Alpha- and beta-thalassemia are inherited hemoglobinopathies causing chronic hemolytic anemia, ineffective erythropoiesis, iron overload, and complications including fatigue and organ damage. Management has relied on supportive care such as transfusions and chelation, with no prior disease-modifying oral therapies approved for all subtypes. Mitapivat, a first-in-class oral pyruvate kinase activator, targets underlying red blood cell energy deficits to improve survival and function.
Approval was based on two global, randomized, double-blind, placebo-controlled Phase 3 trials: ENERGIZE (n=194 non-transfusion-dependent patients) and ENERGIZE-T (n=258 transfusion-dependent patients), totaling 452 adults representative of real-world thalassemia populations. Patients received mitapivat 100 mg twice daily or placebo. The ENERGIZE primary endpoint was hemoglobin response (≥1.0 g/dL sustained increase from Week 12–24). ENERGIZE-T’s primary endpoint was transfusion reduction response (≥50% reduction in red blood cell units with ≥2-unit decrease in any 12-week period through Week 48). Key secondary endpoints included additional transfusion measures, fatigue, and quality-of-life assessments.
Both trials met primary and all key secondary endpoints. In ENERGIZE, mitapivat achieved significantly higher hemoglobin response rates versus placebo, alongside improvements in markers of hemolysis and patient-reported fatigue. In ENERGIZE-T, mitapivat demonstrated substantial reductions in transfusion burden. Safety profile included common adverse reactions (≥5%) of headache and insomnia. Hepatocellular injury occurred in a small subset, prompting a boxed warning and REMS program requiring liver function monitoring before initiation, every 4 weeks for 24 weeks, and thereafter as indicated.
FDA approval of AQVESME™ (mitapivat) on December 23, 2025, establishes the first oral disease-modifying treatment for anemia in adults with alpha- or beta-thalassemia, regardless of transfusion status. By activating pyruvate kinase to enhance red blood cell metabolism, mitapivat addresses core pathophysiology, offering meaningful clinical benefits in hemoglobin stabilization, transfusion reduction, and symptom relief. Availability is anticipated in late January 2026 following REMS implementation. This milestone provides new hope for approximately 6,000 diagnosed U.S. adults, with ongoing studies exploring broader applications in rare anemias.
