Erythrocyte pyruvate kinase activation in red cell disorders.

Purpose of review: In red cells, pyruvate kinase is a key enzyme in the final step of glycolytic degradative process, which generates a constant energy supply via ATP production. This commentary discusses recent findings on pyruvate kinase activators as new therapeutic option in hereditary red cell disorders such as thalassemic syndromes or sickle cell disease (SCD).

Recent findings: Mitapivat and etavopivat are two oral pyruvate kinase activators. Studies in a mouse model for β thalassemia have shown beneficial effects of mitapivat on both red cell survival and ineffective erythropoiesis, with an amelioration of iron homeostasis. This was confirmed in a proof-of-concept study in patients with nontransfusion-dependent thalassemias. Both mitapivat and etavopivat have been evaluated in mouse models for SCD, showing an increased 2-3DPG/ATP ratio and a reduction in haemolysis as well as in sickling. These data were confirmed in proof-of-concept clinical studies with both molecules carried in patients with SCD.

Summary: Preclinical and clinical evidence indicate that pyruvate kinase activators represent new therapeutic option in hemoglobinopathies or SCD. Other red cell disorders such as hereditary spherocytosis or hereditary anaemias characterized by defective erythropoiesis might represent additional areas to investigate the therapeutic impact of pyruvate kinase activators.