Assessment of Angiogenic Biomarkers in A Phase 2 Study of Bevacizumab for Chronic Bleeding and Iron Deficiency Anemia in HHT
Hanny Al-Samkari, MD from Massachusetts General Hospital (MGH) has been awarded a $40,000 grant from Cure HHT for his research entitled “Assessment of Angiogenic Biomarkers in A Phase 2 Study of Bevacizumab for Chronic Bleeding and Iron Deficiency Anemia in Hereditary Hemorrhagic Telangiectasia”. Dr. Al-Samkari, is a hematologist, clinical investigator and Associate Director of the HHT Center of Excellence at MGH.
Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu syndrome), is an autosomal dominant rare bleeding disorder affecting 1 in 5,000 people. Aberrant connections of arteries and veins [arteriovenous malformations (AVMs) or telangiectasias] form in organs, causing pulmonary hypertension, heart failure, and stroke. They also form on mucosa, causing hyperfibrinolysis, chronic gastrointestinal bleeding, epistaxis, and severe iron deficiency anemia. There are no FDA-approved medications for HHT. Local cautery treatments, regular iron infusions and red cell transfusions are used to support patients. Vascular endothelial growth factor (VEGF, also known as VEGF-A) is an angiogenic cytokine elevated in HHT due to defects in TGF-β signaling. Increased VEGF signaling drives AVM formation and its normalization suppresses AVM formation in HHT mouse models.
Bevacizumab is a recombinant anti-VEGF antibody approved to treat malignancies. We developed an off-label intravenous bevacizumab treatment pathway for HHT patients and have published the outcomes of our first 13 patients.
If confirmed in this clinical trial, systemic bevacizumab would be a breakthrough, becoming the standard of care to manage HHT-associated bleeding and anemia.
Proposed Research Study
20 HHT patients will be enrolled. Following a 3-month on-study pretreatment period in which iron infusion and red cell transfusion requirements will be objectively calculated, patients will receive bevacizumab for 6 months. Change in hemoglobin, red cell transfusion, iron infusion, and epistaxis severity pre- and post-treatment will be evaluated. Dr. Al-Samkari will perform a cross-sectional study on enrolled patients and utilize multivariable logistic analyses to assess if levels of angiogenic biomarkers predict baseline HHT disease characteristics. He will also assess for a predictive effect of baseline angiogenic biomarker levels on bevacizumab treatment response.
Hypothesis. Systemic bevacizumab is safe and efficacious in treatment of chronic bleeding and iron deficiency anemia in HHT. Angiogenic biomarker levels in HHT patients predict disease characteristics and response to anti-angiogenic treatment.
Specific Aim 1. Evaluate the efficacy and safety of bevacizumab to treat chronic GI bleeding and epistaxis in HHT as measured by change in red cell transfusions, iron infusions, hemoglobin levels, epistaxis severity, and HHT-related quality of life (HHT-QOL).
Specific Aim 2.
(A) Determine if baseline VEGF-A, VEGF-B, VEGF-C, VEGF-D, sVEGFR1, sVEGFR2, sVEGFR3, Ang1, Ang2, sTie2, PlGF, and bFGF predict HHT disease characteristics.
(B) Determine if these angiogenic biomarkers predict treatment response or non-response to bevacizumab.
The funding of this grant is made possible by a generous gift from Stephen and Tamar Olitsky.