AG-519

AG-519 is a small molecule drug developed by Agios Pharmaceuticals as an oral activator of pyruvate kinase-R (PKR), the red blood cell isoform of pyruvate kinase. It was investigated for the treatment of pyruvate kinase deficiency, a rare inherited disorder that leads to hemolytic anemia due to mutations in PKR. The drug acts as a potent and selective PKR agonist, increasing ATP production and reducing 2,3-diphosphoglycerate (2,3-DPG) levels in red blood cells—mechanistically improving cellular energy and potentially prolonging red cell lifespan[1][2][5][6][8]. Clinical studies demonstrated proof-of-mechanism with robust pharmacodynamic effects; however, development was discontinued after Phase 1 trials due to safety concerns related to liver toxicity at higher doses[1][2]. No approved drugs currently target the underlying cause of pyruvate kinase deficiency.