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Among patients with alpha or beta thalassemia who are not transfusion-dependent, mitapivat appears to be both well tolerated and to improve clinical outcomes, according to research presented at the European Hematology Association (EHA) 2021 Virtual Congress.
Alpha and beta thalassemia are linked with insufficient erythropoiesis and hemolysis, and reduced adenosine triphosphate levels in thalassemic red blood cells (RBCs). Mitapivat (AG-348), an orally administered RBC pyruvate kinase (PKR) activator, showed increased adenosine triphosphate production in preclinical study. Mitapivat has also previously been linked with increased hemoglobin levels among patients with PK deficiency and sickle cell disease.
For this open-label phase 2 study (ClinicalTrials.gov Identifier: NCT03692052), researchers evaluated the safety and efficacy of a 24-week core treatment period of mitapivat among patients with alpha or beta thalassemia who are not transfusion-dependent. Enrolled patients received oral mitapivat 50 mg twice daily, increasing, if tolerated, to 100 mg twice daily at week 6.
Overall, 20 patients (5 with alpha thalassemia and 15 with beta thalassemia) were enrolled and received mitapivat. Fifteen patients were female and the mean patient age was 45.3 years; the mean baseline hemoglobin level was 4.9 g/dL.
A total of 95% of patients (19) completed the core study period, with 1 patient discontinuing treatment because of an adverse event. A total of 17 patients continued to an extension period.
In the core period, 16 (80%) patients – 5 of 5 in the alpha-thalassemia group and 11 of 15 in the beta-thalassemia group – had a hemoglobin response. The mean time to a first increase of hemoglobin of more than 1 g/dL was 4.5 weeks, and the mean hemoglobin increase from baseline during weeks 12 to 24 was 1.3 g/dL.
All patients with alpha-thalassemia and 8 of 15 patients with beta-thalassemia had a sustained response.
One serious grade 3 renal impairment event led to treatment discontinuation; 3 non-serious 3 grade adverse events led to dose reduction from 100 mg, though 2 successfully rechallenged this dose.
Treatment-related events occurring in at least 25% of patients included initial insomnia (10 patients), dizziness (6 patients), and headache (5 patients). Dose escalation did not appear to increase the rate of these events.
Disclosure: The study author(s) declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
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Kuo KHM, Layton DM, La A, et al. Results from a phase 2, open-label, multicenter study of the oral pyruvate kinase activator mitapivat in adults with non–transfusion- dependent alpha- or beta-thalassemia. Paper presented at: European Hematology Association 2021 Virtual Congress; June 2021. Abstract S267.