ENERGIZE: A GLOBAL PHASE 3 STUDY OF MITAPIVAT DEMONSTRATING EFFICACY AND SAFETY IN ADULTS WITH ALPHA- OR BETA-NON–TRANSFUSION-DEPENDENT THALASSEMIA
Background: In thalassemia, ATP production in erythroid cells is too low to meet the demand of oxidative stress and ensuing cellular damage; this leads to ineffective erythropoiesis (IE) and chronic hemolytic anemia. Guidelines for non–transfusion-dependent thalassemia (NTDT) recommend raising hemog...
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Elsevier
2024-10-01
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| Series: | Hematology, Transfusion and Cell Therapy |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2531137924003882 |
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| author | AT Taher H Al-Samkari Y Aydinok M Besser G Luna S Gheuens A Glenthj AS Goh A Kattamis SR Loggetto KM Musallam P Ricchi E Salido-Fiérrez S Sheth V Viprakasit MD Cappellini KH Kuo |
| author_facet | AT Taher H Al-Samkari Y Aydinok M Besser G Luna S Gheuens A Glenthj AS Goh A Kattamis SR Loggetto KM Musallam P Ricchi E Salido-Fiérrez S Sheth V Viprakasit MD Cappellini KH Kuo |
| author_sort | AT Taher |
| collection | DOAJ |
| description | Background: In thalassemia, ATP production in erythroid cells is too low to meet the demand of oxidative stress and ensuing cellular damage; this leads to ineffective erythropoiesis (IE) and chronic hemolytic anemia. Guidelines for non–transfusion-dependent thalassemia (NTDT) recommend raising hemoglobin (Hb) by ≥1 g/dL to reduce morbidities from IE and anemia. No oral disease-modifying therapies are approved for the treatment of β-thalassemia, and no agents are approved for α-thalassemia. Mitapivat is a first-in-class, oral, activator of pyruvate kinase that increases ATP production. Mitapivat may reduce metabolic stress, addressing the underlying pathophysiology across the full range of thalassemias, with the potential to reduce complications and improve health-related quality of life (HRQoL). Aims: To assess the efficacy and safety of mitapivat vs placebo (pbo) in adults with α- or β-NTDT in ENERGIZE (NCT04770753), a phase 3, double-blind, randomized, pbo-controlled, global trial. Methods: Adults (≥18 years) with α- or β-NTDT and baseline (BL) Hb ≤10 g/dL were randomized 2:1 to mitapivat 100 mg twice daily or pbo for 24 weeks (wks). NTDT was defined as ≤5 red blood cell (RBC) units transfused 24 wks before randomization and no RBC transfusions ≤8 wks before informed consent or during screening. The primary endpoint was Hb response: ≥1.0 g/dL increase in average Hb concentration over Wks 12–24 compared with BL. Key secondary endpoints were changes from BL in average Hb concentration and Functional Assessment of Chronic Illness Therapy–Fatigue Scale (FACIT-Fatigue) score over Wks 12–24. Safety and markers of hemolysis and erythropoiesis were among the secondary endpoints. Results: 194 patients (pts) were randomized (mitapivat n = 130; pbo n = 64); 94.8% completed the 24-wk trial. Mean age was 41.2 years, mean BL Hb was 8.3 g/dL, 86.6% received no transfusions in the 24 wks before randomization, and 32.0% had α-NTDT. BL characteristics were similar between treatment arms. Mitapivat demonstrated statistically significant improvements vs pbo for Hb response (42.3% vs 1.6%, respectively; 2-sided p < 0.0001), and for changes from BL in Wks 12–24 average Hb (least-squares mean [LSM] difference (95% CI): 0.96 g/dL (0.78, 1.15); 2-sided p < 0.0001) and Wks 12–24 average FACIT-Fatigue score (LSM difference (95% CI): 3.40 (1.21, 5.59); 2-sided p < 0.0026). Results favored mitapivat across all prespecified subgroups. Improvements in several markers of hemolysis and erythropoiesis were also observed, consistent with the proposed mechanism of mitapivat. The proportion of pts with treatment-emergent adverse events (TEAEs) of any grade was similar across treatment arms (mitapivat 82.9%; pbo 79.4%). The most common TEAEs (≥10% of pts) with mitapivat were headache, initial insomnia, nausea, and upper respiratory tract infection. Among mitapivat-treated pts, 6.2% had serious TEAEs (none considered treatment related) and 3.1% had TEAEs leading to treatment discontinuation; none occurred with pbo. Summary/Conclusion: Mitapivat significantly increased Hb and improved fatigue vs pbo; improvements were observed across all prespecified subgroups. 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-thalassemia). Mitapivat may represent a new oral treatment option addressing both pathophysiology and HRQoL in thalassemia. |
| format | Article |
| id | doaj-art-c8f32b3099bd4cf3bf04a8b5b36f0ab4 |
| institution | OA Journals |
| issn | 2531-1379 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Hematology, Transfusion and Cell Therapy |
| spelling | doaj-art-c8f32b3099bd4cf3bf04a8b5b36f0ab42025-08-20T02:17:37ZengElsevierHematology, Transfusion and Cell Therapy2531-13792024-10-0146S32S3310.1016/j.htct.2024.09.055ENERGIZE: A GLOBAL PHASE 3 STUDY OF MITAPIVAT DEMONSTRATING EFFICACY AND SAFETY IN ADULTS WITH ALPHA- OR BETA-NON–TRANSFUSION-DEPENDENT THALASSEMIAAT Taher0H Al-Samkari1Y Aydinok2M Besser3G Luna4S Gheuens5A Glenthj6AS Goh7A Kattamis8SR Loggetto9KM Musallam10P Ricchi11E Salido-Fiérrez12S Sheth13V Viprakasit14MD Cappellini15KH Kuo16Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, LebanonDivision of Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, United StatesDepartment of Paediatric Haematology and Oncology, Ege University School of Medicine, Izmir, TurkeyDepartment of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United KingdomCentre de Référence Syndromes Drépanocytaires Majeurs, Thalassémies et Autres Pathologies Rares du Globule Rouge et de l’Érythropoïèse, Hôpital Henri Mondor APHP, Paris, FranceAgios Pharmaceuticals, Inc., Cambridge, United StatesDepartment of Haematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, DenmarkHaematology Unit, Department of Medicine, Hospital Pulau Pinang, Penang, MalaysiaThalassemia Unit, First Department of Pediatrics, National and Kapodistrian University of Athens, Athens, GreeceSão Paulo Blood Bank - GSH Group, São Paulo, BrazilCenter for Research on Rare Blood Disorders (CR-RBD), Burjeel Medical City, Abu Dhabi, UAEUnità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo, Nazionale, Cardarelli, Napoli, ItalyDepartment of Haematology, Hospital Clínico Universitario Virgen de la Arrixaca-IMIB, Murcia, SpainDivision of Hematology and Oncology, Department of Pediatrics, Weill Cornell Medicine, New York, United StatesDepartment of Pediatrics & Thalassemia Center, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, ThailandDepartment of Clinical Sciences and Community, University of Milan, Ca'Granda Foundation IRCCS Maggiore Policlinico Hospital, Milan, ItalyDivision of Hematology, University of Toronto, Toronto, CanadaBackground: In thalassemia, ATP production in erythroid cells is too low to meet the demand of oxidative stress and ensuing cellular damage; this leads to ineffective erythropoiesis (IE) and chronic hemolytic anemia. Guidelines for non–transfusion-dependent thalassemia (NTDT) recommend raising hemoglobin (Hb) by ≥1 g/dL to reduce morbidities from IE and anemia. No oral disease-modifying therapies are approved for the treatment of β-thalassemia, and no agents are approved for α-thalassemia. Mitapivat is a first-in-class, oral, activator of pyruvate kinase that increases ATP production. Mitapivat may reduce metabolic stress, addressing the underlying pathophysiology across the full range of thalassemias, with the potential to reduce complications and improve health-related quality of life (HRQoL). Aims: To assess the efficacy and safety of mitapivat vs placebo (pbo) in adults with α- or β-NTDT in ENERGIZE (NCT04770753), a phase 3, double-blind, randomized, pbo-controlled, global trial. Methods: Adults (≥18 years) with α- or β-NTDT and baseline (BL) Hb ≤10 g/dL were randomized 2:1 to mitapivat 100 mg twice daily or pbo for 24 weeks (wks). NTDT was defined as ≤5 red blood cell (RBC) units transfused 24 wks before randomization and no RBC transfusions ≤8 wks before informed consent or during screening. The primary endpoint was Hb response: ≥1.0 g/dL increase in average Hb concentration over Wks 12–24 compared with BL. Key secondary endpoints were changes from BL in average Hb concentration and Functional Assessment of Chronic Illness Therapy–Fatigue Scale (FACIT-Fatigue) score over Wks 12–24. Safety and markers of hemolysis and erythropoiesis were among the secondary endpoints. Results: 194 patients (pts) were randomized (mitapivat n = 130; pbo n = 64); 94.8% completed the 24-wk trial. Mean age was 41.2 years, mean BL Hb was 8.3 g/dL, 86.6% received no transfusions in the 24 wks before randomization, and 32.0% had α-NTDT. BL characteristics were similar between treatment arms. Mitapivat demonstrated statistically significant improvements vs pbo for Hb response (42.3% vs 1.6%, respectively; 2-sided p < 0.0001), and for changes from BL in Wks 12–24 average Hb (least-squares mean [LSM] difference (95% CI): 0.96 g/dL (0.78, 1.15); 2-sided p < 0.0001) and Wks 12–24 average FACIT-Fatigue score (LSM difference (95% CI): 3.40 (1.21, 5.59); 2-sided p < 0.0026). Results favored mitapivat across all prespecified subgroups. Improvements in several markers of hemolysis and erythropoiesis were also observed, consistent with the proposed mechanism of mitapivat. The proportion of pts with treatment-emergent adverse events (TEAEs) of any grade was similar across treatment arms (mitapivat 82.9%; pbo 79.4%). The most common TEAEs (≥10% of pts) with mitapivat were headache, initial insomnia, nausea, and upper respiratory tract infection. Among mitapivat-treated pts, 6.2% had serious TEAEs (none considered treatment related) and 3.1% had TEAEs leading to treatment discontinuation; none occurred with pbo. Summary/Conclusion: Mitapivat significantly increased Hb and improved fatigue vs pbo; improvements were observed across all prespecified subgroups. 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-thalassemia). Mitapivat may represent a new oral treatment option addressing both pathophysiology and HRQoL in thalassemia.http://www.sciencedirect.com/science/article/pii/S2531137924003882 |
| spellingShingle | AT Taher H Al-Samkari Y Aydinok M Besser G Luna S Gheuens A Glenthj AS Goh A Kattamis SR Loggetto KM Musallam P Ricchi E Salido-Fiérrez S Sheth V Viprakasit MD Cappellini KH Kuo ENERGIZE: A GLOBAL PHASE 3 STUDY OF MITAPIVAT DEMONSTRATING EFFICACY AND SAFETY IN ADULTS WITH ALPHA- OR BETA-NON–TRANSFUSION-DEPENDENT THALASSEMIA Hematology, Transfusion and Cell Therapy |
| title | ENERGIZE: A GLOBAL PHASE 3 STUDY OF MITAPIVAT DEMONSTRATING EFFICACY AND SAFETY IN ADULTS WITH ALPHA- OR BETA-NON–TRANSFUSION-DEPENDENT THALASSEMIA |
| title_full | ENERGIZE: A GLOBAL PHASE 3 STUDY OF MITAPIVAT DEMONSTRATING EFFICACY AND SAFETY IN ADULTS WITH ALPHA- OR BETA-NON–TRANSFUSION-DEPENDENT THALASSEMIA |
| title_fullStr | ENERGIZE: A GLOBAL PHASE 3 STUDY OF MITAPIVAT DEMONSTRATING EFFICACY AND SAFETY IN ADULTS WITH ALPHA- OR BETA-NON–TRANSFUSION-DEPENDENT THALASSEMIA |
| title_full_unstemmed | ENERGIZE: A GLOBAL PHASE 3 STUDY OF MITAPIVAT DEMONSTRATING EFFICACY AND SAFETY IN ADULTS WITH ALPHA- OR BETA-NON–TRANSFUSION-DEPENDENT THALASSEMIA |
| title_short | ENERGIZE: A GLOBAL PHASE 3 STUDY OF MITAPIVAT DEMONSTRATING EFFICACY AND SAFETY IN ADULTS WITH ALPHA- OR BETA-NON–TRANSFUSION-DEPENDENT THALASSEMIA |
| title_sort | energize a global phase 3 study of mitapivat demonstrating efficacy and safety in adults with alpha or beta non transfusion dependent thalassemia |
| url | http://www.sciencedirect.com/science/article/pii/S2531137924003882 |
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