Safety and Efficacy of Mitapivat in Pyruvate Kinase Deficiency

N Engl J Med. 2019 Sep 5;381(10):933-944. doi: 10.1056/NEJMoa1902678.


Background: Pyruvate kinase deficiency is caused by mutations in PKLR and leads to congenital hemolytic anemia. Mitapivat is an oral, small-molecule allosteric activator of pyruvate kinase in red cells.

Methods: In this uncontrolled, phase 2 study, we evaluated the safety and efficacy of mitapivat in 52 adults with pyruvate kinase deficiency who were not receiving red-cell transfusions. The patients were randomly assigned to receive either 50 mg or 300 mg of mitapivat twice daily for a 24-week core period; eligible patients could continue treatment in an ongoing extension phase.

Results: Common adverse events, including headache and insomnia, occurred at the time of drug initiation and were transient; 92% of the episodes of headache and 47% of the episodes of insomnia resolved within 7 days. The most common serious adverse events, hemolytic anemia and pharyngitis, each occurred in 2 patients (4%). A total of 26 patients (50%) had an increase of more than 1.0 g per deciliter in the hemoglobin level. Among these patients, the mean maximum increase was 3.4 g per deciliter (range, 1.1 to 5.8), and the median time until the first increase of more than 1.0 g per deciliter was 10 days (range, 7 to 187); 20 patients (77%) had an increase of more than 1.0 g per deciliter in the hemoglobin level at more than 50% of visits during the core study period, with improvement in markers of hemolysis. The response was sustained in all 19 patients remaining in the extension phase, with a median follow-up of 29 months (range, 22 to 35). Hemoglobin responses were observed only in patients who had at least one missense PKLR mutation and were associated with the red-cell pyruvate kinase protein level at baseline.

Conclusions: The administration of mitapivat was associated with a rapid increase in the hemoglobin level in 50% of adults with pyruvate kinase deficiency, with a sustained response during a median follow-up of 29 months during the extension phase. Adverse effects were mainly low-grade and transient. (Funded by Agios Pharmaceuticals; number, NCT02476916.).

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Anemia, Hemolytic, Congenital Nonspherocytic / blood
  • Anemia, Hemolytic, Congenital Nonspherocytic / drug therapy*
  • Anemia, Hemolytic, Congenital Nonspherocytic / genetics
  • Catechols
  • Drug Administration Schedule
  • Female
  • Follow-Up Studies
  • Headache / chemically induced
  • Hemoglobins / metabolism*
  • Humans
  • Male
  • Mutation
  • Piperazines / administration & dosage*
  • Piperazines / adverse effects
  • Pyruvate Kinase / blood
  • Pyruvate Kinase / deficiency*
  • Pyruvate Kinase / genetics
  • Pyruvate Metabolism, Inborn Errors / blood
  • Pyruvate Metabolism, Inborn Errors / drug therapy*
  • Pyruvate Metabolism, Inborn Errors / genetics
  • Quinolines / administration & dosage*
  • Quinolines / adverse effects
  • Sleep Initiation and Maintenance Disorders / chemically induced
  • Tyrphostins
  • Young Adult


  • 3-methoxyl-5-(2-,2-dicyanoethenyl)catechol
  • Catechols
  • Hemoglobins
  • Piperazines
  • Quinolines
  • Tyrphostins
  • mitapivat
  • Pyruvate Kinase

Supplementary concepts

  • Pyruvate Kinase Deficiency of Red Cells

Associated data