Pyruvate kinase activators in hereditary haemolytic anaemias: current evidence and clinical potential

Abstract

Hereditary haemolytic anaemias represent the most prevalent group of genetic disorders worldwide and have a substantial impact on global health. Current treatments are few and primarily supportive. Recent studies suggest a crucial and overlapping role of metabolic impairment of red blood cells in these diseases, extending beyond the primary genetic defect. Pyruvate kinase activators enhance glycolysis, thereby targeting this shared metabolic impairment by increasing ATP production and improving cellular homeostasis. The first pyruvate kinase activator has been approved for the treatment of pyruvate kinase deficiency. Clinical trials evaluating pyruvate kinase activators in other haemolytic disorders, including thalassaemia, sickle cell disease, and red blood cell membrane disorders have provided evidence of clinical efficacy by ameliorating haemolytic anaemia and improving other disease-related outcomes, while maintaining a generally favourable safety profile. Ongoing preclinical and translational research continues to provide further insights into other potential indications for pyruvate kinase activators.