Background
ENERGIZE-T is a global, double-blind, randomized, placebo-controlled phase 3 trial across 19 countries. N=258 adults (≥18 yr) with transfusion-dependent alpha- or beta-thalassemia. Mitapivat is an oral allosteric activator of pyruvate kinase, addressing the absence of oral disease-modifying therapy in thalassemia.
Results
Interventions and follow up: Arm A: Mitapivat 100 mg PO BID — 171 patients
Arm B: Placebo PO BID — 87 patients (randomized 2:1), for 48 weeks
Primary endpoint: Transfusion reduction response (TRR) — ≥50% reduction in transfused RBC units with ≥2-unit reduction over any consecutive 12-week period through week 48 vs baseline
mFollow up: 48-week double-blind treatment period
Results: TRR: 30% (52/171) vs 13% (11/87); adjusted difference 18 percentage points (95% CI 8–27); P=.0003
Double-blind completion: 92%
Arm B: Placebo PO BID — 87 patients (randomized 2:1), for 48 weeks
Primary endpoint: Transfusion reduction response (TRR) — ≥50% reduction in transfused RBC units with ≥2-unit reduction over any consecutive 12-week period through week 48 vs baseline
mFollow up: 48-week double-blind treatment period
Results: TRR: 30% (52/171) vs 13% (11/87); adjusted difference 18 percentage points (95% CI 8–27); P=.0003
Double-blind completion: 92%
Adverse events
Any AE: 90% vs 84%
Common (mitapivat): headache, URTI, initial insomnia, diarrhea, fatigue
Serious AE: 11% vs 15%
Hepatocellular injury: 5 patients (ENERGIZE + ENERGIZE-T), within first 6 months, reversible on discontinuation
Discontinuation due to AE: 6% vs 1%
Deaths: none
Common (mitapivat): headache, URTI, initial insomnia, diarrhea, fatigue
Serious AE: 11% vs 15%
Hepatocellular injury: 5 patients (ENERGIZE + ENERGIZE-T), within first 6 months, reversible on discontinuation
Discontinuation due to AE: 6% vs 1%
Deaths: none
Conclusions
Mitapivat significantly reduced transfusion burden versus placebo in transfusion-dependent alpha- or beta-thalassemia and was generally well tolerated. It is the first oral disease-modifying therapy shown to reduce transfusion requirements in this population.
Key Limitations
Modest absolute response — only 30% of mitapivat patients met the transfusion-reduction threshold; the 48-week endpoint leaves long-term durability, iron-overload, and organ outcomes unproven. A hepatocellular-injury signal warrants liver monitoring. Placebo-controlled with no active comparator.
Clinical Context
On Dec 23, 2025 the FDA approved mitapivat (AQVESME) for anemia in adults with alpha- or beta-thalassemia — both transfusion-dependent and non-transfusion-dependent — based on ENERGIZE and ENERGIZE-T. It is the first FDA-approved therapy for anemia across both thalassemia subtypes and the first oral option, complementing luspatercept (approved for beta-thalassemia) and extending disease-modifying options to alpha-thalassemia, which previously had none.