Agios Pharmaceuticals, Inc. announced that data from the core period of the open-label, Phase 2 study of PYRUKYND® (mitapivat) in adults with non-transfusion-dependent a- or ß-thalassemia were published on August 11, 2022, in The Lancet. Data from this study were previously presented at the 2021 European Hematology Association (EHA) Annual Congress. PYRUKYND® is a first-in-class, investigational, oral, small molecule allosteric activator of wild-type and a variety of mutated pyruvate kinase (PK) enzymes.

As reported in the publication, 16 of 20 patients (80%; p<0.0001), including five of five (100%) with a-thalassemia and 11 of 15 (73%) with ß-thalassemia, achieved the primary endpoint of hemoglobin response, a =1.0 g/dL increase in hemoglobin concentration from baseline at one or more assessment between Weeks 4–12. The mean time to hemoglobin response was 4.5 weeks. Of the 16 patients who achieved the primary endpoint, 13 had a sustained response, defined as =1.0 g/dL increase in hemoglobin at two or more assessments between Week 12 and Week 24.

A trend in decreasing concentrations of markers of hemolysis (total bilirubin and LDH concentrations) was observed in both a- and ß-thalassemia patients, with decreases observed as early as Week 2. Decreases in erythropoietin concentrations were also observed in both a- and ß-thalassemia patients. The greater change in markers of hemolysis and erythropoiesis was observed in the first 8 weeks of treatment, and improvements were maintained over the duration of the core period. The most common adverse events were initial insomnia (50%, including 1 patient [5%] with Grade 3), dizziness (30%, all Grade 1) and headache (25%, all Grade 2 or lower).

Initial insomnia was the only Grade 3 or worse treatment-emergent adverse event considered to be treatment-related. One patient who had ß-thalassemia discontinued after Week 4 due to a treatment-emergent adverse event deemed unrelated to the study drug. PYRUKYND® was approved in February 2022 by the U.S. Food and Drug Administration (FDA) for the treatment of hemolytic anemia in adults with PK deficiency.

PYRUKYND® is also under review by the European Medicines Agency (EMA) as a potential treatment for adults with PK deficiency, and Agios expects a regulatory decision in the EU by the end of 2022. Both the FDA and EMA have granted orphan drug designation to PYRUKYND® in PK deficiency. In addition, PYRUKYND® has been granted FDA orphan drug designation for the treatment of thalassemia and sickle cell disease, for which enrollment for ongoing pivotal studies is underway.

The open-label Phase 2 study evaluated the efficacy, safety, pharmacokinetics and pharmacodynamics of mitapivat treatment in adults with non-transfusion-dependent a- or ß-thalassemia who have a baseline hemoglobin concentration of =10 g/dL. The trial enrolled 20 patients. All patients were treated with an initial dose of mitapivat 50 mg twice daily followed by a dose-level increase to 100 mg twice daily at the Week 6 visit based on safety evaluations and hemoglobin concentrations.

Following the completion of the 24-week core period, patients had the opportunity to enroll in an optional 10-year extension period, which is evaluating long-term efficacy and safety of mitapivat in this population. Initial data from the extension period, which highlighted the long-term safety profile and durable improvement in hemoglobin and markers of hemolysis associated with mitapivat treatment in non-transfusion-dependent a- and ß-thalassemia, were presented at the 2021 American Society of Hematology (ASH) Annual Meeting and Exposition. Thalassemia is a rare, inherited blood disorder caused by mutations in either a- or ß-globin genes, resulting in excessive destruction of red blood cells.

Globin precipitates in thalassemia cause oxidative damage, leading to hemolytic anemia, ineffective erythropoiesis and iron overload. Thalassemia is associated with serious complications, including fatigue, jaundice, facial bone deformities, delayed growth and development, abdominal swelling, dark urine and reduced life expectancy. Current management strategies for ß-thalassemia can include ??red blood cell transfusions, splenectomy and stem cell transplant, which are associated with short- and long-term risks.

There are currently no approved therapies for a-thalassemia. PYRUKYND is a pyruvate kinase activator indicated for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency.