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Publications

Journal Article Randomized Controlled Trial Multicenter Study Clinical Trial, Phase III Ppublish 3 citations

PubMed: 42721980 DOI: 10.1016/S0140-6736(26)00874-3

Efficacy and safety of mitapivat in adults with transfusion-dependent α-thalassaemia or β-thalassaemia (ENERGIZE-T): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial.

Lancet 408(10559):1010-1018

Authors: Maria Domenica Cappellini, Sujit Sheth, Ali Taher, Hanny Al-Samkari, Ali Bülent Antmen, David Beneitez, Giovanna Cannas, Thomas Coates, Lauren Czapla, Jayme L Dahlin, Jeremie H Estepp, Elizabeth Feenstra, Pencho Georgiev, Sarah Gheuens, Gavrielle M Price, Andreas Glenthøj, Khaled M Musallam, Kareem Osman, John B Porter, Hui Shao, Katrin Uhlig, Eduard J van Beers, Vip Viprakasit, Kevin H M Kuo, Antonis Kattamis

Affiliations

  • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, SC Medicina ad Indirizzo Metabolico, Milan, Italy.
  • Weill Cornell Medicine, New York, NY, USA.
  • American University of Beirut Medical Center, Beirut, Lebanon.
  • Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Acıbadem Adana Hospital, Adana, Turkey.
  • Vall d'Hebron Hospital Universitari, Vall d'Hebron Institute of Oncology, Universitat Autonoma de Barcelona, Barcelona, Spain.
  • Edouard Herriot Hospital, Lyon, France.
  • Children's Hospital Los Angeles, Los Angeles, CA, USA.
  • Agios Pharmaceuticals, Cambridge, MA, USA.
  • St George University Hospital for Active Treatment and Medical University Plovdiv, Plovdiv, Bulgaria.
  • Danish Red Blood Cell Center, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.
  • Center for Research on Rare Blood Disorders and Thalassemia & Sickle Cell Center, Burjeel Cancer Institute, Burjeel Medical City, Abu Dhabi, United Arab Emirates; Department of Public Health & Epidemiology, Khalifa University, Abu Dhabi, United Arab Emirates; Division of Hematology and Oncology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA.
  • University College London Hospitals, London, UK.
  • University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
  • Siriraj Hospital, Mahidol University, Bangkok, Thailand.
  • Division of Hematology, University of Toronto, Toronto, ON, Canada.
  • National and Kapodistrian University of Athens, Athens, Greece.

Abstract

BACKGROUND

The absence of disease-modifying therapies for patients with α-thalassaemia and oral disease-modifying therapies for patients with β-thalassaemia has been a substantial unmet need in these patients. We assessed the efficacy and safety of mitapivat, an oral allosteric activator of pyruvate kinase, in adults with transfusion-dependent thalassaemia.

METHODS

ENERGIZE-T is a global, double-blind, randomised, placebo-controlled, phase 3 trial, conducted across 19 countries in North America, Europe, Asia-Pacific, South America, and the Middle East. Patients aged 18 years or older with transfusion-dependent α-thalassaemia or β-thalassaemia were randomly allocated (2:1) with a central interactive response technology system, stratified by geographical region and thalassaemia genotype, to receive 100 mg mitapivat or placebo orally twice a day for 48 weeks. The primary endpoint was transfusion reduction response (TRR), defined as a reduction of at least 50% in transfused red blood cell units with a reduction of at least two units in any consecutive 12-week period until week 48 compared with baseline. Efficacy was analysed in the full analysis set, comprising all randomly allocated patients. Type, severity, and relationship of adverse events and serious adverse events were assessed in patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov (NCT04770779) and is active but not recruiting.

FINDINGS

Between Nov 30, 2021 and May 2, 2023, 305 patients were screened, of whom 258 were randomly allocated (median age 33·5 years [IQR 27·0-44·0]; 136 [53%] female and 122 [47%] male participants). Of 258 patients allocated, 238 (92%) completed the double-blind treatment period. All patients were required to have a safety follow-up approximately 4 weeks after the final dose of study drug, regardless of completion of the double-blind period or continuation into the open-label extension period. In the full analysis set, TRRs occurred in 52 (30%) of 171 patients in the mitapivat group and 11 (13%) of 87 in the placebo group (adjusted difference 18 percentage points [95% CI 8-27]; two-sided p=0·0003). The safety analysis set comprised 172 patients in the mitapivat group (including one patient allocated to the placebo group who received one dose of mitapivat in error) and 85 in the placebo group. Adverse events were reported in 155 (90%) patients treated with mitapivat and 71 (84%) treated with placebo; the most common events with mitapivat were headache, upper respiratory tract infection, initial insomnia, diarrhoea, and fatigue. Serious adverse events were reported in 19 (11%) patients treated with mitapivat and 13 (15%) treated with placebo. Ten (6%) patients who received mitapivat and one (1%) who received placebo discontinued study treatment due to adverse events. No deaths were reported.

INTERPRETATION

Mitapivat significantly reduced the transfusion burden and was generally well tolerated, showing a favourable benefit-risk profile. These findings support mitapivat as the first oral disease-modifying therapy for adults with transfusion-dependent α-thalassaemia or β-thalassaemia, providing a new treatment option to reduce transfusion burden in this patient population.

FUNDING

Agios Pharmaceuticals, Inc.

MeSH

Safety, Pharmaceutical Preparations, Drug-Related Side Effects And Adverse Reactions, Therapeutics