Sickle cell disease (SCD) is a genetic disorder in which deoxygenation results in polymerization of mutated hemoglobin S (HbS) and triggers the downstream effects of red blood cell (RBC) deformation (sickling), hemolytic anemia, vaso-occlusion, inflammation, predisposition to infection, and chronic organ damage. Two distinct pathophysiologic mechanisms of SCD—severe anemia and vasculopathy—overlap to cause severe morbidity. Chronic anemia and recurrent cycles of ischemia-reperfusion injury, often manifesting as fatigue and/or pain (vaso-occlusive crisis [VOC]), accumulate over the lifespan, resulting in end-organ parenchymal damage. The severity of steady-state anemia predicts CNS injury (including stroke and neurocognitive impairment), renal disease, and cardiopulmonary dysfunction (pulmonary hypertension). Long-term complications contribute to decreased quality of life and are associated with early death.
Voxelotor (GBT440) is an oral once-daily therapy that modulates Hb affinity for oxygen, thereby inhibiting HbS polymerization and the resultant sickling of RBCs, potentially interrupting the molecular pathogenesis of the disease. The Hemoglobin Oxygen Affinity Modulation to Inhibit HbS PolymErization (HOPE) study (NCT03036813) is an ongoing, phase 3, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of voxelotor in patients with SCD aged 12 to 65 years.
Conclusions: Data from Part A of the HOPE study demonstrate that treatment with voxelotor resulted in a dose-dependent increase in Hb with a large proportion of patients achieving Hb >1 g/dL improvement from baseline compared with placebo at 12 weeks. In addition, there was a dose-dependent decrease in hemolysis markers. Voxelotor was generally well tolerated at both doses. Hemolytic anemia of SCD has severe and life-threatening consequences and presents an unmet medical need. Voxelotor has potential to ameliorate complications of anemia associated with SCD.
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