The phase III, double-blind, placebo-controlled, global ENERGIZE study assessed the safety and activity of mitapivat versus placebo in adults with α- or β- non-transfusion-dependent thalassaemia (NTDT). Mitapivat significantly increased haemoglobin and improved fatigue as compared to placebo. Mitapivat was generally well tolerated with a low treatment discontinuation rate. These data are the first proof of efficacy of a disease-modifying therapy across the full range of NTDT (α- and β-thalassaemia).
Mitapivat is an activator of the red cell-specific form of pyruvate kinase (PKR) and pyruvate kinase M2 (PKM2) isoforms of pyruvate kinase (PK), which acts in glycolysis to generate adenosine triphosphate (ATP). In preclinical thalassaemia models, mitapivat reduced oxidative stress, and improved erythropoiesis, haemolysis and anaemia. A phase II study of mitapivat in α- or β- non-transfusion-dependent thalassaemia (NTDT) demonstrated improvements in haemoglobin (Hb) and markers of erythropoiesis and haemolysis.
ENERGIZE is a phase III study of mitapivat in adults with α- or β-NTDT with Hb < 10.0 g/dL. Non-transfusion-dependence was defined as ≤5 RBC units transfused during the 24-week period before randomisation and no RBC transfusions ≤8 weeks before informed consent and during screening. Patients were randomised in a 2:1 ratio to mitapivat (100 mg, twice daily) or placebo for 24 weeks. Thereafter, all patients could enrol into an open-label extension phase with mitapivat 100 mg, twice daily up to five years. Primary endpoint of the study was Hb response, defined as an increase of at least 1.0 g/dL in average Hb concentration from week 12 through week 24, as compared to baseline. Key secondary endpoints were change from baseline in average Functional Assessment of Chronic Illness Therapy – Fatigue Scale (FACIT-Fatigue) score from week 12 through week 24, as well as change from baseline in average Hb concentration from week 12 through week 24.
In total, 235 patients were assessed for eligibility, of which 194 patients were randomised to mitapivat (N= 130) or placebo (N= 64). Mean age was 41.2 years, mean baseline Hb was 8.3 g/dL, 86.6% received no transfusions in the 24 weeks before randomisation, and 32.0% had α-NTDT. Baseline characteristics were similar between treatment arms. Mitapivat demonstrated a statistically significant improvement in Hb response vs. placebo (42.3% vs. 1.6%, p< 0.0001). Among responders in the mitapivat arm, mean change from baseline in average Hb concentration from week 12 to 24 was 1.56 g/dL. Interestingly, Hb response rates were higher for mitapivat vs. placebo across all prespecified subgroups. Furthermore, mitapivat demonstrated a statistically significant improvement from baseline in average FACIT-Fatigue score from weeks 12-24 vs. placebo (4.85 vs. 1.46, p= 0.0026) and change from baseline in average Hb from weeks 12-24 versus placebo (least-squares mean difference of 0.96 g/dL, p< 0.0001). In addition, improvements in markers of haemolysis and erythropoiesis were observed in favour of the mitapivat group.
The proportion of patients with treatment-emergent adverse events (TEAEs) was similar in both groups (mitapivat 82.9%; placebo 79.4%). The most common TEAEs (≥10%) with mitapivat were headache, insomnia, nausea, and upper respiratory tract infections. Of patients treated with mitapivat, 6.2% had serious TEAEs, none of which were treatment-related. No serious adverse events were reported in the placebo group.
This global study was the first to enrol both patients with α- and β-thalassemia. The primary and key secondary endpoints were met, with statistically significant improvements in Hb and fatigue with mitapivat vs. placebo. Furthermore, improvements in markers of haemolysis and erythropoietic activity were observed, consistent with the mechanism of mitapivat. Mitapivat was generally well tolerated, with a low treatment discontinuation rate and a safety profile consistent with other studies.
Reference
Taher A, et al. ENERGIZE: A global, phase 3 study of mitapivat demonstrating efficacy and safety in adults with alpha- or beta-non-transfusion-dependent thalassemia. Presented at EHA 2024; Abstract S104.
Top
