A systematic review of safety and efficacy of pyruvate kinase activators in inherited hemolytic anemia

Abstract Inherited hemolytic anemias are genetically heterogeneous disorders that often share pathophysiological features, including red-cell metabolic stress, chronic hemolysis, ineffective erythropoiesis, and impaired quality of life. Because mature erythrocytes depend almost entirely on glycolysis for adenosine triphosphate (ATP) generation, pharmacologic activation of pyruvate kinase offers a rational strategy to improve red-cell energy homeostasis and potentially modify disease manifestations. We systematically searched PubMed, Embase, and Scopus from inception through July 5, 2026, and screened ClinicalTrials.gov and American Society of Hematology (ASH) and European Hematology Association (EHA) conference abstracts for studies evaluating pyruvate kinase activators in hemolytic anemia including pyruvate kinase deficiency (PKD), sickle cell disease (SCD), thalassemia, and hereditary spherocytosis (HS). Eligible studies reported efficacy and/or safety outcomes for mitapivat, etavopivat, tebapivat, or related agents. Twenty-one eligible reports evaluated pyruvate kinase activators across PKD, SCD, thalassemia, and HS. Overall, the strongest evidence was observed in PKD and thalassemia, where treatment improved hemoglobin levels and reduced transfusion burden in relevant patient groups. In SCD, activation of pyruvate kinase consistently improved hematologic, hemolytic, and pharmacodynamic markers, but evidence for clinical outcomes such as vaso-occlusive events, fatigue, and organ protection remains less definitive and varies across agents. In HS, early single-arm SATISFY data suggest potential benefit, although confirmatory comparative studies are still needed. Pyruvate kinase activation is clinically established in PKD and thalassemia, promising but still evolving in SCD, and investigational in HS. Future studies should standardize response definitions, confirm patient-centered and clinical-event benefits, and clarify long-term safety, responder biomarkers, and combination strategies.