A Study of Tebapivat (AG-946) in Participants With Anemia Due to Lower-Risk Myelodysplastic Syndromes (LR-MDS)

NCT ID: NCT05490446

Last Updated: 2025-12-26

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 87 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2022-11-07
• Study Completion Date: 2029-03-31

Brief Summary

This purpose of this study is to establish proof of concept of tebapivat in participants with LR-MDS in Phase 2a and to evaluate the effect of tebapivat on transfusion independence (TI) in participants with LR-MDS in phase 2b.

Conditions

Myelodysplastic Syndromes

Keywords

Anemia; Lower-Risk Myelodysplastic Syndromes

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Core Period: Phase 2a - Tebapivat 5 mg

Participants will receive 5 milligrams (mg) tebapivat orally, once daily for up to 16 weeks. At the discretion of the investigator, participants who complete the Core Period will be eligible to receive the same dose in Extension Period for up to 156 weeks.

Group Type: EXPERIMENTAL

Tebapivat

Intervention Type: DRUG

Tebapivat Tablet

Core Period: Phase 2b - Tebapivat 10 mg

Participants will receive 10 mg tebapivat, orally, once daily for up to 24 weeks. At the discretion of the investigator, participants who complete the Core Period will be eligible to receive the same dose in Extension Period for up to 156 weeks.

Group Type: EXPERIMENTAL

Tebapivat

Intervention Type: DRUG

Tebapivat Tablet

Core Period: Phase 2b - Tebapivat 15 mg

Participants will receive 15 mg tebapivat, orally, once daily for up to 24 weeks. At the discretion of the investigator, participants who complete the Core Period will be eligible to receive the same dose in Extension Period for up to 156 weeks.

Group Type: EXPERIMENTAL

Tebapivat

Intervention Type: DRUG

Tebapivat Tablet

Core Period: Phase 2b - Tebapivat 20 mg

Participants will receive 20 mg tebapivat, orally, once daily for up to 24 weeks. At the discretion of the investigator, participants who complete the Core Period will be eligible to receive the same dose in Extension Period for up to 156 weeks.

Group Type: EXPERIMENTAL

Tebapivat

Intervention Type: DRUG

Tebapivat Tablet

Interventions

Tebapivat

Tebapivat Tablet

Intervention Type: DRUG

Other Intervention Names

AG-946

Eligibility Criteria

Inclusion Criteria

Phase 2a

1. At least 18 years of age at the time of providing informed consent;

2. Documented diagnosis of myelodysplastic syndromes (MDS) according to World Health Organization (WHO) classification (Arber et al, 2016), that meets Revised International Prognostic Scoring System (IPSS-R) classification of lower-risk disease (risk score: ≤3.5) and <5% blasts as determined by the participant's bone marrow biopsy/aspirate during the Screening Period;

3. Nontransfused or with low transfusion burden (LTB), based on transfusion history from the participant's medical record, according to revised International Working Group (IWG) 2018 criteria:

• Nontransfused (NTD): <3 red blood cell (RBC) units in the 16-week period before administration of the first dose of study drug and no transfusions in the 8-week period before administration of the first dose of study drug, or
• LTB: 3 to 7 RBC units in the 16-week period before administration of the first dose of study drug and <4 RBC units in the 8-week period before administration of the first dose of study drug;

4. A hemoglobin (Hb) concentration <11.0 grams per deciliter (g/dL) during the 4-week Screening Period;

5. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2;

6. If taking iron chelation therapy, the iron chelation therapy dose must have been stable and started ≥56 days before administration of the first dose of study drug;

7. Women of childbearing potential (WOCBP) must be abstinent of sexual activities that may result in pregnancy as part of their usual lifestyle or agree to use a highly effective method of contraception from the time of providing informed consent, throughout the study, and for 28 days after the last dose of study drug; if the highly effective method of contraception is hormonal contraception, then an acceptable barrier method must also be used. Men with partners who are WOCBP must be abstinent of sexual activities that may result in pregnancy as part of their usual lifestyle or agree to use a condom from the time of providing informed consent throughout the study and for 28 days after the last dose of study drug;

8. Written informed consent from the participant before any study-related procedures are conducted and willing to comply with all study procedures for the duration of the study.

Phase 2b

1. At least 18 years of age at the time of providing informed consent;

2. Documented diagnosis of MDS according to WHO classification (Arber et al, 2016), that meets IPSS-R classification of lower-risk disease (risk score: ≤3.5) and <5% blasts as determined by the participant's bone marrow biopsy/aspirate during the Screening Period;

3. With LTB, or high transfusion burden (HTB), based on transfusion history from the participant's medical record, according to revised IWG 2018 criteria:

1. LTB: 3 to 7 RBC units from at least 2 transfusion episodes in the 16-week period before administration of the first dose of study drug AND <4 RBC units in the 8-week period before administration of the first dose of study drug, or

2. HTB: ≥8 RBC units in the 16-week period before administration of the first dose of study drug AND ≥4 RBC units in the 8-week period before administration of the first dose of study drug

If a participant's transfusion burden does not fall into either the LTB or HTB category, as defined per IWG 2018 criteria, then the transfusion burden will be categorized based on their transfusion history in the 16-week period before administration of the first dose of study drug.

4. Pretransfusion Hb concentration available for a minimum of 2 and at least half (50%) of the transfusions received in the 16-week period before administration of the first dose of study drug

5. A Hb concentration <10.0 g/dL during the 4-week Screening Period;

6. Up to 2 prior therapies including erythropoiesis-stimulating agents (ESAs) (eg, erythropoietin [EPO], EPO + granulocyte colony-stimulating factor [G-CSF]) and/or luspatercept;

7. ECOG Performance Status score of 0, 1, or 2;

8. If taking iron chelation therapy, the iron chelation therapy dose must have been stable and started ≥56 days before administration of the first dose of study drug;

9. WOCBP must be abstinent of sexual activities that may result in pregnancy as part of their usual lifestyle or agree to use a highly effective, from the time of providing informed consent throughout the study and for 28 days after the last dose of study drug; if the highly effective method of contraception is hormonal contraception, then an acceptable barrier method must be used. Men with partners who are WOCBP must be abstinent of sexual activities that may result in pregnancy as part of their usual lifestyle or agree to use a condom from the time of providing informed consent throughout the study and for 28 days after the last dose of study drug;

10. Written informed consent from the participant before any study-related procedures are conducted and willing to comply with all study procedures for the duration of the study.

Exclusion Criteria

Phase 2a

1. Known history of acute myeloid leukemia (AML);

2. Secondary MDS, defined as MDS that is known to have arisen as a result of chemical injury or treatment with chemotherapy and/or radiation for other diseases;

3. Prior exposure to a pyruvate kinase activator and/or disease-modifying agents for underlying MDS:

• Immunomodulatory drugs (IMiDs) such as lenalidomide; at the Investigator's discretion and in consultation with the Medical Monitor, participants who received ≤1 week of treatment with IMiDs may not be excluded, provided their last dose was ≥8 weeks before administration of the first dose of study drug
• Hypomethylating agents (HMAs); at the Investigator's discretion and in consultation with the Medical Monitor, participants who received ≤2 doses of HMAs may not be excluded, provided that their last dose was ≥8 weeks before administration of the first dose of study drug
• Isocitrate dehydrogenase (IDH) inhibitors
• Immunosuppressive therapy (IST)
• Allogeneic or autologous stem cell transplant;

4. Currently receiving treatment with ESAs±G-CSF and/or luspatercept. Treatment with ESAs±G-CSF must have been stopped for ≥28 days before administration of the first dose of study drug; treatment with luspatercept must have been stopped for ≥65 days before administration of the first dose of study drug;

5. History of active and/or uncontrolled cardiac or pulmonary disease within 6 months before providing informed consent, including but not limited to:

• New York Heart Association Class III or IV heart failure or clinically significant dysrhythmia
• Myocardial infarction, unstable angina pectoris, or unstable hypertension; high risk thrombosis; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism
• Heart rate-corrected QT interval using Fridericia's method of ≥470 milliseconds for female participants and ≥450 milliseconds for male participants, except for right or left bundle branch block
• Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided heart failure, and radiographic pulmonary fibrosis >50%
• Severe pulmonary hypertension as defined by severe symptoms associated with hypoxia, right-sided heart failure, and oxygen indicated;

6. History of hepatobiliary disorders, as defined by:

• Serum aspartate aminotransferase (AST) >2.5 × upper limit of normal (ULN) (unless due to hemolysis and/or hepatic iron deposition) and alanine aminotransferase (ALT) >2.5 × ULN (unless due to hepatic iron deposition)
• Serum bilirubin >ULN, if the elevation is associated with clinically symptomatic choledocholithiasis, cholecystitis, biliary obstruction, or hepatocellular disease;

7. Renal dysfunction, as defined by an estimated glomerular filtration rate (eGFR) <45 milliliters per minute (mL/min)/1.73 m^2;

8. Active infection requiring systemic antimicrobial therapy at the time of providing informed consent. If antimicrobial therapy is required during the Screening Period, screening procedures should not be performed while antimicrobial therapy is being administered, and the last dose of antimicrobial therapy must be administered ≥7 days before administration of the first dose of study drug;

9. Major surgery within 12 weeks before administration of the first dose of study drug. Participants must have completely recovered from any previous surgery before administration of the first dose of study drug;

10. For any malignancy except MDS: History of malignancy (active or treated) ≤5 years before providing informed consent for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ;

11. Positive test for hepatitis C virus (HCV) antibody (Ab) with evidence of active HCV infection, or positive test for hepatitis B surface antigen (HBsAg);

12. Positive test for HIV-1 Ab or HIV-2 Ab;

13. Absolute neutrophil count (ANC) <500/microliter (μL) (0.5 × 10^9/L);

14. Platelet count ≤75,000/μL during Screening (75 × 10^9/L) platelet transfusions within 28 days before Screening or during Screening;

15. Nonfasting triglyceride concentration >500 mg/dL;

16. Receiving inhibitors of P-glycoprotein (P-gp) that have not been stopped for ≥5 days or a time frame equivalent to 5 half-lives (whichever is longer) before administration of the first dose of study drug;

17. Current enrollment or past participation (within 4 weeks or a time frame equivalent to 5 half-lives of the investigational study drug before administration of the first dose of study drug or, whichever is longer) in any other clinical study involving an investigational treatment or device;

18. Known allergy to tebapivat or its excipients;

19. Pregnant or breastfeeding;

20. Any medical, hematologic, psychological, or behavioral condition(s) or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study and/or could confound the interpretation of the study data. Also excluded are:

• Participants who are institutionalized by regulatory or court order;
• Participants with any condition(s) that could create undue influence (including but not limited to incarceration, involuntary psychiatric confinement, and financial or familial affiliation with the Investigator or Sponsor).

Phase 2b

1. Known history of AML;

2. Secondary MDS, defined as MDS that is known to have arisen as a result of chemical injury or treatment with chemotherapy and/or radiation for other diseases;

3. Prior exposure to a pyruvate kinase activator, including exposure to tebapivat in the Phase 2a part of this study, and/or disease-modifying agents for underlying MDS:

• Imetelstat; at the Investigator's discretion and in consultation with the Medical Monitor, participants who received ≤2 doses of imetelstat may not be excluded, provided that their last dose was ≥8 weeks before administration of the first dose of study drug
• IMiDs such as lenalidomide; at the Investigator's discretion and in consultation with the Medical Monitor, participants who received ≤1 week of treatment with IMiDs may not be excluded, provided their last dose was ≥8 weeks before administration of the first dose of study drug
• HMAs; at the Investigator's discretion and in consultation with the Medical Monitor, participants who received ≤2 doses of HMAs may not be excluded, provided that their last dose was ≥8 weeks before administration of the first dose of study drug
• IDH inhibitors
• IST
• Allogeneic or autologous stem cell transplant;

4. Currently receiving treatment with ESAs±G-CSF and/or luspatercept. Treatment with ESAs±G-CSF must have been stopped for ≥28 days before administration of the first dose of study drug; treatment with luspatercept must have been stopped for ≥65 days before administration of the first dose of study drug;

5. History of active and/or uncontrolled cardiac or pulmonary disease within 6 months before providing informed consent, including but not limited to:

• New York Heart Association Class III or IV heart failure or clinically significant dysrhythmia
• Myocardial infarction, unstable angina pectoris, or unstable hypertension; high risk thrombosis; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism
• Heart rate-corrected QT interval using Fridericia's method of ≥470 milliseconds for female participants and ≥450 milliseconds for male participants, except for right or left bundle branch block
• Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided heart failure, and radiographic pulmonary fibrosis >50%
• Severe pulmonary hypertension as defined by severe symptoms associated with hypoxia, right-sided heart failure, and oxygen indicated

6. History of hepatobiliary disorders, as defined by:

• Serum AST >2.5 × ULN (unless due to hemolysis and/or hepatic iron deposition) and ALT >2.5 × ULN (unless due to hepatic iron deposition)
• Serum bilirubin >ULN, if the elevation is associated with clinically symptomatic choledocholithiasis, cholecystitis, biliary obstruction, or hepatocellular disease

7. Renal dysfunction, as defined by an eGFR <45 mL/min/1.73 m^2;

8. Active infection requiring systemic antimicrobial therapy at the time of providing informed consent. If antimicrobial therapy is required during the Screening Period, screening procedures should not be performed while antimicrobial therapy is being administered, and the last dose of antimicrobial therapy must be administered ≥7 days before administration of the first dose of study drug;

9. Major surgery within 12 weeks before administration of the first dose of study drug. Participants must have completely recovered from any previous surgery before administration of the first dose of study drug;

10. For any malignancy except MDS: History of malignancy (active or treated) ≤5 years before providing informed consent, except for nonmelanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ.;

11. Positive test for HCV Ab with evidence of active HCV infection, or positive test for HBsAg;

12. Positive test for HIV-1 Ab or HIV-2 Ab;

13. ANC <500/μL (0.5 × 10^9/L);

14. Platelet count < 75,000/μL (75 × 10^9 /L) during Screening; platelet transfusions within 28 days before Screening or during Screening;

15. Nonfasting triglyceride concentration >500 mg/dL;

16. Receiving inhibitors of P-gp that have not been stopped for ≥5 days or a time frame equivalent to 5 half-lives (whichever is longer) beforeadministration of the first dose of study drug;

17. Current enrollment or past participation (within 4 weeks or a time frame equivalent to 5 half-lives of the investigational study drug before administration of the first dose of study drug or, whichever is longer) in any other clinical study involving an investigational treatment or device;

18. Known allergy to tebapivat or its excipients;

19. Pregnant or breastfeeding;

20. Any medical, hematologic, psychological, or behavioral condition(s) or prior or current therapy that, in the opinion of the Investigator, may confer an unacceptable risk to participating in the study and/or could confound the interpretation of the study data. Also excluded are:

• Participants who are institutionalized by regulatory or court order
• Participants with any condition(s) that could create undue influence (including but not limited to incarceration, involuntary psychiatric confinement, and financial or familial affiliation with the Investigator or Sponsor).

21. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, autoimmune or hereditary hemolytic anemia, hypothyroidism, or any type of known clinically significant bleeding.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Agios Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Medical Affairs

Role: STUDY_CHAIR

Agios Pharmaceuticals, Inc.

Locations

Innovative Clinical Research Institute Whittier

Lakewood, California, United States

David Geffen School of Medicine at UCLA

Los Angeles, California, United States

Emad Ibrahim, MD, Inc.

Redlands, California, United States

Smilow Cancer Hospital at Yale New Haven

New Haven, Connecticut, United States

Mayo Clinic Jacksonville - PPDS

Jacksonville, Florida, United States

Edward H. Kaplan MD & Associates

Skokie, Illinois, United States

Washington University School of Medicine

St Louis, Missouri, United States

Memorial Sloan Kettering Cancer Center

Long Island City, New York, United States

Duke Adult Blood and Marrow Clinic

Durham, North Carolina, United States

Monash Health, Monash Medical Centre

Clayton, Victoria, Australia

Ordensklinikum Linz GmbH Elisabethinen

Linz, Upper Austria, Austria

Fakultni nemocnice Ostrava

Ostrava, , Czechia

Hôpital de La Conception

Marseille, Bouches-du-Rhône, France

CHU Angers

Angers, Maine-et-Loire, France

CHRU Lille

Lille, , France

Hôpital Saint Louis

Paris, , France

Medizinische Hochschule Hannover

Hanover, Lower Saxony, Germany

Universitatsklinikum Dusseldorf

Düsseldorf, North Rhine-Westphalia, Germany

Universitatsklinikum Leipzig

Leipzig, Saxony, Germany

University Hospital of Alexandroupolis

Alexandroupoli, , Greece

Attikon University General Hospital

Athens, , Greece

University General Hospital of Patras

Pátrai, , Greece

Hippokration Hospital

Thessaloniki, , Greece

Shaare Zedek Medical Center

Jerusalem, , Israel

Tel Aviv Sourasky Medical Center PPDS

Tel Aviv, , Israel

Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico

Milan, Lombardy, Italy

Fondazione IRCCS Policlinico San Matteo di Pavia

Pavia, Lombardy, Italy

Istituto Clinico Humanitas

Rozzano, Lombardy, Italy

Azienda Ospedaliera Ordine Mauriziano di Torino

Turin, Piedmont, Italy

Fondazione PTV Policlinico Tor Vergata

Roma, , Italy

MTZ Clinical Research Powered by PRATIA - PPDS

Warsaw, Masovian Voivodeship, Poland

Pratia Onkologia Katowice - PRATIA - PPDS

Katowice, Silesian Voivodeship, Poland

SPZOZ MiSWiA z Warminsko-Mazurskim Centrum Onkologii w Olsztynie

Olsztyn, Warmian-Masurian Voivodeship, Poland

Kyungpook National University Hospital

Daegu, , South Korea

Asan Medical Center - PPDS

Seoul, , South Korea

The Catholic University of Korea, Seoul St. Mary's Hospital

Seoul, , South Korea

C.H. Regional Reina Sofia - PPDS

Córdoba, , Spain

Hospital Universitario La Paz - PPDS

Madrid, , Spain

Hospital Universitario HM Sanchinarro - CIOCC

Madrid, , Spain

Complejo Asistencial Universitario de Salamanca - H. Clinico

Salamanca, , Spain

Hospital Universitario Virgen del Rocio - PPDS

Seville, , Spain

Aberdeen Royal Infirmary - PPDS

Aberdeen, Aberdeen City, United Kingdom

Western General Hospital Edinburgh - PPDS

Edinburgh, , United Kingdom

Kings College Hospital

London, , United Kingdom

Churchill Hospital-NHS Oxford

Oxford, , United Kingdom

Countries

United States; Australia; Austria; Czechia; France; Germany; Greece; Israel; Italy; Poland; South Korea; Spain; United Kingdom

Other Identifiers

AG946-C-002

Identifier Type: -

Identifier Source: org_study_id

2022-500609-42-00

Identifier Type: OTHER

Identifier Source: secondary_id