Erythrocyte pyruvate kinase activation in red cell disorders.

Purpose of the review. In red cells, pyruvate kinase (PK) 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 PK 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 PK activators. Studies in a mouse model for  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 non-transfusion-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 hemolysis as well as in sickling. These data were confirmed in proof-of-concept clinical studies with both molecules carried in patients with SCD. Summary. Pre-clinical and clinical evidence indicate that PK activators represent new therapeutic option in hemoglobinopathies or SCD. Other red cell disorders such as hereditary spherocytosis or hereditary anemias characterized by defective erythropoiesis might represent additional areas to investigate the therapeutic impact of PK activators.