Mitapivat sulfate

Mitapivat (AG-348) is an oral, allosteric activator of pyruvate kinase (PK) that catalyzes the final step of glycolysis. The drug is active on both wild-type and mutant enzymes, in animal models and in healthy volunteers, where it increases adenosine triphosphate (ATP) levels and decreases 2,3-diphosphoglycerate (2,3-DPG). Mitapivat is metabolized by cytochrome P450 and is an inhibitor of aromatase. PK deficiency is a hereditary recessive enzyme defect causing chronic hemolytic anemia, frequently transfusion-dependent, complicated by iron overload and gallstones, and with limited therapeutic options (splenectomy). Clinical trials in PK deficiency demonstrated a rapid and sustained hemoglobin increase in approximately 50% of patients, confirmed in an extension study up to 3 years, and in a randomized, placebo-controlled trial, with limited safety concerns. Mitapivat is also effective in transfusion-dependent patients by reducing/avoiding transfusions in a fraction of them. Given its activity on ATP and 2,3-DPG, mitapivat is under investigation in thalassemia and sickle cell disease with promising results.