Mitapivat in adults with non-transfusion-dependent α-thalassaemia or β-thalassaemia (ENERGIZE): a phase 3, international, randomised, double-blind, placebo-controlled trial

Abstract

Background: Non-transfusion-dependent (NTD) thalassaemia is characterised by ineffective erythropoiesis and haemolytic anaemia, leading to long-term complications, poor quality of life, and early mortality. No oral disease-modifying therapies are approved for β-thalassaemia and no agents are approved for α-thalassaemia. The objective of this study was to evaluate the efficacy and safety of mitapivat, an oral activator of pyruvate kinase, in adults with NTD α-thalassaemia or NTD β-thalassaemia.

Methods: ENERGIZE is a phase 3, double-blind, randomised, placebo-controlled trial followed by an open-label extension conducted at 70 hospitals in 18 countries globally. Participants had to be aged 18 years or older with NTD α-thalassaemia or NTD β-thalassaemia and haemoglobin concentrations of 10 g/dL or lower. Participants were randomly assigned 2:1 to mitapivat or placebo (100 mg orally twice a day for 24 weeks) via a central interactive response technology system using block randomisation, stratified by baseline haemoglobin concentration and thalassaemia genotype. Everyone was masked to the patients' treatment assignment until the study was unblinded for the analysis of the primary endpoint. The primary endpoint was haemoglobin response (≥1·0 g/dL increase from baseline in mean haemoglobin concentration from week 12 through week 24), analysed in all patients who were randomly assigned. Safety was analysed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT04770753, and is active but not recruiting.

Findings: Between Nov 8, 2021, and March 31, 2023, 235 patients were screened, of whom 194 were enrolled (123 [63%] were female and 71 [37%] were male). 130 patients were randomly assigned to mitapivat and 64 patients to placebo and formed the full analysis set. One patient in each group was randomly assigned but not given treatment and was therefore excluded from the safety analysis set (mitapivat 129 patients and placebo 63 patients). Seven patients in the mitapivat group and one patient in the placebo group discontinued treatment before the end of the 24-week double-blind period. 55 (42%) of 130 patients in the mitapivat group had a haemoglobin response versus one (2%) of 64 in the placebo group (least-squares mean difference 41% [95% CI 32-50], two-sided p<0·0001). Adverse events were reported in 107 (83%) of 129 patients who received mitapivat and 50 (79%) of 63 patients who received placebo. The most commonly reported adverse events with mitapivat were headache (29 [22%] of 129 patients in the mitapivat group vs six [10%] of 63 in the placebo group), initial insomnia (18 [14%] vs three [5%]), nausea (15 [12%] vs five [8%]), and upper respiratory tract infection (14 [11%] vs four [6%]). No deaths were reported.

Interpretation: Mitapivat could be a new oral treatment for adults with NTD α-thalassaemia or NTD β-thalassaemia by increasing haemoglobin concentration and improving fatigue.

Funding: Agios Pharmaceuticals.