PB2396 DESIGN OF A PHASE 2, OPEN‐LABEL, MULTICENTER STUDY OF MITAPIVAT (AG‐348) IN ADULTS WITH NON–TRANSFUSION‐DEPENDENT THALASSEMIA

Background: The thalassemias are a group of disorders in which mutation (s) in the α‐ and/or β‐globin locus lead to an imbalance between α‐ and β‐globin production. The disease is characterized by the precipitation of excess α‐ or β‐globin, ineffective erythropoiesis, and peripheral hemolysis, with resultant anemia. Energy supply in the form of ATP appears to be insufficient in thalassemic red blood cells (RBCs) to maintain RBC membrane fitness and clearance of globin precipitates. Mitapivat (AG‐348) is an oral, small‐molecule, allosteric activator of the RBC‐specific form of pyruvate kinase (PK‐R). In healthy adults, mitapivat activates wild‐type PK‐R and increases ATP levels in RBCs. In adults with a mutant PK‐R and non–transfusion‐dependent anemia due to pyruvate kinase deficiency (NCT02476916), oral mitapivat was well tolerated and induced rapid, durable hemoglobin (Hb) increases. In β‐thalassemic mice, mitapivat increases ATP levels, reduces ineffective erythropoiesis, and improves anemia, RBC survival, and indices of iron overload. These data support the hypothesis that increased ATP synthesis mediated via the activation of PK‐R by mitapivat may improve the survival of thalassemic RBCs in the bone marrow and/or peripheral circulation. A phase 2 study of mitapivat is ongoing to further inform this hypothesis. Aims: To report the design of the ongoing phase 2 study of mitapivat in adults with non–transfusion‐dependent thalassemia (NTDT). Methods: This phase 2, multicenter, open‐label study (NCT03692052) is evaluating the efficacy, safety, pharmacokinetics, and pharmacodynamics of mitapivat in adults with NTDT. It consists of a 24‐week core period followed by a 2‐year extension period (Figure). Approximately 17 subjects with NTDT will be enrolled, including a minimum of 8 subjects with β‐thalassemia. All eligible subjects will receive an initial mitapivat dose of 50 mg orally twice daily (BID). At the Week 6 visit the dose may be increased to 100 mg orally BID, depending on safety and Hb response. Key inclusion criteria are: 1) β‐thalassemia (with or without α‐globin gene mutation), Hb E/β‐thalassemia or Hb H disease; 2) baseline Hb ≤9 g/dL; 3) NTDT defined as ≤5 units of RBCs transfused in the preceding 24 weeks and no transfusions in the 8 weeks prior to the first day of study drug); 4) adequate organ function. The primary endpoint is the proportion of subjects who achieve an Hb response, defined as an increase in Hb of ≥1.0 g/dL from baseline at any time between Week 4 and Week 12 (inclusive). Key secondary endpoints include changes in Hb and markers of hemolysis and hematopoietic activity, and assessments of safety and pharmacokinetics. The study is currently enrolling. Results: Not yet available. Summary/Conclusion: This is the first study of mitapivat in subjects with NTDT. The study will provide insights into the efficacy, safety, and pharmacokinetics of PK‐R activation in NTDT. Mitapivat may represent a novel therapeutic approach in the management of anemia in thalassemic syndromes.