Results From Part A Of The Hemoglobin Oxygen Affinity Modulation To Inhibit Hbs Polymerization (Hope) Trial (Gbt440-031), A Placebo-Controlled Randomized Study Evaluating Voxelotor (Gbt440) In Adults And Adolescents With Sickle Cell Disease

Background: 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.