A Phase 2a/2b, Open-label, Proof of Concept (Phase 2a) and Open-label (Phase 2b), Multicenter, Efficacy, and Safety Study of AG-946in Participants With Anemia Due to Lower-Risk Myelodysplastic Syndromes

Trial ID: 2022-500609-42-00
Protocol: AG946-C-002
Sponsor: Agios Pharmaceuticals Inc.

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Diseases & Conditions

Anaemia Myelodysplastic syndrome

Objectives

The primary objective of this study is to establish a **proof-of-concept** for AG-946 in participants with lower-risk myelodysplastic syndromes (LR-MDS) during Phase 2a, and to evaluate the effect of AG-946 on transfusion independence in participants with LR-MDS during Phase 2b. This is clinically relevant as it aims to address the unmet need for effective treatments in managing anemia associated with LR-MDS, potentially reducing the dependency on blood transfusions and improving patient outcomes.

Secondary objectives include:

Phase 2a: Evaluating the safety of AG-946, its effect on additional measures of anemia, the transfusion burden in participants with low transfusion burden, the pharmacokinetics of AG-946, and its effect on pharmacodynamic biomarkers.
Phase 2b: Evaluating the safety of AG-946, its effect on anemia, additional measures of transfusion burden, the pharmacokinetics of AG-946, and its effect on pharmacodynamic biomarkers.

Participants

The clinical trial involves a total of **53 participants** diagnosed with **Anemia Due to Lower-Risk Myelodysplastic Syndromes**. The study population includes both male and female subjects, aged 18 years and older, who are considered part of a vulnerable population. Participants were selected based on specific criteria, including a documented diagnosis of myelodysplastic syndromes (MDS) according to the World Health Organization classification, with a lower-risk disease classification as per the IPSS-R criteria. The general health status of participants is characterized by an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2, indicating they are fully active or capable of self-care. Lifestyle considerations include the requirement for stable iron chelation therapy, if applicable, and adherence to effective contraception methods for women of childbearing potential and their partners. The trial aims to establish proof-of-concept for AG-946 and evaluate its effect on transfusion independence in this specific patient group.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy and safety of **AG-946** in participants with **anemia due to lower-risk myelodysplastic syndromes** (LR-MDS). This study is structured as a Phase 2a/2b, open-label, multicenter trial. The primary objective of Phase 2a is to establish proof-of-concept for AG-946, while Phase 2b aims to assess the effect of AG-946 on transfusion independence in participants with LR-MDS. The trial is expected to conclude by August 2026, with recruitment having commenced in February 2023.

Participants will be involved in the study for a maximum treatment period of 180 days, during which they will receive AG-946 in the form of a coated tablet administered orally. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, diagnosis, and transfusion history; regular follow-up visits to monitor hemoglobin levels, transfusion requirements, and any adverse events; and an end-of-study visit to assess overall outcomes and collect final data. The primary endpoints include hemoglobin response and transfusion independence, while secondary endpoints focus on safety, changes in hemoglobin concentration, and pharmacokinetic parameters.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial's design ensures that all participants are closely monitored throughout the study duration to maintain the integrity of the data collected and to safeguard participant well-being.

Treatment

The clinical trial involves the administration of the experimental medication **AG-946**, which is provided in the form of a **coated tablet**. The active substance in this medication is **AG-946 phosphate**, a chemical compound developed by Agios Pharmaceuticals. The medication is administered orally, with a maximum daily dose of 20 mg. The total maximum dose over the treatment period is 25,200 mg, with the treatment duration not exceeding 180 days. The trial aims to evaluate the efficacy and safety of AG-946 in participants with anemia due to lower-risk myelodysplastic syndromes (LR-MDS).

Another formulation of the experimental medication, also named **AG-946**, is included in the study. This formulation contains the active substance **AG-946** without the phosphate component. It is similarly provided as a **coated tablet** and is administered orally. The dosing regimen mirrors that of the AG-946 phosphate formulation, with a maximum daily dose of 20 mg and a total maximum dose of 25,200 mg over a treatment period of up to 180 days. Both formulations are chemically derived and are not designated as orphan drugs or pediatric formulations.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial documentation. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen. The trial is structured to establish proof-of-concept and evaluate the effect of AG-946 on transfusion independence in the target patient population.

Efficacy

The efficacy of AG-946 in participants with anemia due to lower-risk myelodysplastic syndromes (LR-MDS) will be assessed through a series of primary and secondary endpoints. In Phase 2a, the primary endpoints include **hemoglobin (Hb) response**, defined as a ≥1.5-g/dL increase from baseline in the average Hb concentration from Week 8 through Week 16, and transfusion independence (TI), defined as being transfusion-free for ≥8 consecutive weeks during the Core Period for participants with low transfusion burden (LTB) only. In Phase 2b, the primary endpoint is transfusion independence, defined as transfusion-free for ≥8 consecutive weeks (TI8) during the Core Period.

Secondary endpoints for Phase 2a include the assessment of adverse events (AEs), serious adverse events (SAEs), discontinuations due to AEs, and laboratory abnormalities during the Core Period. Additional secondary endpoints involve Hb 1.0+ response, defined as a ≥1.0-g/dL increase from baseline in the average Hb concentration from Week 8 through Week 16, and changes from baseline in Hb concentration and total transfused red blood cell (RBC) units during the Core Period. Pharmacokinetic parameters of AG-946 and pharmacodynamic parameters, including 2,3-diphosphoglycerate (2,3-DPG) and adenosine triphosphate (ATP), will also be measured.

For Phase 2b, secondary endpoints include changes from baseline in Hb concentration and total transfused RBC units from Week 8 through Week 24, time to first TI8, and transfusion-free status for ≥12 consecutive weeks (TI12) during the Core Period. The duration of TI, defined as the longest transfusion-free period during the Core Period, will also be evaluated. Plasma concentration and pharmacokinetic parameters of AG-946, along with whole blood concentrations of pharmacodynamic parameters, including 2,3-DPG and ATP, will be assessed.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Phase 2a: 1. At least 18 years of age at the time of providing informed consent 2. Documented diagnosis of MDS according to World Health Organization (WHO) classification, that meets IPSS-R classification of lowerrisk 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 LTB, based on transfusion history from the participant’s medical record, according to revised IWG 2018 criteria: a. NTD: <3 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 b. 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. An Hb concentration <11.0 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, 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 HTB, based on transfusion history from the participant’s medical record according to revised IWG 2018 criteria: a. 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 b. 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. An 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 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. 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

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Exclusion Criteria

1.Known history of acute myeloid leukemia
18.Known allergy to AG-946 or its excipients (silicified microcrystalline cellulose, croscarmellose sodium, sodium stearyl fumarate, and the Opadry® II Blue film coat [polyvinyl alcohol, titanium dioxide, macrogol/polyethylene glycol, talc, FD&C blue #2/indigo carmine aluminum lake/E132])
19.Pregnant or breastfeeding
13.Absolute neutrophil count <500/μL (0.5 × 109/L)
20.Any medical, hematologic, psychological, or behavioural 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
10.For any malignancy, except MDS: History of malignancy (active or treated) ≤5 years before providing informed consent, except for no melanomatous skin cancer in situ, cervical carcinoma in situ, or breast carcinoma in situ.
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
Phase 2a: 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 luspatercept, EPO, or G-CSF. Treatment with EPO or 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 (phase 2a) or randomization (phase 2b).
15.Nonfasting triglyceride concentration >500 mg/dL
16.Receiving inhibitors of P-glycoprotein 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
6.History of hepatobiliary disorders, as defined by: a. 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) b. Serum bilirubin >ULN, if the elevation is associated with clinically symptomatic choledocholithiasis, cholecystitis, biliary obstruction, or hepatocellular disease
5.History of active and/or uncontrolled cardiac or pulmonary disease within 6 months before providing informed consent, including but not limited to: a.New York Heart Association Class III or IV heart failure or clinically significant dysrhythmia. b.Myocardial infarction, unstable angina pectoris, or unstable hypertension; high risk thrombosis; hemorrhagic, embolic, or thrombotic stroke; deep venous thrombosis; or pulmonary or arterial embolism c.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 d.Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sided heart failure, and radiographic pulmonary fibrosis >50% e.Severe pulmonary hypertension as defined by severe symptoms associated with hypoxia, right-sidedheart failure, and oxygen indicated
Phase 2b: 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.
Renal dysfunction, as defined by an estimated glomerular filtration rate (eGFR) <45mL/min/1.73 m2
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
14.Platelet count ≤75,000/μL (75 × 109/L) during Screening; platelet transfusions within 28 days before or during Screening
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.
Positive test for hepatitis C virus antibodywith 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
17.Current enrolment or past participation (within 4 weeks or a time frame equivalent to 5half-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
Phase 2b: 3. Prior exposure to a pyruvate kinase activator, including exposure to AG-946 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

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Recruiting	08 Feb 2023	4
Czechia	Not Recruiting	08 Feb 2023	3
France	Not Recruiting	08 Feb 2023	8
Germany	Not Recruiting	08 Feb 2023	6
Greece	Not Recruiting	08 Feb 2023	8
Italy	Not Recruiting	08 Feb 2023	10
Poland	Not Recruiting	08 Feb 2023	25
Spain	Not Recruiting	08 Feb 2023	14