要IV铁或 输血他们的生活质量往往很差，与社会交往隔绝， 这种疾病的遗传缺陷已经被发现，他们有 已经发现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唑帕尼（Votrient），其减少血管生成信号传导，包括VEGF- 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 帕唑帕尼-类似产品用于GI出血。此外，一项小型试点临床研究显示了令人鼓舞的结果（一些 改变生活），如在一组严重输血依赖性HHT患者中的标签外使用。这些临床 案例导致FDA为我们的项目提供了突破性的认定。 在两种严重程度的分层中拟定了一项双盲、安慰剂对照研究（n=40 Rx和n=20 pbo） 水平患者表型，“重度”和“中度”。严重组将提供亚肿瘤剂量（100 mg/d），持续6个月。中剂量组将被分配到两个剂量，每天50 mg和100 mg。疗效 将通过显示鼻出血持续时间减少50%和/或血清中2gm/dl升高来证明 血红蛋白。 HHT基金会拥有超过10，000人的数据库，以及来自我们10个国家的庞大患者网络， 预计在北美的研究中心，这项工作的招聘将是可行的。除了临床指标外， 鼻出血和血清血红蛋白;将评价生活质量、疲劳和鼻出血日记。如果成功 如果pazopanib被开发出来，它将成为这种疾病的第一个注册药剂。

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.