Antiangiogenic Therapy to Reduce Bleeding and Improve Health-Related Quality of Life in Hereditary Hemorrhagic Telangiectasia

Project Summary/Abstract Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant bleeding disorder affecting 1 in 5000 people in the US, is a devastating lifelong condition with no FDA-approved treatments. Accordingly, there is an urgent need for efficacious systemic therapies in HHT to reduce bleeding and improve health-related quality of

life (HRQOL). Patients with HHT develop fragile telangiectasias along the gut and nasal mucosa secondary to elevated vascular endothelial growth factor (VEGF). This leads to recurrent severe epistaxis and chronic gastrointestinal bleeding, resulting in iron deficiency anemia (and dependence on blood transfusions and/or iron

infusions) and severely diminished HRQOL. We and others have previously successfully used systemic bevacizumab, an anti-VEGF monoclonal antibody, as an off-label agent to treat chronic bleeding in HHT, documenting in multicenter observational studies a 70-80% reduction in red cell transfusions and iron infusions,

a 3-4 g/dL mean hemoglobin rise, and 50% reduction in epistaxis severity compared to before bevacizumab treatment. However, this observational work is limited in generalizability given heterogeneity in patients, variable drug dosing, and non-standardized thresholds for administration of red cells and iron. Furthermore, the impact

of bevacizumab on HRQOL and the angiogenic milieu is unknown. Therefore, we will perform a phase II clinical trial of systemic bevacizumab in adults with HHT dependent on iron infusions and/or blood transfusions to determine the impact of bevacizumab on bleeding and HRQOL. The primary endpoint will be a composite

measurement of red cell transfusions and iron infusions, the Hematologic Support Score (HSS). We will evaluate the impact of bevacizumab on HRQOL in HHT as a secondary endpoint utilizing PROMIS instruments and a novel HHT-specific QOL tool. Finally, we will evaluate the effect of bevacizumab on angiogenic biomarkers in

HHT, to better understand how it impacts the HHT angiogenic milieu. Our central hypothesis is that systemic bevacizumab significantly reduces chronic bleeding in HHT as measured by reductions in the HSS and improvements in hemoglobin and HRQOL. Success would pave the way for a larger definitive trial and establish

a blueprint for conducting future studies repurposing other antiangiogenics for HHT. The applicant, Dr. Hanny Al-Samkari, is well-qualified to execute this research and is committed to becoming an independent hemostasis clinical investigator with a focus on drug repurposing and biomarker research in HHT.

He will be mentored by Dr. David Kuter, with Dr. Neil Zakai, Dr. Karla Ballman and Dr. Dan Duda serving as co- mentors. Each mentor contributes unique expertise necessary for his transition to an independent HHT NIH physician scientist. To achieve his goals, he has proposed a comprehensive five-year career development plan

of rigorous coursework that synergizes with the research plan aims. The MGH Division of Hematology Oncology

is internationally-recognized for its tradition of clinical trial excellence, scientific discovery and mentorship, so is an ideal environment for completion of these scientific and career development objectives.