Voxelotor for the treatment of sickle cell disease.

: The clinical manifestations of sickle cell disease (SCD) result from an inherited mutation in the beta-globin chain of hemoglobin (Hb) that causes Hb tetramers to polymerize when deoxygenated. The resulting erythrocyte deformation causes mechanical obstruction of blood flow by sickled cells, hemolysis, anemia and end-organ injury. While pain is the hallmark symptom of SCD, chronic organ injury as a result of anemia, inflammation and progressive vasculopathy play a major role in morbidity and mortality. Due to the complex pathophysiology of SCD, the need for an individualized, multi-modal pharmacologic approach is apparent. Until 2018, hydroxyurea was the only disease-modifying pharmacologic therapy approved for use in SCD. Since then, three new agents have been approved including voxelotor, the subject of this review.: Published pre-clinical and clinical data are reviewed. Voxelotor is a first-in-class small-molecule agent that binds to Hb and increases oxygen affinity, preventing polymerization. Recent clinical trials have shown that it increases Hb concentration and reduces hemolysis in patients with SCD. This increase in Hb concentration may significantly impact morbidity and mortality from chronic organ injury.: The mechanism of action, published studies and current opinions on the clinical use of voxelotor in SCD are presented.