IMPROVEMENTS IN FATIGUE AND 6-MINUTE WALK TEST IN ADULTS WITH ALPHA- OR BETA-NON–TRANSFUSION-DEPENDENT THALASSEMIA: THE PHASE 3 ENERGIZE TRIAL OF MITAPIVAT

Abstract

Background: Thalassemia, a group of inherited disorders characterized by ineffective erythropoiesis and chronic hemolytic anemia, is associated with wide-ranging impacts on health-related quality of life (HRQoL), such as impaired physical functioning and fatigue. Anemia has been associated with increased symptom burden and poor HRQoL in patients (pts) with non–transfusion-dependent thalassemia (NTDT). There are no available oral disease-modifying therapies that have been shown to improve HRQoL in β-thalassemia and no agents are approved for α-thalassemia. In a phase 2 study of pts with NTDT, improvements in hemoglobin were observed with mitapivat, a first-in-class, oral, allosteric activator of pyruvate kinase, and it has the potential to improve HRQoL. Aims: To evaluate the impact of mitapivat vs placebo on fatigue, physical function, and other thalassemia symptoms in adults with α- or β-NTDT in ENERGIZE, a phase 3, double-blind, randomized, placebo-controlled, global trial. Methods: Adults (≥18 years) were randomized 2:1 to mitapivat 100 mg twice daily or placebo for 24 weeks (wks). NTDT was defined as ≤5 red blood cell (RBC) units transfused in the 24 wks before randomization and no RBC transfusions ≤8 wks before informed consent or during screening. The Functional Assessment of Chronic Illness Therapy–Fatigue Scale (FACIT-Fatigue), 6-Minute Walk Test (6MWT), and Patient Global Impression of Change (PGIC) of Fatigue, Thalassemia Symptoms, and Walking Capacity were among the outcomes assessed. Changes from baseline (BL) for FACIT-Fatigue (Wks 12–24) and 6MWT (Wk 24), and the results of PGIC-Fatigue, (Wks 12–24), PGIC-Thalassemia Symptoms, and PGIC-Walking Capacity (both Wk 24) were summarized. The clinically meaningful within-person change (MWPC) threshold for FACIT-Fatigue was estimated to be a ≥4.5-point change from BL in average score from Wks 12–24, using an anchor-based method. Results: 194 pts were randomized (mitapivat n = 130; placebo n = 64); BL characteristics were similar between treatment arms. Mitapivat demonstrated a statistically significant improvement compared with placebo in change from BL to Wk 12–24 average FACIT-Fatigue score; least-squares mean (LSM) change from BL was 4.85 for mitapivat vs 1.46 for placebo (LSM difference (95% CI): 3.40 (1.21, 5.59); 2-sided p < 0.0026), and 36.2% of pts in the mitapivat arm achieved the MWPC threshold of ≥4.5 vs 21.9% in the placebo arm. For the 6MWT, LSM change from BL to Wk 24 was 30.48 m for mitapivat and 7.11 m for placebo (LSM difference (95% CI): 23.36 m (6.90, 39.83)). The observed frequency of pts with improvements (reporting feeling much/a little better) in PGIC-Fatigue was higher for pts in the mitapivat arm than the placebo arm at Wk 12 (63.1% vs 23.4%), Wk 16 (69.2% vs 23.4%), Wk 20 (62.3% vs 28.1%), and Wk 24 (60.8% vs 31.3%). Improvements in PGIC-Thalassemia Symptoms and PGIC-Walking Capacity were also reported in a higher frequency of pts in the mitapivat arm than in the placebo arm at Wk 24 (67.7% vs 32.8%; 55.4% vs 28.1%, respectively). Summary/Conclusion: Mitapivat is the first oral, disease-modifying, investigational therapy with which meaningful improvements in aspects of HRQoL, including fatigue and walking capacity, were observed in a clinical trial that enrolled both pts with α-NTDT and pts with β-NTDT.