Mitapivat: New dawn in pyruvate kinase deficiency and beyond

Mitapivat is the first in class oral allosteric activator of pyruvate kinase enzyme, leading to increased ATP production. Since red blood cells (RBC) rely on anaerobic metabolism, converting phosphoenolpyruvate to pyruvate in Embden– Meyerhof glycolytic pathway is the most important step for ATP production. Deficiency of ATP in patients with pyruvate kinase deficiency (PKD) leads to the destruction of RBCs. In hemoglobinopathies, including thalassemia and sickle cell disease, increased stress and utilization leads to rapid depletion of ATP resources.

Phase II DRIVE PK study was the first randomized controlled trial that showed benefits in adult patients without regular transfusion requirement in regards to a rise in hemoglobin ≥1.0 g/dl and improvement in other parameters of hemolysis even with a low 50 mg twice daily dose. Minor adverse effects, including headache, insomnia, and nausea were reported.

Subsequent adult studies like ACTIVATE III (non-transfusion-dependent) and ACTIVATE III – T (transfusion-dependent) in patients with PKD showed sustained hemoglobin response in 16/40 (40%) patients. It was tolerated well, and the adverse effect profile was similar to the previous study except for hypertriglyceridemia and hypertension in two patients.

Phase I/II trials on patients with thalassemia and sickle cell anemia have also shown promising results in reducing transfusion burden and other disease-related co-morbidities, paving the way for further studies.

Mitapivat appears to be a safe, well-tolerated, and effective drug for PKD and other RBC pathologies in adults. Results of ongoing pediatric studies in these settings are awaited to reveal its safety profile in children.