Mitapivat in adults with non-transfusion-dependent α-thalassaemia or β-thalassaemia (ENERGIZE): a phase 3, international, randomised, double-blind, placebo-controlled trial
Issued Date
2025-01-01
Resource Type
ISSN
01406736
eISSN
1474547X
Scopus ID
2-s2.0-105008758451
Journal Title
Lancet
Rights Holder(s)
SCOPUS
Bibliographic Citation
Lancet (2025)
Suggested Citation
Taher A.T., Al-Samkari H., Aydinok Y., Besser M., Boscoe A.N., Dahlin J.L., De Luna G., Estepp J.H., Gheuens S., Gilroy K.S., Glenthøj A., Sim Goh A., Iyer V., Kattamis A., Loggetto S.R., Morris S., Musallam K.M., Osman K., Ricchi P., Salido-Fiérrez E., Sheth S., Tai F., Tevich H., Uhlig K., Urbstonaitis R., Viprakasit V., Cappellini M.D., Kuo K.H.M. Mitapivat in adults with non-transfusion-dependent α-thalassaemia or β-thalassaemia (ENERGIZE): a phase 3, international, randomised, double-blind, placebo-controlled trial. Lancet (2025). doi:10.1016/S0140-6736(25)00635-X Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/111004
Title
Mitapivat in adults with non-transfusion-dependent α-thalassaemia or β-thalassaemia (ENERGIZE): a phase 3, international, randomised, double-blind, placebo-controlled trial
Author(s)
Taher A.T.
Al-Samkari H.
Aydinok Y.
Besser M.
Boscoe A.N.
Dahlin J.L.
De Luna G.
Estepp J.H.
Gheuens S.
Gilroy K.S.
Glenthøj A.
Sim Goh A.
Iyer V.
Kattamis A.
Loggetto S.R.
Morris S.
Musallam K.M.
Osman K.
Ricchi P.
Salido-Fiérrez E.
Sheth S.
Tai F.
Tevich H.
Uhlig K.
Urbstonaitis R.
Viprakasit V.
Cappellini M.D.
Kuo K.H.M.
Al-Samkari H.
Aydinok Y.
Besser M.
Boscoe A.N.
Dahlin J.L.
De Luna G.
Estepp J.H.
Gheuens S.
Gilroy K.S.
Glenthøj A.
Sim Goh A.
Iyer V.
Kattamis A.
Loggetto S.R.
Morris S.
Musallam K.M.
Osman K.
Ricchi P.
Salido-Fiérrez E.
Sheth S.
Tai F.
Tevich H.
Uhlig K.
Urbstonaitis R.
Viprakasit V.
Cappellini M.D.
Kuo K.H.M.
Author's Affiliation
Harvard Medical School
University of Toronto Faculty of Medicine
Weill Cornell Medicine
National and Kapodistrian University of Athens
Rigshospitalet
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
American University of Beirut
Hôpital Henri Mondor
Khalifa University of Science and Technology
Siriraj Hospital
Cambridge University Hospitals NHS Foundation Trust
Hospital Clínico Universitario Virgen de la Arrixaca
Ege University Medical School
Hospital Pulau Pinang
Agios Pharmaceuticals
Burjeel Medical City
Azienda Ospedaliera Rilievo Naz. A.
São Paulo Blood Bank – GSH Group
University of Toronto Faculty of Medicine
Weill Cornell Medicine
National and Kapodistrian University of Athens
Rigshospitalet
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
American University of Beirut
Hôpital Henri Mondor
Khalifa University of Science and Technology
Siriraj Hospital
Cambridge University Hospitals NHS Foundation Trust
Hospital Clínico Universitario Virgen de la Arrixaca
Ege University Medical School
Hospital Pulau Pinang
Agios Pharmaceuticals
Burjeel Medical City
Azienda Ospedaliera Rilievo Naz. A.
São Paulo Blood Bank – GSH Group
Corresponding Author(s)
Other Contributor(s)
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.