GBT-440

GTB-440 is a modulator of sickle hemoglobin S (HbS). It binds to the N‐terminal valine of one of the haemoglobin α chains and increases HbS affinity for oxygen. GBT440 dose‐dependently increases HbS affinity for oxygen (EC₅₀ = 8·2 μM) for purified HbS and (EC₅₀ = 415 μM) for whole blood from sickle cell disease (SCD) patients. It delays in vitro HbS polymerization and prevents sickling of RBCs. In a murine model of SCD, GBT-440 (100 and 150 mg/kg for 9–12 d) increases the half‐life of RBCs, reduces reticulocyte counts and prevents ex vivo RBC sickling.