TY - JOUR
T1 - Mitapivat versus Placebo for Pyruvate Kinase Deficiency
AU - Al-Samkari, Hanny
AU - Galactéros, Frédéric
AU - Glenthøj, Andreas
AU - Rothman, Jennifer A.
AU - Andres, Oliver
AU - Grace, Rachael F.
AU - Morado-Arias, Marta
AU - Layton, D. Mark
AU - Onodera, Koichi
AU - Verhovsek, Madeleine
AU - Barcellini, Wilma
AU - Chonat, Satheesh
AU - Judge, Malia P.
AU - Zagadailov, Erin
AU - Xu, Rengyi
AU - Hawkins, Peter
AU - Beynon, Vanessa
AU - Gheuens, Sarah
AU - van Beers, Eduard J.
N1 - Funding Information:
Supported by Agios Pharmaceuticals .
Publisher Copyright:
Copyright © 2022 Massachusetts Medical Society
Copyright © 2022 Massachusetts Medical Society.
PY - 2022/4/14
Y1 - 2022/4/14
N2 - BACKGROUND Pyruvate 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. METHODS In 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. RESULTS Sixteen 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. CONCLUSIONS In 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.
AB - BACKGROUND Pyruvate 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. METHODS In 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. RESULTS Sixteen 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. CONCLUSIONS In 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.
KW - Adult
KW - Anemia, Hemolytic, Congenital Nonspherocytic/drug therapy
KW - Double-Blind Method
KW - Hemoglobins/analysis
KW - Hemolysis/drug effects
KW - Humans
KW - Piperazines/pharmacology
KW - Pyruvate Kinase/deficiency
KW - Pyruvate Metabolism, Inborn Errors/drug therapy
KW - Quinolines/pharmacology
UR - http://www.scopus.com/inward/record.url?scp=85128313033&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa2116634
DO - 10.1056/NEJMoa2116634
M3 - Article
C2 - 35417638
AN - SCOPUS:85128313033
SN - 0028-4793
VL - 386
SP - 1432
EP - 1442
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 15
ER -