Safety and efficacy of mitapivat in pyruvate kinase deficiency

Rachael F. Grace, Christian Rose, D. Mark Layton, Frédéric Galactéros, Wilma Barcellini, D. Holmes Morton, Eduard J. Van Beers, Hassan Yaish, Yaddanapudi Ravindranath, Kevin H.M. Kuo, Sujit Sheth, Janet L. Kwiatkowski, Ann J. Barbier, Susan Bodie, Bruce Silver, Lei Hua, Charles Kung, Peter Hawkins, Marie Hélène Jouvin, Chris BowdenBertil Glader

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)933-944
Number of pages12
JournalNew England Journal of Medicine
Issue number10
Publication statusPublished - Sept 5 2019

ASJC Scopus subject areas

  • Medicine(all)


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