• Hanny Al-Samkari, Frédéric Galactéros, Andreas Glenthøj, Jennifer A Rothman, Oliver Andres, Rachael F Grace, Marta Morado-Arias, D Mark Layton, Koichi Onodera, Madeleine Verhovsek, Wilma Barcellini, Satheesh Chonat, Malia P Judge, Erin Zagadailov, Rengyi Xu, Peter Hawkins, Vanessa Beynon, Sarah Gheuens, Eduard J van Beers, and ACTIVATE Investigators.
• From the Division of Hematology Oncology, Massachusetts General Hospital (H.A.-S.) and the Dana-Farber/Boston Children's Cancer and Blood Disorders Center (R.F.G.), Harvard Medical School, Boston, and Agios Pharmaceuticals, Cambridge (M.P.J., E.Z., R.X., P.H., V.B., S.G.) - all in Massachusetts; Unité des Maladies Génétiques du Globule Rouge, Centre Hospitalier Universitaire Henri Mondor, Créteil, France (F.G.); the Department of Hematology, Copenhagen University Hospital, Rigshospitalet, Copenhagen (A.G.); Duke University Medical Center, Durham, NC (J.A.R.); the Department of Pediatrics, University of Würzburg, Würzburg, Germany (O.A.); the Hematology Department, Hospital Universitario La Paz, Madrid (M.M.-A.); Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (D.M.L.); Tohoku University Hospital, Sendai, Japan (K.O.); McMaster University, Hamilton, ONT, Canada (M.V.); Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan (W.B.); Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, and the Department of Pediatrics, Emory University, Atlanta (S.C.); and the Benign Hematology Center, Van Creveldkliniek, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands (E.J.B.).
• N. Engl. J. Med. 2022 Apr 14; 386 (15): 1432-1442.

BackgroundPyruvate kinase deficiency is a rare, hereditary, chronic condition that is associated with hemolytic anemia. In a phase 2 study, mitapivat, an oral, first-in-class activator of erythrocyte pyruvate kinase, increased the hemoglobin level in patients with pyruvate kinase deficiency.MethodsIn this global, phase 3, randomized, placebo-controlled trial, we evaluated the efficacy and safety of mitapivat in adults with pyruvate kinase deficiency who were not receiving regular red-cell transfusions. The patients were assigned to receive either mitapivat (5 mg twice daily, with potential escalation to 20 or 50 mg twice daily) or placebo for 24 weeks. The primary end point was a hemoglobin response (an increase from baseline of ≥1.5 g per deciliter in the hemoglobin level) that was sustained at two or more scheduled assessments at weeks 16, 20, and 24. Secondary efficacy end points were the average change from baseline in the hemoglobin level, markers of hemolysis and hematopoiesis, and the change from baseline at week 24 in two pyruvate kinase deficiency-specific patient-reported outcome measures.ResultsSixteen of the 40 patients (40%) in the mitapivat group had a hemoglobin response, as compared with none of the 40 patients in the placebo group (adjusted difference, 39.3 percentage points; 95% confidence interval, 24.1 to 54.6; two-sided P<0.001). Patients who received mitapivat had a greater response than those who received placebo with respect to each secondary end point, including the average change from baseline in the hemoglobin level. The most common adverse events were nausea (in 7 patients [18%] in the mitapivat group and 9 patients [23%] in the placebo group) and headache (in 6 patients [15%] and 13 patients [33%], respectively). Adverse events of grade 3 or higher occurred in 10 patients (25%) who received mitapivat and 5 patients (13%) who received placebo.ConclusionsIn patients with pyruvate kinase deficiency, mitapivat significantly increased the hemoglobin level, decreased hemolysis, and improved patient-reported outcomes. No new safety signals were identified in the patients who received mitapivat. (Funded by Agios Pharmaceuticals; ACTIVATE ClinicalTrials.gov number, NCT03548220.).Copyright © 2022 Massachusetts Medical Society.

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