A Study Evaluating the Efficacy and Safety of Mitapivat in Participants With Non-Transfusion-Dependent Alpha- or Beta-Thalassemia (α- or β-NTDT)

NCT04770753 | Active Not Recruiting Phase 3 Results DMC FDA Drug

• 2 other identifiers: AG348-C-0172021-000211-23
• Study Type: interventional
• Target: 194
• Locations: 18 countries
• Sites: 68

Brief Summary

The primary purpose of this study was to compare the effect of mitapivat versus placebo on hemolytic anemia in participants with alpha- or beta-non-transfusion dependent thalassemia (NTDT).

Conditions

Non-Transfusion-dependent Alpha-Thalassemia; Non-Transfusion-dependent Beta-Thalassemia

Outcome Measures

Primary Outcomes (1)

• Double-Blind Period: Percentage of Participants Who Achieved Hemoglobin (Hb) Response From Week 12 Through Week 24 Compared With Baseline

  Hb response is defined as ≥10 grams/ liter (g/L) (1.0 gram per deciliter) (g/dL) increase in average Hb concentration from Week 12 through Week 24 compared with baseline. Hb response was tested using the Mantel-Haenszel stratum weighted method adjusting for randomization stratification factors. Baseline is defined as the average of all assessments within 42 days before randomization for subjects randomized and not dosed or within 42 days before the start of study treatment for subjects randomized and dosed.

  Double-Blind Period: Baseline up to Week 12 through Week 24

Secondary Outcomes (23)

• Double-Blind Period: Change From Baseline in Average Functional Assessment of Chronic Illness Therapy (FACIT) -Fatigue Subscale Score From Week 12 Through Week 24

  Double-Blind Period: Baseline, Week 12 through Week 24

• Double-Blind Period: Change From Baseline in Average Hb Concentration From Week 12 Through Week 24

  Double-Blind Period: Baseline, Week 12 through Week 24

• Double-Blind Period: Percentage of Participants Who Achieved Hb 1.5+ Response From Week 12 Through Week 24 Compared With Baseline

  Double-Blind Period: Baseline up to Week 12 through Week 24

• Double-Blind Period: Change From Baseline in Indirect Bilirubin at Week 24

  Double-Blind Period: Baseline, Week 24

• Double-Blind Period: Change From Baseline in Lactate Dehydrogenase (LDH) at Week 24

  Double-Blind Period: Baseline, Week 24

Study Arms (2)

Mitapivat

EXPERIMENTAL

Mitapivat 100 milligrams (mg), orally, twice daily (BID) for 24 weeks in double blind (DB) period and for up to 5 years in open label extension (OLE) period.

Drug: Mitapivat

Placebo

PLACEBO COMPARATOR

Placebo matching mitapivat, orally, BID for 24 weeks in double blind period followed by Mitapivat 100 mg, orally, BID for up to 5 years in open label extension period.

Drug: Placebo Matching Mitapivat; Drug: Mitapivat

Interventions

Placebo Matching Mitapivat DRUG

Tablets

Placebo

Mitapivat DRUG

Tablets

Also known as: AG-348, AG-348 sulfate hydrate, Mitapivat sulfate

Mitapivat; Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Documented diagnosis of thalassemia (β-thalassemia with or without α-globin gene mutations, hemoglobin E (HbE)/β-thalassemia, or α-thalassemia/hemoglobin H \[HbH\] disease) based on Hb electrophoresis, Hb high-performance liquid chromatography (HPLC)), and/or deoxyribonucleic acid (DNA) analysis;
• Hb concentration ≤10.0 grams per deciliter (g/dL) (100.0 grams per liter \[g/L\]), based on an average of at least 2 Hb concentration measurements (separated by ≥7 days) collected during the Screening Period;
• Non-transfusion-dependent, defined as ≤5 red blood cell (RBC) units during the 24-week period before randomization; and no RBC transfusions ≤8 weeks before providing informed consent and no RBC transfusions during the Screening Period;
• If taking hydroxyurea, the hydroxyurea dose must be stable for ≥16 weeks before randomization;
• Women of child-bearing potential (WOCBP) must be abstinent of sexual activities that may result in pregnancy as part of their usual lifestyle or agree to use 2 forms of contraception, one of which must be considered highly effective, from the time of providing informed consent, throughout the study, and for 28 days after the last dose of study drug. The second form of contraception can be an acceptable barrier method;
• Written informed consent before any study-related procedures are conducted and willing to comply with all study procedures for the duration of the study.

You may not qualify if:

• Pregnant, breastfeeding, or parturient
• Documented history of homozygous or heterozygous sickle hemoglobin (HbS) or hemoglobin C (HbC);
• Prior exposure to gene therapy or prior bone marrow or stem cell transplantation;
• Currently receiving treatment with luspatercept; the last dose must have been administered ≥18 weeks before randomization;
• Currently receiving treatment with hematopoietic stimulating agents; the last dose must have been administered ≥18 weeks before randomization;
• History of malignancy, (active or treated) ≤5 years before providing informed consent;
• History of active and/or uncontrolled cardiac or pulmonary disease ≤6 months before providing informed consent, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ;
• Hepatobiliary disorders;
• Estimated glomerular filtration rate \<45 milliliters per minute (mL/min)/1.73 m\^2 by Chronic Kidney Disease Epidemiology Collaboration creatinine equation;
• Nonfasting triglycerides \>440 milligrams per deciliter (mg/dL) (5 millimoles per liter \[mmol/L\]);
• Active infection requiring systemic antimicrobial therapy at the time of providing informed consent;
• Positive test for hepatitis C virus antibody (HCVAb) with evidence of active HCV infection, or positive test for hepatitis B surface antigen (HBsAg);
• Positive test for human immunodeficiency virus (HIV)-1 antibody (Ab) or HIV-2 Ab;
• History of major surgery (including splenectomy) ≤16 weeks before providing informed consent and/or a major surgical procedure planned during the study;
• Current enrollment or past participation (≤12 weeks before administration of the first dose of study drug or a timeframe equivalent to 5 half-lives of the investigational study drug, whichever is longer) in any other clinical study involving an investigational treatment or device;

Sponsors & Collaborators

• Agios Pharmaceuticals, Inc.: lead

Study Sites (68)

San Diego Hospital, UC San Diego Health

La Jolla, California, 92093, United States

Location

Stanford Medicine

Palo Alto, California, 94304-1601, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114-2696, United States

Location

Weill Cornell Medical Center

New York, New York, 10065-4870, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710-3038, United States

Location

Penn Medicine - University of Pennsylvania Health System

Philadelphia, Pennsylvania, 19104, United States

Location

Universidade de Caxias do Sul

Caxias do Sul, 95070-560, Brazil

Location

Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto - USP

Ribeirão Preto, 14051-260, Brazil

Location

HEMORIO Instituto Nacional de Hematologia

Rio de Janeiro, 20211-030, Brazil

Location

Praxis Pesquisa Medica

Santo André, 09090-790, Brazil

Location

GSH Banco de Sangue de São Paulo

São Paulo, 04006-002, Brazil

Location

Instituto do Cancer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidad de São Paulo

São Paulo, 05403-000, Brazil

Location

MHAT "Dr. Nikola Vasiliev" AD

Kyustendil, 2500, Bulgaria

Location

SHATHD Sofia

Sofia, 1756, Bulgaria

Location

Toronto General Hospital, University Health Network

Toronto, M5G 2C4, Canada

Location

Rigshospitalet

Copenhagen, 2100, Denmark

Location

CHU Hôpital Henri Mondor

Créteil, 94010, France

Location

Hopital Edouard Herriot, CHU de Lyon

Lyon, 69003, France

Location

Laiko General Hospital

Athens, 115 26, Greece

Location

Children's Hospital Agia Sophia, National and Kapodistrian University of Athens Medical School

Athens, 115 27, Greece

Location

University General Hospital of Patras

Rio, 26504, Greece

Location

Ippokrateio General Hospital

Thessaloniki, 546 42, Greece

Location

Ospedale "A. Perrino" - Brindisi

Brindisi, 72100, Italy

Location

Ospedale Pediatrico Microcitemico

Cagliari, 09121, Italy

Location

Ospedale Sant'Anna

Ferrara, 44124, Italy

Location

Ente Ospedaliero Ospedali Galliera

Genova, 16128, Italy

Location

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, 20122, Italy

Location

A.O.U Di Modena

Modena, 41124, Italy

Location

A.O.R.N. "A. Cardarelli"

Naples, 80131, Italy

Location

AOU L. Vanvitelli Universita degli Studi della Campania Luigi Vanvitelli

Naples, 80138, Italy

Location

A.O.U. San Luigi Gonzaga

Orbassano, 10043, Italy

Location

Chronic Care Center

Beirut, 9999, Lebanon

Location

Hospital Sultanah Bahiyah

Alor Star, 05460, Malaysia

Location

Hospital Ampang

Ampang, 68000, Malaysia

Location

Hospital Sultanah Aminah Johor Bahru

Johor Bahru, 80100, Malaysia

Location

Hospital Queen Elizabeth, Kota Kinabalu

Kota Kinabalu, 88586, Malaysia

Location

Hospital Tunku Azizah

Kuala Lumpur, 50300, Malaysia

Location

Hospital Tengku Ampuan Afzan

Kuantan, 25100, Malaysia

Location

Hospital Umum Sarawak

Kuching, 93586, Malaysia

Location

Hospital Pulau Pinang

Pulau Pinang, 10990, Malaysia

Location

Erasmus MC

Rotterdam, 3015 GD, Netherlands

Location

Universitair Medisch Centrum Utrecht

Utrecht, 3584 CX, Netherlands

Location

King Abdulaziz Hospital - Al Ahsa

Al Mubarraz, 36428, Saudi Arabia

Location

King Abdullah International Medical Research Center

Riyadh, 14611, Saudi Arabia

Location

Hospital Universitario Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Universitario La Paz

Madrid, 28046, Spain

Location

Hospital Universitario Virgen Arrixaca

Murcia, 30120, Spain

Location

Hospital Universitario Virgen del Rocío

Seville, 41013, Spain

Location

China Medical University, Taiwan

Taichung, 40447, Taiwan

Location

Phramongkutklao Hospital

Bangkok, 10400, Thailand

Location

Ramathibodi Hospital

Bangkok, 10400, Thailand

Location

Faculty of Medicine Siriraj Hospital

Bangkok, 10700, Thailand

Location

Maharaj Nakorn Chiang Mai Hospital

Chiang Mai, 50200, Thailand

Location

Srinagarind Hospital, Khon Kaen University

Khon Kaen, 40002, Thailand

Location

Naresuan University Hospital

Mueang Phitsanulok, 65000, Thailand

Location

King Chulalongkorn Memorial Hospital

Pathum Wan, 10330, Thailand

Location

Acibadem Adana Hospital

Adana, 01130, Turkey (Türkiye)

Location

Akdeniz University Faculty of Medicine

Antalya, 07059, Turkey (Türkiye)

Location

Çukurova University

Balcalı, 01330, Turkey (Türkiye)

Location

Ege University Faculty of Medicine

Bornova, 35040, Turkey (Türkiye)

Location

Istanbul University Faculty of Medicine

Fatih, 34093, Turkey (Türkiye)

Location

Hacettepe University

Mersin, 06230, Turkey (Türkiye)

Location

Burjeel Medical City

Abu Dhabi, United Arab Emirates

Location

Thalassemia Centre Dubai

Dubai, 4545, United Arab Emirates

Location

Cambridge University Hospitals NHS Foundation Trust - Addenbrookes Hospital

Cambridge, CAM, CB2 0QQ, United Kingdom

Location

Manchester Royal Infirmary, Manchester University NHS Foundation Trust

Manchester, LAN, M13 9WL, United Kingdom

Location

University College London

London, NW1 2PG, United Kingdom

Location

Imperial College Healthcare NHS Trust - Hammersmith Hospital

London, W12 OHS, United Kingdom

Location

Related Publications (1)

• Taher AT, Al-Samkari H, Aydinok Y, Besser M, Boscoe AN, Dahlin JL, De Luna G, Estepp JH, Gheuens S, Gilroy KS, Glenthoj A, Sim Goh A, Iyer V, Kattamis A, Loggetto SR, Morris S, Musallam KM, Osman K, Ricchi P, Salido-Fierrez E, Sheth S, Tai F, Tevich H, Uhlig K, Urbstonaitis R, Viprakasit V, Cappellini MD, Kuo KHM; ENERGIZE investigators. Mitapivat in adults with non-transfusion-dependent alpha-thalassaemia or beta-thalassaemia (ENERGIZE): a phase 3, international, randomised, double-blind, placebo-controlled trial. Lancet. 2025 Jul 5;406(10498):33-42. doi: 10.1016/S0140-6736(25)00635-X. Epub 2025 Jun 19.

  PMID: 40544857 DERIVED

MeSH Terms

Interventions

mitapivat

Results Point of Contact

• Title: Agios Medical Affairs
• Organization: Agios Pharmaceuticals, Inc .

medinfo@agios.com

833-228-8474

Study Officials

• Medical Affairs

  Agios Pharmaceuticals, Inc.

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 18, 2021
• First Posted: February 25, 2021
• Study Start: December 20, 2021
• Primary Completion: November 13, 2023
• Study Completion (Estimated): December 1, 2028
• Last Updated: April 24, 2026
• Results First Posted: January 24, 2025

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

BU (2); NL (2); US (6); GB (4); FR (2); MY (8); GR (4); IT (9); TU (6); SA (2); TW (1); LE (1); BR (6); DK (1); AE (2); ES (4); CA (1); TH (7)