Pomalidomide Reduces Bleeding and Alters Expression of Angiogenesis-Related Proteins in Patients with Hereditary Hemorrhagic Telangiectasia

Background: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant genetic disorder characterized by abnormal blood vessel formation, recurrent and severe epistaxis, gastrointestinal bleeding, as well as pulmonary, hepatic and cerebral arteriovenous malformation (AVM). The pathogenesis of HHT appears to involve dysregulation of TGF-β signaling in endothelial cells, though other mechanisms may also contribute. Elevated levels of VEGF have been described in some studies of HHT, though detailed molecular profiling of factors that regulate angiogenesis has not been performed, particularly before and after effective therapy. We have recently completed a pilot study of patients with HHT treated with pomalidomide that demonstrated safety and efficacy and suggested that pomalidomide may be a potential treatment option for this disorder (NCT02287558). Here, we describe the outcomes of this study and present correlative studies of potential biomarkers in the plasma of treated patients before, during and after treatment with pomalidomide. Methods: Eligible patients had 1) GI bleeding requiring transfusion of ≥ 4 units PRBC or 4 iron infusions, or 2) epistaxis with epistaxis severity score (ESS) ≥ 4 requiring ≥ 2 units PRBC or 500 mg intravenous iron, each within the preceding four months. The primary efficacy endpoint was a 50% reduction in parenteral iron infusion or blood transfusion. A key secondary endpoint was the effect of pomalidomide on the ESS. Treatment was initiated with 1 mg of pomalidomide daily, increasing by 1 mg/month to a maximum of 5 mg of daily. This dose, or a lower dose on which the patient had ceased bleeding was continued for four months and then tapered. The relative expression of 55 angiogenesis-related proteins was determined semi-quantitatively in the plasma of study subjects using the human angiogenesis proteome profiler array. In addition, the expression of seven angiogenesis-related proteins was determined quantitatively by electrochemiluminescence using a validated immunoassay (Meso Scale Discovery). Heparin-binding EGF-like growth factor (HB-EGF) levels were determined using a conventional sandwich ELISA. Results: Nine patients provided informed consent. One subject was not treated due to an intervening cardiac event. Two subjects developed a drug-related AE (rash) within three weeks of treatment initiation and were removed from the study, thus we report on 6 patients. Two subjects were on study for only 5 months and removed for non-drug related AEs; both had primarily GI bleeding. One of these met the primary endpoint while the other did not; however, this individual demonstrated a significant reduction in the ESS. The remaining four patients completed the study and all met the primary endpoint and demonstrated significant reductions in the ESS. Proteomic profiling of angiogenic biomarkers revealed a statistically significant basal elevation of vascular endothelial growth factor A (VEGF-A), VEGF-C, placental growth factor (PIGF), fibroblast growth factor-basic (FGF-basic) and heparin-binding EGF-like growth factor (HB-EGF) when compared to healthy, age matched controls. Levels of VEGF-D, soluble vascular endothelial growth factor receptor-1 (VEGFR1/Flt1), and tyrosine kinase-2 (Tie-2) exhibited a wide distribution at baseline, but overall were not significantly higher than those in healthy, matched controls. Responses to pomalidomide were associated with significant reductions of several angiogenic mediators including VEGF-A, VEGF-C, MMP8, MMP9, TIMP-4, Angiopoietin 1, and most notably HB-EGF. Conclusion: This pilot study conducted at the Cleveland Clinic HHT center provides demonstrates safety and efficacy of pomalidomide, a third generation thalidomide analogue, in patients with HHT. Differences in levels of several angiogenic mediators in patients HHT suggest a complex underlying pathogenesis with significant differences between individual patients. Angiogenic profiling indicates that pomalidomide treatment of HHT patients promotes the reduction of VEGF-A, VEGF-C, MMP8, MMP9, TIMP-4, Angiopoietin 1, and most notably HB-EGF, which may serve as potential biomarkers of pomalidomide efficacy. This study was supported by Celgene, Summit NJ Disclosures McCrae: Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Sanofi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Pomalidomide in Hereditary Hemorrhagic Telangiectasia