Abstract

Pyruvate kinase deficiency (PKD) is rare disease caused by mutations in the PKLR gene that results in lifelong, chronic hemolytic anemia. It is an autosomal recessive disease with a variable clinical presentation, ranging from mild to life threatening, but often associated with severe and debilitating comorbidities. PK-deficient red blood cells (RBCs) are characterized by dysregulation in cellular metabolism associated with defective glycolysis, including a build-up of the upstream metabolite 2,3-disphosphoglycerate (2,3-DPG) and deficiency in critical energetic metabolites such as ATP. Since mature RBCs are entirely dependent on glycolysis for ATP production, insufficient energy production affects red cell homeostasis and survival, including cellular membrane integrity, promoting premature removal of PK-deficient RBC from the circulation by the spleen. Pyrukynd® is a first-in-class oral allosteric activator of mutant and wild-type red cell pyruvate kinase (PKR) and has been approved by the FDA for the treatment of adults with PK Deficiency. Because of the fundamental role PKR plays in red cell biology, Pyrukynd® also has been demonstrated to be safe and efficacious in proof-of-concept studies in thalassemia and sickle cell anemia as part of the Agios clinical development effort to expand therapeutic indications. This presentation will discuss the discovery and development of Pyrukynd®—a scientific journey from bench to bedside.