Pyruvate kinase deficiency is a rare, congenital form of chronic hemolytic anemia. Current treatments for pyruvate kinase deficiency, including RBC transfusions and splenectomy, are supportive only and do not address the metabolic defect of the disease. Mitapivat, however, is the first of a new class of oral drugs that activates pyruvate kinase, the enzyme in the RBC responsible for catalyzing the last step of glycolysis and producing ATP necessary to maintain RBC health. Newly published results are promising from an open-label, single-arm, phase 3 trial of mitapivat in adults with pyruvate kinase deficiency who required regular transfusions. Between 2018 and 2020, 27 adult patients were enrolled in 20 centers across Europe, North America, and Asia (74% female; 74% White) and received at least one dose of mitapivat. Twenty patients completed the study, and the median duration of exposure to mitapivat was 40.3 weeks. Compared to individual transfusion records 24 weeks prior to the study initiation, mitapivat reduced the number of RBC transfusions in 37% (10/27) of patients (p=0.0002). All patients experienced adverse events, but all resolved without mitapivat dose modification. Furthermore, another single-arm, multi-center phase 2 trial of mitapivat in 20 non-transfusion dependent α-thalassemia or β-thalassemia patients found that mitapivat increased hemoglobin >1.0g/dL in 80% of study participants including all five with α-thalassemia. While these studies are encouraging that mitapivat may address the metabolic defect of some hemoglobinopathies and anemias, additional studies evaluating long-term safety and predicting which patients will respond to mitapivat are needed.
- Glenthoj A, van Beers EJ, Al-Samkari H, Viprakasit V, et al. Mitapivat in adults with pyruvate-kinase deficiency receiving regular transfusions (ACTIVATE-T): a multicenter, open-label, single-arm, phase 3 trial. The Lancet Haematology 2022
- Kuo KHM, Layton DM, Lal A, Al-Samkari H, et at. Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in adults with non-transfusion dependent α-thalassaemia or β-thalassaemia: an open label, multicentre, phase 2 study. The Lancet 2022; 400(10351); 493-501
- Costa FF. Mitapivat for treatment of pyruvate kinase deficiency. The Lancet Haematology 2022
