Safety and Efficacy of Mitapivat in Pyruvate Kinase Deficiency.

Abstract

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.).

• Authors: 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 Bowden, Bertil Glader
• Journal: The New England journal of medicine (N Engl J Med) Vol. 381 Issue 10 Pg. 933-944 (09 05 2019) ISSN: 1533-4406 [Electronic] United States
• PMID: 31483964 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Massachusetts Medical Society.

Chemical References

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

Topics

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