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

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

This purpose of this study is to establish proof of concept of AG-946 in participants with LR-MDS in Phase 2a and to compare the effect of AG-946 versus placebo and to detect a dose response for erythroid response in participants with LR-MDS in Phase 2b.

Participants will receive AG-946, 5 milligrams (mg) orally, once daily for up to 16 weeks. At the discretion of the investigator, participants who complete Core Period will be eligible to receive the same dose in Extension Period for up to 156 weeks.

At the discretion of the investigator, participants who received placebo in the Double-blind Period will receive AG-946, 2 mg orally, once daily for up to 156 weeks.

At the discretion of the investigator, participants who received placebo in the Double-blind Period will receive AG-946, 3 mg orally, once daily for up to 156 weeks.

At the discretion of the investigator, participants who received placebo in the Double-blind Period will receive AG-946, 5 mg orally, once daily for up to 156 weeks.

Hb response is defined as a ≥1.5-grams per deciliter (g/dL) increase from baseline in the average Hb concentration from Week 8 through Week 16.

Transfusion Independence is defined as transfusion-free for ≥8 consecutive weeks during the Core Period (participants With Low Transfusion Burden [LTB] only).

mHI-E Response is defined as: ≥1.5-g/dL increase from baseline in Hb concentration for ≥8 consecutive weeks during the Double-blind Period (participants who are nontransfused [NTD]) Transfusion independence, defined as transfusion-free for ≥8 consecutive weeks during the Double-blind Period (participants with LTB only) ≥50% reduction in total transfused RBC units for ≥8 consecutive weeks during the Double-blind Period compared with baseline (participants with high transfusion burden [HTB] only)

Phase 2a: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Leading to Discontinuation During the Core Period

An AE is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. An SAE is any AE or suspected adverse reaction that results in death, is immediately life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, results in congenital anomaly/birth defect, or is considered an important medical event.

Hb 1.0+ response is defined as a ≥1.0-g/dL increase from baseline in the average Hb concentration from Week 8 through Week 16

Phase 2a: Number of Participants With ≥1.5-g/dL increase From Baseline in the Hb Concentration at ≥2 Consecutive Time Points From Week 8 through Week 16

Phase 2a: Number of Participants With ≥50% Reduction in Total Transfused RBC Units for ≥8 Consecutive Weeks During the Core Period Compared With Baseline

Day 1 and Week 8 (≤60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (≤60 minutes predose)

Day 1 and Week 8 (≤60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (≤60 minutes predose)

Day 1 and Week 8 (≤60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (≤60 minutes predose)

Phase 2a: Area Under the Concentration-time Curve From 0 to t Hours (AUC0-t) of AG-946 During the Core Period

Day 1 and Week 8 (≤60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (≤60 minutes predose)

Phase 2a: Area Under the Concentration-time Curve From 0 to the End of the Dosing Interval (AUC0-τ) of AG-946 During the Core Period

Day 1 and Week 8 (≤60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (≤60 minutes predose)

Day 1 and Week 8 (≤60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (≤60 minutes predose)

Day 1 and Week 8 (≤60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (≤60 minutes predose)

Day 1 and Week 8 (≤60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (≤60 minutes predose)

Phase 2b: Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Leading to Discontinuation During the Double-blind Period

An AE is any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. An SAE is any AE or suspected adverse reaction that results in death, is immediately life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, results in congenital anomaly/birth defect, or is considered an important medical event.

Transfusion independence is defined as transfusion-free for ≥8 consecutive weeks during the Double-blind Period.

mHI-E Response is defined as: ≥1.5-g/dL increase from baseline in Hb concentration for ≥8 consecutive weeks during the Double-blind Period (participants who are NTD) Transfusion independence, defined as transfusion-free for ≥8 consecutive weeks during the Double-blind Period (participants with LTB only) ≥50% reduction in total transfused RBC units for ≥8 consecutive weeks during the Double-blind Period compared with baseline (participants with HTB only)

Phase 2b: Maximum Duration of mHI-E Response for Participants Who Achieved an mHI-E Response During the Double-blind Period

mHI-E Response is defined as: ≥1.5-g/dL increase from baseline in Hb concentration for ≥8 consecutive weeks during the Double-blind Period (participants who are NTD) Transfusion independence, defined as transfusion-free for ≥8 consecutive weeks during the Double-blind Period (participants with LTB only) ≥50% reduction in total transfused RBC units for ≥8 consecutive weeks during the Double-blind Period compared with baseline (participants with HTB only)

Day 1 and Week 8 (≤60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (≤60 minutes predose)

Day 1 and Week 8 (≤60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (≤60 minutes predose)

Day 1 and Week 8 (≤60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (≤60 minutes predose)

Phase 2b: Area Under the Concentration-time Curve From 0 to t Hours (AUC0-t) of AG-946 During the Double-blind Period

Day 1 and Week 8 (≤60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (≤60 minutes predose)

Phase 2b: Area Under the Concentration-time Curve From 0 to the End of the Dosing Interval (AUC0-τ) of AG-946 During the Double-blind Period

Day 1 and Week 8 (≤60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (≤60 minutes predose)

Day 1 and Week 8 (≤60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (≤60 minutes predose)

Phase 2b: Whole Blood Concentrations of 2,3-diphosphoglycerate (2,3-DPG) During the Double-blind Period

Day 1 and Week 8 (≤60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (≤60 minutes predose)

Day 1 and Week 8 (≤60 minutes predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and at Weeks 2, 4, 12, and 16 (≤60 minutes predose)

Phase 2b: Correlation Between AG-946 Plasma Concentration/exposure and Percentage of Participants With mHI-E Response During the Double-blind Period, as Assessed by Regression Analysis

mHI-E Response is defined as: ≥1.5-g/dL increase from baseline in Hb concentration for ≥8 consecutive weeks during the Double-blind Period (participants who are NTD) Transfusion independence, defined as transfusion-free for ≥8 consecutive weeks during the Double-blind Period (participants with LTB only) ≥50% reduction in total transfused RBC units for ≥8 consecutive weeks during the Double-blind Period compared with baseline (participants with HTB only)

Phase 2b: Correlation Between AG-946 Plasma Concentration/exposure and Change From Baseline in Hb Concentration During the Double-blind Period, as Assessed by Regression Analysis

Phase 2b: Correlation Between AG-946 Plasma Concentration/exposure and Percentage of Participants Having AEs of Clinical Interest During the Double-blind Period, as Assessed by Regression Analysis

Inclusion Criteria: Phase 2a At least 18 years of age at the time of providing informed consent; 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; 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; An hemoglobin (Hb) concentration <11.0 grams per deciliter (g/dL) during the 4-week Screening Period; Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2; 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; 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; 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 At least 18 years of age at the time of providing informed consent; 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; Nontransfused, with LTB, or with high transfusion burden (HTB), based on transfusion history from the participant's medical record, according to revised IWG 2018 criteria: NTD: <3 RBC units in the 16-week period before randomization and no transfusions in the 8-week period before randomization, or LTB: 3 to 7 RBC units in the 16-week period before randomization and <4 RBC units in the 8-week period before randomization, or HTB: ≥8 RBC units in the 16-week period before randomization and ≥4 RBC units in the 8-week period before randomization; An Hb concentration <11.0 g/dL during the 4-week Screening Period; Up to 2 prior therapies including erythropoiesis-stimulating agents (ESAs) (eg, erythropoietin [EPO], EPO + granulocyte colony-stimulating factor [G-CSF]) and/or luspatercept; ECOG Performance Status score of 0, 1, or 2; If taking iron chelation therapy, the iron chelation therapy dose must have been stable and started ≥56 days before randomization; 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; 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 Known history of acute myeloid leukemia (AML); 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; 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; 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; 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; 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; Renal dysfunction, as defined by an estimated glomerular filtration rate (eGFR) <45 milliliters per minute (mL/min)/1.73 m^2; 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; 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; 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; Positive test for hepatitis C virus (HCV) antibody (Ab) with evidence of active HCV infection, or positive test for hepatitis B surface antigen (HBsAg); Positive test for HIV-1 Ab or HIV-2 Ab; Absolute neutrophil count (ANC) <500/microliter (μL) (0.5 × 109/L); Platelet count ≤75,000/μL during Screening (75 × 109/L) platelet transfusions within 28 days before Screening or during Screening; Nonfasting triglyceride concentration >500 mg/dL; 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; 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; Known allergy to AG-946 or its excipients; Pregnant or breastfeeding; 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 Known history of AML; 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; 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: 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 randomization 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 randomization IDH inhibitors IST Allogeneic or autologous stem cell transplant; Currently receiving treatment with ESAs±G-CSF and/or luspatercept. Treatment with ESAs±G-CSF must have been stopped for ≥28 days before randomization; treatment with luspatercept must have been stopped for ≥65 days before randomization; 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; 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; Renal dysfunction, as defined by an eGFR <45 mL/min/1.73 m^2; 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 randomization; Major surgery within 12 weeks before randomization. Participants must have completely recovered from any previous surgery before randomization; 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.; Positive test for HCV Ab with evidence of active HCV infection, or positive test for HBsAg; Positive test for HIV-1 Ab or HIV-2 Ab; ANC <500/μL (0.5 × 109/L); Platelet count <50,000/μL (50 × 109/L) during Screening; platelet transfusions within 28 days before Screening or during Screening; Nonfasting triglyceride concentration >500 mg/dL; 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) before randomization; Current enrollment or past participation (within 4 weeks or a time frame equivalent to 5 half-lives of the investigational study drug before randomization or, whichever is longer) in any other clinical study involving an investigational treatment or device; Known allergy to AG-946 or its excipients, including placebo; Pregnant or breastfeeding; 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).