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

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 HealthOrganization (WHO) classification (Arber et al, 2016), that meets RevisedInternational Prognostic Scoring System (IPSS-R) classification of lower-riskdisease (risk score: ≤3.5) and <5% blasts as determined by the participant's bonemarrow biopsy/aspirate during the Screening Period;

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

• Nontransfused (NTD): <3 red blood cell (RBC) units in the 16-week period beforeadministration 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 firstdose of study drug and <4 RBC units in the 8-week period before administrationof the first dose of study drug;

4. A hemoglobin (Hb) concentration <11.0 grams per deciliter (g/dL) during the 4-weekScreening 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 beenstable 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 thatmay result in pregnancy as part of their usual lifestyle or agree to use a highlyeffective 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 thehighly effective method of contraception is hormonal contraception, then anacceptable barrier method must also be used. Men with partners who are WOCBP must beabstinent of sexual activities that may result in pregnancy as part of their usuallifestyle or agree to use a condom from the time of providing informed consentthroughout the study and for 28 days after the last dose of study drug;

8. Written informed consent from the participant before any study-related proceduresare conducted and willing to comply with all study procedures for the duration ofthe 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 theScreening Period;

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

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

5. HTB: ≥8 RBC units in the 16-week period before administration of the first doseof study drug AND ≥4 RBC units in the 8-week period before administration ofthe first dose of study drug If a participant's transfusion burden does not fall into either the LTB or HTBcategory, as defined per IWG 2018 criteria, then the transfusion burden will becategorized based on their transfusion history in the 16-week period beforeadministration of the first dose of study drug.

6. 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 thefirst dose of study drug

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

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

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

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

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

12. Written informed consent from the participant before any study-related proceduresare conducted and willing to comply with all study procedures for the duration ofthe 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 chemicalinjury or treatment with chemotherapy and/or radiation for other diseases;

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

• Immunomodulatory drugs (IMiDs) such as lenalidomide; at the Investigator'sdiscretion and in consultation with the Medical Monitor, participants whoreceived ≤1 week of treatment with IMiDs may not be excluded, provided theirlast dose was ≥8 weeks before administration of the first dose of study drug

• Hypomethylating agents (HMAs); at the Investigator's discretion and inconsultation with the Medical Monitor, participants who received ≤2 doses ofHMAs may not be excluded, provided that their last dose was ≥8 weeks beforeadministration 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 withESAs±G-CSF must have been stopped for ≥28 days before administration of the firstdose of study drug; treatment with luspatercept must have been stopped for ≥65 daysbefore administration of the first dose of study drug;

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

• New York Heart Association Class III or IV heart failure or clinicallysignificant dysrhythmia

• Myocardial infarction, unstable angina pectoris, or unstable hypertension; highrisk thrombosis; hemorrhagic, embolic, or thrombotic stroke; deep venousthrombosis; or pulmonary or arterial embolism

• Heart rate-corrected QT interval using Fridericia's method of ≥470 millisecondsfor female participants and ≥450 milliseconds for male participants, except forright or left bundle branch block

• Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sidedheart failure, and radiographic pulmonary fibrosis >50%

• Severe pulmonary hypertension as defined by severe symptoms associated withhypoxia, 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 alanineaminotransferase (ALT) >2.5 × ULN (unless due to hepatic iron deposition)

• Serum bilirubin >ULN, if the elevation is associated with clinicallysymptomatic choledocholithiasis, cholecystitis, biliary obstruction, orhepatocellular disease;

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

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

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

11. Positive test for hepatitis C virus (HCV) antibody (Ab) with evidence of active HCVinfection, 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 transfusionswithin 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 daysor 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 equivalentto 5 half-lives of the investigational study drug before administration of the firstdose of study drug or, whichever is longer) in any other clinical study involving aninvestigational 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 orcurrent therapy that, in the opinion of the Investigator, may confer an unacceptablerisk to participating in the study and/or could confound the interpretation of thestudy data. Also excluded are:

• Participants who are institutionalized by regulatory or court order;

• Participants with any condition(s) that could create undue influence (includingbut not limited to incarceration, involuntary psychiatric confinement, andfinancial 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 chemicalinjury or treatment with chemotherapy and/or radiation for other diseases;

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

• Imetelstat; at the Investigator's discretion and in consultation with theMedical Monitor, participants who received ≤2 doses of imetelstat may not beexcluded, provided that their last dose was ≥8 weeks before administration ofthe first dose of study drug

• IMiDs such as lenalidomide; at the Investigator's discretion and inconsultation with the Medical Monitor, participants who received ≤1 week oftreatment with IMiDs may not be excluded, provided their last dose was ≥8 weeksbefore administration of the first dose of study drug

• HMAs; at the Investigator's discretion and in consultation with the MedicalMonitor, participants who received ≤2 doses of HMAs may not be excluded,provided that their last dose was ≥8 weeks before administration of the firstdose of study drug

• IDH inhibitors

• IST

• Allogeneic or autologous stem cell transplant;

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

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

• New York Heart Association Class III or IV heart failure or clinicallysignificant dysrhythmia

• Myocardial infarction, unstable angina pectoris, or unstable hypertension; highrisk thrombosis; hemorrhagic, embolic, or thrombotic stroke; deep venousthrombosis; or pulmonary or arterial embolism

• Heart rate-corrected QT interval using Fridericia's method of ≥470 millisecondsfor female participants and ≥450 milliseconds for male participants, except forright or left bundle branch block

• Severe pulmonary fibrosis as defined by severe hypoxia, evidence of right-sidedheart failure, and radiographic pulmonary fibrosis >50%

• Severe pulmonary hypertension as defined by severe symptoms associated withhypoxia, 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 clinicallysymptomatic choledocholithiasis, cholecystitis, biliary obstruction, orhepatocellular 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 providinginformed consent. If antimicrobial therapy is required during the Screening Period,screening procedures should not be performed while antimicrobial therapy is beingadministered, and the last dose of antimicrobial therapy must be administered ≥7days 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 beforeadministration of the first dose of study drug;

10. For any malignancy except MDS: History of malignancy (active or treated) ≤5 yearsbefore 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 forHBsAg;

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 transfusionswithin 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 frameequivalent to 5 half-lives (whichever is longer) beforeadministration of the firstdose of study drug;

17. Current enrollment or past participation (within 4 weeks or a time frame equivalentto 5 half-lives of the investigational study drug before administration of the firstdose of study drug or, whichever is longer) in any other clinical study involving aninvestigational 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 orcurrent therapy that, in the opinion of the Investigator, may confer an unacceptablerisk to participating in the study and/or could confound the interpretation of thestudy data. Also excluded are:

• Participants who are institutionalized by regulatory or court order

• Participants with any condition(s) that could create undue influence (includingbut not limited to incarceration, involuntary psychiatric confinement, andfinancial or familial affiliation with the Investigator or Sponsor).

21. Known clinically significant anemia due to iron, vitamin B12, or folatedeficiencies, autoimmune or hereditary hemolytic anemia, hypothyroidism, or any typeof known clinically significant bleeding.