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

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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.