ENERGIZE-T: A Global, Phase 3, Double-Blind, Randomized, Placebo-Controlled Study of Mitapivat in Adults with Transfusion-Dependent Alpha- or Beta-Thalassemia

Introduction: Transfusions and iron chelators have improved survival and outcomes in transfusion-dependent (TD)-thalassemia. However, they are associated with adverse effects, such as end organ complications and high healthcare resource utilization, and can become a burden for patients (pts), limiting adherence and negatively impacting quality of life. These limitations highlight a need for new agents targeting disease pathophysiology. There are no approved oral disease-modifying therapies for β-thalassemia, and no therapies are approved for α-thalassemia. Mitapivat is a first-in-class, oral, allosteric activator of pyruvate kinase that increases adenosine triphosphate production, which may improve thalassemic red blood cell (RBC) health by addressing their increased cellular energy demands. In a phase 3 trial in non–transfusion-dependent (NTD)-α- or β-thalassemia (ENERGIZE [NCT04770753]), mitapivat significantly improved hemoglobin levels and fatigue vs placebo.

Aim: To assess the efficacy and safety of mitapivat vs placebo in adults with TD-α- or β-thalassemia in ENERGIZE-T (NCT04770779).

Methods: Adults (≥18 years) with TD-α- or β-thalassemia from 19 countries were randomized 2:1 to mitapivat 100 mg or placebo twice daily for 48 weeks. TD was defined as 6–20 RBC units transfused and a ≤6-week transfusion-free period during the 24-week period before randomization. Randomization was stratified by thalassemia genotype (β⁰/β⁰ and non-β⁰/β⁰, including HbE/β-thalassemia and α-thalassemia/HbH) and geographic region. The primary endpoint was transfusion reduction response (TRR, a ≥50% reduction in transfused RBC units and a reduction of ≥2 units of transfused RBCs in any consecutive 12-week period through Week 48 compared with baseline [BL]). Key secondary endpoints were: TRR2, a ≥50% reduction from BL in transfused RBC units in any consecutive 24-week period through Week 48; TRR3, a ≥33% reduction from BL in transfused RBC units in Weeks 13–48; and TRR4, a ≥50% reduction from BL in transfused RBC units in Weeks 13–48. Transfusion independence (TI, transfusion-free for ≥8 consecutive weeks through Week 48) and safety were among the secondary endpoints.

Results: A total of 258 pts were randomized (mitapivat: N=171; placebo: N=87); 155 (90.6%) and 83 (95.4%) pts in the mitapivat and placebo arms, respectively, completed the 48-week double-blind period. Overall, mean age was 35.5 years; 70.9% of pts had a 24-week BL transfusion burden of >12 RBC units; and 44.2% had β⁰/β⁰ genotype. There was no imbalance in BL characteristics between treatment arms deemed to impact the interpretation of the results.

A TRR was achieved in 30.4% of pts in the mitapivat arm vs 12.6% in the placebo arm (2-sided p=0.0003). Statistically significant reductions in transfusion burden for mitapivat vs placebo were also demonstrated by all key secondary endpoints: 13.5% vs 2.3% (2-sided p=0.0003) achieved TRR2; 14.6% vs 1.1% (2-sided p<0.0001) achieved TRR3; and 7.6% vs 1.1% (2-sided p=0.0056) achieved TRR4. Overall results for these endpoints were not driven by any of the individual prespecified subgroups, including genotype and BL transfusion burden. A higher proportion of pts in the mitapivat arm achieved TI (9.9%) vs the placebo arm (1.1%).

The proportion of pts with any treatment-emergent adverse events (TEAEs) was similar across treatment arms (mitapivat: 90.1%; placebo: 83.5%). TEAEs occurring in ≥10% of pts on mitapivat were headache, upper respiratory tract infection, initial insomnia, diarrhea, and fatigue. Serious TEAEs were reported in 11.0% and 15.3% of pts on mitapivat and placebo, respectively; 2.3% and 1.2%, respectively, were considered treatment-related. Discontinuation due to TEAEs occurred in 5.8% of pts on mitapivat and 1.2% on placebo.

Conclusions: In a globally representative population with TD-α- or β-thalassemia, mitapivat vs placebo significantly reduced transfusion burden and demonstrated a durable reduction of up to 36 weeks (Weeks 13–48). Mitapivat was generally safe and well tolerated with a low treatment discontinuation rate. These data, alongside data in NTD-α- or β-thalassemia from ENERGIZE, demonstrate the efficacy of mitapivat across the full range of thalassemia, supporting it as a potential oral disease-modifying therapy.