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FDA grants approval to mitapivat for non-transfusion-dependent and transfusion-dependent alpha- or beta-thalassemia

On December 23, 2025, the U.S. Food and Drug Administration (FDA) granted approval to mitapivat for the treatment of adult patients with non-transfusion-dependent (NTD) and transfusion-dependent (TD) alpha- or beta-thalassemia.1  

Alpha- (α-) and beta (β)-thalassemias are a heterogeneous group of inherited hemoglobin (Hb) disorders that result from a decreased synthesis of alpha or beta Hb chains, leading to ineffective erythropoiesis.2 These non-malignant diseases are characterized by chronic anemia, organ damage from iron overload, and diminished quality of life.2 Patients with TD thalassemia endure frequent transfusions and the associated burdens, while NTD patients have lacked approved therapeutic options.

Mitapivat is a first‑in‑class oral allosteric activator of red blood cell pyruvate kinase (PKR) that boosts glycolytic adenosine triphosphate (ATP) production and reduces 2,3‑diphosphoglycerate levels in erythrocytes.3 This mechanism of action has made it a promising treatment approach for pyruvate kinase deficiency (PKD), but also for hereditary hemolytic anemias characterized by greater erythrocyte energy demands, such as sickle cell disease (SCD) and thalassemia.3

The approval of mitapivat in thalassemia is supported by data from two global Phase III clinical trials, ENERGIZE (NCT04770753) and ENERGIZE-T (NCT04770779).1  

In the ENERGIZE trial, 194 patients with NTD α- or β-thalassemia were enrolled and randomized in a 2:1 fashion to receive mitapivat (n = 130) or placebo (n = 64) for 24 weeks. The primary endpoint of the study was hemoglobin response, defined as a ≥1 g/dL increase in mean hemoglobin concentration from week 12 to week 24, which was achieved in 42.3% of patients in the mitapivat arm and 1.6% in the placebo arm (95% CI: 32–50; 2-sided p < 0.0001).4 The therapy also led to improvements in fatigue, with significant increases in the Functional Assessment of Chronic Illness Therapy–Fatigue Scale (FACIT-Fatigue) score from weeks 12 to 24 (2-sided p < 0.0026). In terms of safety, mitapivat was generally well-tolerated, with a low discontinuation rate: 3.1% of mitapivat-treated patients experienced treatment-emergent adverse events (TEAEs) leading to treatment discontinuation. Adverse events (AEs) were observed in 82.9% of patients receiving mitapivat and 79.3% of patients receiving placebo. The most commonly reported AEs in the mitapivat arm were headache, initial insomnia, nausea, and upper respiratory tract infection.4 

The ENERGIZE-T trial investigated mitapivat in patients with TD α- or β-thalassemia, randomizing 258 patients to receive 100 mg mitapivat twice daily (n = 171) or placebo (n = 87). Of the enrolled patients, 90.6% in the mitapivat arm and 95.4% in the placebo arm completed the 48-week double-blind period. In the mitapivat arm, 30.4% of patients achieved the primary endpoint of transfusion reduction response (TRR), defined as a ≥50% reduction in transfused red blood cell (RBC) units and a reduction of ≥2 units of transfused RBCs in any consecutive 12-week period through week 48 compared with baseline.5 This was significantly greater than in the placebo arm, in which 12.6% of patients achieved TRR (2-sided p = 0.0003). All key secondary endpoints were also met, with mitapivat treatment resulting in transfusion independence (TI) in 9.9% of patients as compared with 1.1% in the placebo arm.5 The occurrence of TEAEs was similar in mitapivat-treated patients (90.1%) and those in the placebo arm (83.5%), with the most common TEAEs in patients on mitapivat being headache, upper respiratory tract infection, initial insomnia, diarrhea, and fatigue. Treatment discontinuation was reported in 5.8% of patients treated with mitapivat.5

We recently interviewed Maria Domenica Cappellini, MD, from the University of Milan, Milan, Italy, who shared insight into the potential of mitapivat in thalassemia treatment. Prof. Cappellini believes that mitapivat represents ‘a good alternative option to luspatercept because patients respond differently to one drug over the other. So, [mitapivat treatment] can be an opportunity for those who are not responding to luspatercept.’ 

The approval of mitapivat represents a landmark moment in the treatment of patients with thalassemia. Prior to this milestone, no oral disease-modifying therapies had been approved for β-thalassemia, and α-thalassemia lacked any approved therapies.4 Therefore, this agent addresses the need for novel agents targeting disease pathophysiology and provides hope for adults living with these non-malignant hematological disorders.

References

  1. Agios Pharmaceuticals, Inc. Press Release: U.S. FDA Approves Agios’ AQVESME™ (mitapivat) for the Treatment of Anemia in Adults with Alpha- or Beta-Thalassemia. Available here. (Last accessed 05/01/2026).
  2. Kattamis A, Kwiatkowski J, and Aydinok Y. Thalassaemia. The Lancet. 2022 Jun;399(10343):2310–2324.
  3. Al-Samkari H, van Beers EJ. Mitapivat, a novel pyruvate kinase activator, for the treatment of hereditary hemolytic anemias. Ther Adv Hematol. 2021 Dec;12:20406207211066070.
  4. Taher AT, Al-Samkari H, Aydinok Y, et al. Mitapivat in adults with non-transfusion-dependent α-thalassaemia or β-thalassaemia (ENERGIZE): a phase 3, international, randomised, double-blind, placebo-controlled trial. Lancet. 2025 Jul;406(10498):33-42.
  5. Cappellini MD, Sheth S, Taher AT, et al. ENERGIZE-T: A Global, Phase 3, Double-Blind, Randomized, Placebo-Controlled Study of Mitapivat in Adults with Transfusion-Dependent Alpha- or Beta-Thalassemia. Blood. 2024 Nov;144(1),409.

Written by Natalie Markova

Edited by Anya Dragojlovic Kerkache