ENERGIZE: A global, phase 3 study of mitapivat demonstrating efficacy and safety in adults with alpha or beta non–transfusion dependent thalassemia

ENERGIZE: A global, phase 3 study of mitapivat demonstrating

efficacy and safety in adults with alpha- or beta-non-

transfusion-dependent thalassemia

Ali T Taher, MD, PhD, FRCP1, Hanny Al-Samkari, MD2, Yesim Aydinok, MD3, Martin Besser, MD4, Jayme L Dahlin, MD, PhD5, Gonzalo De Luna, MD6, Jeremie H Estepp, MD5, Sarah Gheuens, MD, PhD5, Keely S Gilroy, PhD5, Andreas Glenthøj, MD, PhD7, Ai Sim Goh, MD, FRCP8, Varsha Iyer, PhD5*, Antonis Kattamis, MD, PhD9, Sandra R Loggetto, MD10, Susan Morris, PhD5, Khaled M Musallam, MD, PhD11, Kareem Osman, MD5, Paolo Ricchi, MD, PhD12, Eduardo Salido-Fiérrez, MD13, Sujit Sheth, MD14, Feng Tai, PhD5, Heather Tevich, MSN5, Katrin Uhlig, MD, MS5, Rolandas Urbstonaitis, PharmD, MBA5, Vip Viprakasit, MD, FRCPT15, Maria Domenica Cappellini, MD16, Kevin HM Kuo, MD, MSc, FRCPC17

1Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon; 2Division of Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 3Department of Paediatric Haematology and Oncology, Ege University School of Medicine, Izmir, Turkey; 4Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; 5Agios Pharmaceuticals, Inc., Cambridge, MA, USA; 6Centre de Référence Syndromes Drépanocytaires Majeurs, Thalassémies et Autres Pathologies Rares du Globule Rouge et de l'Érythropoïèse, Hôpital Henri Mondor APHP, Paris, France; 7Department of Haematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; 8Haematology Unit, Department of Medicine, Hospital Pulau Pinang, Penang, Malaysia; 9Thalassemia Unit, First Department of Pediatrics, National and Kapodistrian University of Athens, Athens, Greece; 10Sao Paulo Blood Bank - GSH Group, São Paulo, Brazil; 11Center for Research on Rare Blood Disorders (CR-RBD), Burjeel Medical City, Abu Dhabi, UAE; 12Unità Operativa Semplice Dipartimentale Malattie Rare del Globulo Rosso, Azienda Ospedaliera di Rilievo, Nazionale, Cardarelli, Napoli, Italy; 13Department of Haematology, Hospital Clínico Universitario Virgen de la Arrixaca- IMIB, Murcia, Spain; 14Division of Hematology and Oncology, Department of Pediatrics, Weill Cornell Medicine, New York, NY, USA; 15Department of Pediatrics & Thalassemia Center, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; 16Department of Clinical Sciences and Community, University of Milan, Ca' Granda Foundation IRCCS Maggiore Policlinico Hospital, Milan, Italy; 17Division of Hematology, University of Toronto, Toronto, ON, Canada

*Former employee of Agios Pharmaceuticals, Inc.

This study was funded by Agios Pharmaceuticals, Inc.	1
Presented at the European Hematology Association (EHA) Hybrid Congress, June 13-16, 2024, Madrid, Spain, and Virtual

Conflict of interest disclosures

• This study was funded by Agios Pharmaceuticals, Inc.
• Presenting author conflict of interest disclosures:
• • Ali T Taher, MD, PhD, FRCP
  • • Agios (consultancy, research funding);
    • Bristol-MyersSquibb (Celgene) (consultancy, research funding);
    • Novo Nordisk (consultancy);
    • Pharmacosmos (consultancy, research funding);
    • Vifor (consultancy, research funding)

2

Changing epidemiology of thalassemia1,2

• The evolutionary association between the thalassemia carrier state and resistance to malaria explains its high prevalence in the area extending from sub-Saharan Africa, the Middle East, and the Mediterranean basin to Southeast Asia1

• Population migrations have also introduced thalassemia to Europe and the Americas, where the disease was previously relatively rare2-4

HbC, hemoglobin C; HbE, hemoglobin E; HbS, hemoglobin S

1. Weatherall DJ. Blood Rev 2012;26:S3-S6; 2. Angastiniotis M et al. Sci World J 2013;2013:727905; 3. Kattamis A et al. Eur J Haematol 2020;105:692-703; 4. Musallam KM et al. Am J Hematol. 2023;98:1436-51. Figure (left) reprinted from Weatherall DJ. Blood Rev 2012;26:S3-S6, Copyright (2012) with permission from Elsevier. Figure (right) reprinted from Angastiniotis M et al. Sci World J 2013;2013:727905 (https://onlinelibrary.wiley.com/doi/10.1155/2013/727905), per CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/).

Pathophysiology of thalassemia

RBC, red blood cell

Pathophysiology of thalassemia

RBC, red blood cell

Pathophysiology of thalassemia

RBC, red blood cell

Non-transfusion-dependent thalassemia (NTDT) and unmet needs1

• Lower Hb levels (<10 g/dL) are associated with reduced overall survival and an increased risk of developing morbidities in NTDT2,3
• No oral disease-modifying therapies are approved for the treatment of β-thalassemia, and none have been shown to improve health-related quality of life (HRQoL)4,5
• There are also currently no agents approved for α-thalassemia6,7

Hb, hemoglobin; HbE, hemoglobin E; HbH, hemoglobin H

1. Musallam KM et al. Haematologica 2013;98:833-44; 2. Musallam KM et al. Am J Hematol 2022;97:E78-80; 3. Musallam KM et al. Ann Hematol 2020;101(1):203-4; 4. Langer AL, Esrick EB. Hematology Am Soc Hematol Educ Program 2021:600-06;

1. Taher AT et al. Expert Rev Hematol 2021;14:897-909; 6. Amid A et al. Nicosia (Cyprus): Thalassaemia International Federation; 2023. https://thalassaemia.org.cy/publications/tif-publications/guidelines-for-the-management-of-%ce%b1-thalassaemia/. Accessed 22May2024; 7. Harewood J, Azevedo AM. In: StatPearls [Internet]. Treasure Island (FL); 2022. Figure adapted from Musallam KM et al. Haematologica 2013;98:833-44, Copyright (2013), with permission from Ferrata Storti Foundation.

Mitapivat enhances cellular energy supply to support increased metabolic demands of thalassemic red cells

• In thalassemia, there is increased energy demand to maintain RBC health1-4

• 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)5,6

• In preclinical thalassemia models, mitapivat reduced oxidative stress, and improved erythropoiesis, hemolysis, and anemia7-9

• A phase 2 study of mitapivat in α- or β-NTDT demonstrated improvements in Hb and markers of erythropoiesis and hemolysis10

ADP, adenosine diphosphate; DPG, diphosphoglyceric acid; FBP, fructose biphosphate; Hb, hemoglobin; NTDT, non-transfusion-dependent thalassemia; PEP, phosphoenolpyruvate; PG, phosphoglycerate; RBC, red blood cell

1. Chakraborty I et al. Arch Med Res 2012;43:112-6; 2. Ting YL et al. Br J Haematol 1994;88:547-54; 3. Shaeffer JR. J Biol Chem 1983;258:13172-7; 4. Khandros E, Weiss MJ. Hematol Oncol Clin North Am 2010;24:1071-88; 5. Kung C et al. Blood 2017;130:1347; 6. Yang H et al. Clin Pharmacol Drug Dev 2019;8:246; 7. Matte A et al. J Clin Invest 2021;131:e144206; 8. Rab MAE et al. Blood 2019;134:3506; 9. Matte A et al. Blood 2023;142:3850; 10. Kuo KHM et al. Lancet 2022;400:493-501.

ENERGIZE: A phase 3 study of mitapivat in adults with α- or β-NTDT

to 6 weeks)	(2:1)
Screening period (up	Randomization

Double-blind period

Mitapivat

(100 mg twice

daily [BID])

Placebo

(BID)

24 weeks

Open-label extension

Safetyfollow-up weeksafter last dose)	Endof study
Mitapivat
(100 mg BID)
(+4
Up to 5 years

Key inclusion criteria

• ≥18 years of age at time of informed consent
• β-thalassemia± α-globin mutations, HbE/ β-thalassemia, or α-thalassemia (HbH disease)
• Non-transfusion-dependent(≤5 RBC units transfused during the 24-week period before randomization and no RBC transfusions ≤8 weeks before informed consent and during screening)
• Hb ≤10.0 g/dL

Key exclusion criteria

• Prior exposure to gene therapy or hematopoietic stem cell transplant
• Homozygous or heterozygous for HbS or HbC
• Receiving treatment with luspatercept or a hematopoietic stimulating agent (last dose must be received ≥18 weeks before randomization)

Randomization stratification factors

• Baseline Hb (≤9.0 g/dL or 9.1-10.0 g/dL)
• Thalassemia genotype (α-thalassemia/HbH or
  β-thalassemia)

Hb, hemoglobin; HbC, hemoglobin C; HbE, hemoglobin E; HbH, hemoglobin H; HbS, hemoglobin S; NTDT, non-transfusion-dependent thalassemia; RBC, red blood cell	9
Kuo KHM et al. Hemasphere 2022;6:23-4.

Endpoints

Primary endpoint

• Hb response, defined as an increase of ≥1.0 g/dL in average Hb concentration from Week 12 through
  Week 24, compared with baseline

Key secondary endpoints

• Change from baseline in average Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-Fatigue) score from Week 12 through Week 24
• Change from baseline in average Hb concentration from Week 12 through Week 24

Secondary efficacy endpoints associated with hemolysis and erythropoietic activity

• Change from baseline in indirect bilirubin, lactate dehydrogenase (LDH), and haptoglobin at Week 24
• Change from baseline in reticulocytes and erythropoietin at Week 24

Safety endpoints

• Type, severity, and relationship of adverse events and serious adverse events

Hb, hemoglobin

10