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Updated: Jan 20, 2026
Pyruvate Oxidation : Production of Acetyl coA in Mitochondria
Safety and Efficacy of Mitapivat in Pyruvate Kinase Deficiency
Rachael F Grace1, Christian Rose1, D Mark Layton1
1From the Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston (R.F.G.), and Agios Pharmaceuticals, Cambridge (A.J.B., S.B., L.H., C.K., P.H., M.-H.J., C.B.) - all in Massachusetts; Hôpital Saint Vincent de Paul, Lille (C.R.), and Unité des Maladies Génétiques du Globule Rouge, Centre Hospitalier Universitaire Henri Mondor, Créteil (F.G.) - both in France; Hammersmith Hospital, Imperial College Healthcare NHS Trust, London (D.M.L.); Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan (W.B.); Central Pennsylvania Clinic, Belleville (D.H.M.), and Children's Hospital of Philadelphia and Perelman School of Medicine of the University of Pennsylvania, Philadelphia (J.L.K.); Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands (E.J.B.); University of Utah, Salt Lake City (H.Y.); Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit (Y.R.); University of Toronto, Toronto (K.H.M.K.); Weill Cornell Medical College, New York (S.S.); Bruce A. Silver Clinical Science and Development, Dunkirk, MD (B.S.); and Stanford University School of Medicine, Palo Alto, CA (B.G.).
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; ClinicalTrials.gov number, NCT02476916.).
Insights
Mitapivat treatment rapidly increased hemoglobin in adults with pyruvate kinase deficiency, with sustained effects over 29 months. Adverse events were mostly mild and temporary, showing potential for this anemia therapy.
Area of Science:
- Hematology
- Pharmacology
Background:
- Pyruvate kinase deficiency (PKD) is a genetic disorder causing congenital hemolytic anemia.
- Mutations in the *PKLR* gene are the primary cause of PKD.
- Mitapivat is an oral, small-molecule allosteric activator targeting red blood cell pyruvate kinase.
Purpose of the Study:
- To evaluate the safety and efficacy of mitapivat in adults with pyruvate kinase deficiency.
- To assess the drug's impact on hemoglobin levels and markers of hemolysis.
- To determine the long-term response and safety profile in an extension phase.
Main Methods:
- An uncontrolled, phase 2 study involving 52 adults with PKD not on transfusions.
- Random assignment to 50 mg or 300 mg mitapivat twice daily for a 24-week core period.
- Inclusion of an ongoing extension phase for eligible patients.
Main Results:
- 50% of patients experienced a hemoglobin increase (>1.0 g/dL), with a mean maximum increase of 3.4 g/dL.
- Hemolysis markers improved, and responses were sustained in 19 patients during a median 29-month follow-up.
- Adverse events like headache and insomnia were transient; serious events (hemolytic anemia, pharyngitis) occurred in 4% of patients.
Conclusions:
- Mitapivat demonstrated a rapid and sustained increase in hemoglobin in 50% of adults with pyruvate kinase deficiency.
- The drug's safety profile was characterized by mainly low-grade, transient adverse effects.
- Hemoglobin response was linked to specific *PKLR* mutations and baseline red-cell pyruvate kinase levels.
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