Mitapivat (AG-348) Demonstrates Safety, Tolerability, and Improvements in Anemia, Hemolysis, Oxygen Affinity, and Hemoglobin S Polymerization Kinetics in Adults with Sickle Cell Disease: A Phase 1 Dose Escalation Study

Background. Hemoglobin S (HbS) polymerization causes red cell sickling, hemolysis, and vaso-occlusion, key pathological features of sickle cell disease (SCD). Mitapivat (AG-348) has potential as an oral anti-sickling agent in SCD via increasing glycolytic activity, which reduces intracellular levels of 2,3-diphosphoglycerate (2,3-DPG) in parallel with increasing adenosine triphosphate (ATP). Reducing 2,3-DPG decreases HbS polymerization, while increasing ATP improves red cell membrane integrity. Here, we report the complete results of our single-center Phase 1 study of multiple ascending doses of mitapivat in subjects with SCD.