Phase 1 Multiple Ascending Dose Study Of Safety, Tolerability, And Pharmacokinetics/Pharmacodynamics Of Mitapivat (Ag-348) In Subjects With Sickle Cell Disease

Background. Sickle cell disease (SCD) is a devastating disorder initiated by polymerization of the deoxy-hemoglobin S (HbS) to form fibers that distort (sickle) erythrocytes. Increased intracellular 2,3- diphosphoglycerate (2,3-DPG) stabilizes fibers and promotes sickling, while decreased intracellular adenosine triphosphate (ATP) levels can lead to hemolysis. Mitapivat (AG-348) is an oral, small molecule, allosteric activator capable of activating both mutant and wild type red cell pyruvate kinase (PKR), thus decreasing 2,3-DPG and increasing ATP levels in red cells and potentially acting as an anti-sickling agent. The safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple ascending doses of mitapivat were assessed in subjects with SCD in a Phase I study.