Adult patients with alpha- or beta-non-transfusion-dependent thalassemia (NTDT) who received mitapivat had long-term improvements in hemoglobin (Hb) concentration and markers of erythropoietic activity and hemolysis, according to study results presented at the 2022 ASH Annual Meeting.

The phase 2, open-label study ( Identifier: NCT03692052) evaluated the efficacy, safety, pharmacokinetics, and pharmacodynamics of mitapivat in adult patients with alpha- or beta-NTDT.

Mitapivat is an investigational, first-in-class, oral, small-molecule allosteric activator of pyruvate kinase in red blood cells, a key enzyme that regulates the production of adenosine triphosphate.

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In previously reported results from the study’s core period, the primary endpoint of Hb response was achieved by 80.0% (16/20) of patients, improvements in markers of hemolysis and erythropoietic activity were observed, and mitapivat was well tolerated at the 50-mg and 100-mg twice daily dose. In the long-term extension, the increase in Hb was sustained with a mean (SD) increase of 1.7 g/dL (0.5) at week 72, and improvements in erythropoietin, total bilirubin, and lactate dehydrogenase were maintained through the data cutoff at week 72. Additionally, mitapivat was generally well tolerated.

The current analysis reported findings regarding erythropoietic activity, hemolysis, and iron homeostasis from the long-term extension through week 72, with a data cutoff on March 27, 2022.

A total of 20 patients (median age, 44 years; 75% female; 50% Asian) were included. Of those included in the cohort, 19 patients completed the core period, 17 entered the extension period, and 16 patients (4 with alpha-NTDT and 12 with beta-NTDT) were continuing at time of data cutoff. The participants had baseline biomarker levels consistent with ineffective erythropoiesis and hemolysis.

The patients had improvement in Hb throughout the extension period, and erythropoietic activity markers were stable or improved by week 72. Markers of hemolysis improved through week 72, and iron homeostasis markers were stable or improved through week 72.

Changes from baseline indicated a sustained increase in Hb with a median (Q1 and Q3) of 1.3 g/dL (0.60 and 1.90, respectively) at week 12 and 1.2 g/dL (–0.03 and 2.2) at week 72. Erythropoietin changed from –35.5 IU/L (–81.0 and –9.0, respectively) at week 12 to –12.5 IU/L (–40.0 and –4.5) at week 72. Soluble transferrin receptor level changed from –31.8 nmol/L (–40.0 and –10.6, respectively) at week 12 to –24.7 nmol/L (–43.5 and –8.2) at week 72. Indirect bilirubin level changed from –10.0 µmol/L (–23.0 and –5.0, respectively) at week 12 to –13.8 µmol/L (–33.5 and –6.5) at week 72.

“These new data suggest that mitapivat’s mechanism of action may ameliorate multiple aspects of the complex pathophysiology underlying α- or β-NTDT,” stated the investigators in their presentation. “Mitapivat may offer a novel disease-modifying approach with potential long-term benefits in hemolysis, erythropoiesis, and iron homeostasis for patients with α- or β-NTDT.”

Disclosure: This study was funded by Agios Pharmaceuticals Inc. Please see the original reference for a full list of authors’ disclosures.

Kuo KHM, Layton DM, Lal A, et al. Mitapivat improves markers of erythropoietic activity in long-term study of adults with alpha- or beta-non–transfusion-dependent thalassemia. Presented at ASH 2022. December 10-13, 2022. Abstract 1030.