Inclusion Criteria:
1. Participants or their legally authorized representative must be willing and able to sign the ICF and to adhere to the protocol requirements.
2. Japanese adult male or female participant \>=18 years of age at the time of signing informed consent.
3. Diagnosis of MDS with or without ring sideroblasts (RS) (as determined in an evaluable bone marrow aspirate collected at Screening to confirm diagnosis) according to WHO 2016 classification that meets the International Prognostic Scoring System-Revised (IPSS-R) classification of very low-, low-, or intermediate-risk MDS.
Note: Due to expected impacts of transfusion, hemoglobin (Hgb) values from blood samples collected within 14 days following a RBC transfusion and platelet count obtained within 7 days following a platelet transfusion cannot be used to evaluate IPSS-R for eligibility.
4. TD\[YY1.1\] cohort: Transfusion dependence assessed in the 16 weeks immediately preceding enrollment in two 8-week blocks classified as either:
1. Low-transfusion burden (LTB), defined as 4 to 7 RBC units per 16 weeks; or
2. HTB\[YY2.1\], defined as \>=8 RBC units per 16 weeks; and
3. For all participants: i. Only transfusion events for a pretransfusion Hgb \<10 g/dL are counted toward eligibility; ii. At least 1 transfusion event in each 8-week block and a minimum of 2 transfusion events separated by \>=7 days within the 16-week period immediately preceding enrollment; and iii. No consecutive 56-day period can be RBC transfusion-free during the 16 week period immediately preceding enrollment.
Note: Only transfusions for the disease under study will be counted towards classification for LTB or HTB participants. Transfusions for intercurrent diseases (bleeding, surgical procedure, infection, etc.) are not considered.
NTD\[YY3.1\] cohort: NTD, defined as 0 to 1 RBC units per 8 weeks immediately preceding enrollment.
Note: RBC transfusions administered when Hgb levels were \<9.0 g/dL are counted for eligibility. RBC transfusions administered for other than MDS-related anemia (bleeding, surgical procedure, infection, etc.) will not be counted as a required transfusion for the purpose of meeting eligibility criteria.
5. TD cohort: Refractory or intolerant to prior erythropoiesis-stimulating agent (ESA) treatment (discontinued \>=4 weeks before enrollment), or unlikely to respond to ESA treatment, defined as follows:
a. Refractory to prior ESA treatment: documentation of nonresponse or a response that was no longer maintained with a prior ESA-containing regimen, either as a single agent or combination (eg, with granulocyte colony-stimulating factor \[G-CSF\]); ESA regimen must have been either: i. Recombinant human erythropoietin (EPO) \>=40,000 IU/week for \>=8 doses or equivalent; or ii. Darbepoetin alpha \>=500 mcrg every 3 weeks for \>=4 doses or equivalent. b. Intolerant to prior ESA treatment: documentation of discontinuation of a prior ESA containing regimen, either as a single agent or combination (eg, with G-CSF), at any time after introduction due to intolerance or an AE.
c. Unlikely to respond to ESA treatment: low chance of response to ESA based on an endogenous serum EPO level \>200 U/L.
Note: Due to expected impacts of transfusion on EPO levels, blood samples collected within the 14 days following an RBC transfusion or within 7 days following a platelet transfusion cannot be used to evaluate serum EPO level for eligibility.
NTD cohort: Hgb \<10 g/dL and exhibiting anemia-related clinical symptoms (eg, fatigue, shortness of breath, or others) during screening.
6. Less than 5% blasts in an evaluable bone marrow aspirate collected at Screening.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
8. Women of childbearing potential (WOCBP), defined as a sexually mature woman who has not undergone surgical sterilization or who has not been naturally postmenopausal for at least 12 consecutive months must
1. Agree to use 1 highly effective method of contraception and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through 60 days after the last dose of study drug; or
2. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, postovulation methods\], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
9. Male participants must, even if he is surgically sterilized (ie, status postvasectomy),
1. Agree to practice effective barrier contraception the time of signing the informed consent through 60 days after the last dose of study drug; or
2. Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence \[eg, calendar, ovulation, symptothermal, postovulation methods\], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception.)
Exclusion Criteria:
Medical History
1. Del(5q) MDS or therapy-related (secondary) MDS.
2. Anemia due to any other known cause (eg, thalassemia, hemolytic anemia, bleeding events, or deficiency of iron, B12, and/or folate).
3. Receipt of RBC transfusion for any reason(s) other than underlying MDS within 16 weeks in TD cohort or 8 weeks in NTD cohort before enrollment.
4. Clinically significant cardiovascular disease defined as:
1. New York Heart Association heart disease class III or IV;
2. Fridericia corrected QT (QTcF) interval \>500 milliseconds during Screening;
3. Presence of uncontrolled hypertension defined as mean systolic blood pressure \>=160 mm Hg or diastolic blood pressure \>=100 mm Hg during Screening; or
4. Uncontrolled arrhythmia, myocardial infarction, or unstable angina within 6 months before Screening.
5. Known ejection fraction \<35%, confirmed by a local echocardiogram performed during Screening, or a previously performed echocardiogram if collected within 6 months before Screening.
6. Stroke, deep vein thrombosis, or pulmonary embolism within 6 months before Screening.
7. Any known history of acute myeloid leukemia (AML).
8. Prior history of malignancies, other than MDS, unless the participant has been free of the disease (including completion of any treatment, including maintenance, for prior malignancy) for \>=5 years. However, participants with a history or concurrent diagnosis of the following conditions are allowed if not requiring systemic therapy:
1. Basal or squamous cell carcinoma of the skin;
2. Carcinoma in situ of the cervix;
3. Carcinoma in situ of the breast; and/or
4. Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis \[TNM\] clinical staging system).
9. History of solid organ or bone marrow transplantation.
10. Active infection requiring intravenous antibiotics within 28 days or oral antibiotics within 14 days before enrollment.
11. History of or known active or chronic infection with HIV, active infectious hepatitis B virus (HBV), or active infectious hepatitis C virus (HCV). Participants who are positive for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis B surface antibody (HBsAb) may be eligible for enrollment if their hepatitis B viral load is below the limit of detection. Participants who are positive for hepatitis C virus antibodies (HCVAb) may be enrolled if their hepatitis C viral load is below the limit of detection.
12. Body mass index \>=40 kg/m\^2.
13. Major surgery within 28 days before enrollment.
14. History of allergy/anaphylaxis to investigational medicinal product (IMP) excipients (refer to the current elritercept \[TAK 226\] IB for a list of excipients) or recombinant proteins.
Treatment History
15. TD cohort: Prior use of TAK 226, luspatercept, imetelstat, or sotatercept. \[YY4.1\] NTD cohort: Prior use of TAK 226, luspatercept, imetelstat, sotatercept, or ESAs.
Note for NTD cohort: At the investigator's discretion in consultation with the medical monitor, may be allowed if received no more than 2 doses of ESAs \>=8 weeks prior to enrollment.
16. Prior use of hypomethylating agents (HMAs), isocitrate dehydrogenase inhibitor, lenalidomide, or immunosuppressive therapy given for treatment of MDS.
17. Iron chelation therapy initiated within 8 weeks before enrollment. Participants on stable doses of iron chelation therapy for \>=8 weeks are allowed.
18. Vitamin B12 or folate therapy initiated within 4 weeks before enrollment. Participants on stable replacement doses for \>=4 weeks and without ongoing concurrent vitamin B12 or folate deficiency are allowed.
19. Androgen use within 8 weeks before enrollment. Participants on stable androgen dosing for hypogonadism for \>=8 weeks are allowed.
20. High-dose corticosteroid use within 4 weeks before enrollment. Participants on stable chronic steroid doses of prednisone/prednisolone \<=10 mg/day or corticosteroid equivalent for \>=4 weeks are allowed.
21. Treatment with any investigational drug within 28 days before Screening or, if the half-life of the product is known, within 5 times the half-life before Screening, whichever is longer.
22. Ongoing participation in another interventional clinical study. Laboratory Exclusions (during Screening)
23. Serum EPO level \>500 U/L. Note: Due to expected impacts of transfusion on EPO levels, laboratory results from blood samples collected within the 14 days following an RBC transfusion cannot be used to evaluate serum EPO level for eligibility.
24. Platelet count \>=450\*10\^3/mcrL or \<=25\*10\^3/mcrL. Note: Due to expected impacts of transfusion, laboratory results from blood samples collected within the 7 days following a platelet transfusion cannot be used to evaluate platelet count for eligibility.
25. Absolute neutrophil count \<=500/mcrL
26. Serum AST or ALT \>=3\*the upper limit of normal (ULN).
27. Total bilirubin \>=2\*ULN unless attributable to Gilbert syndrome.
28. Ferritin \<=50 mcrg/L.
29. Folate \<=2.0 ng/mL.
30. Vitamin B12 \<=200 pg/mL.
31. Estimated glomerular filtration rate \<30 mL/min/1.73m\^2 as determined by Japanese Society of Nephrology. Calculated by the correction formula for Japanese. a)
a) eGFR=194\* (serum creatinine value)\^-1.094\* (age)\^-0.287\* (sex correction factor), Sex correction factor: 0.739 in female.
Miscellaneous
32. Pregnant or lactating female\[YY5.1\]. Note: Participants who may be in the very early stage of pregnancy based on the doctor's interview with a negative pregnancy test are excluded from the study. Participants who are lactating will be eligible if they discontinue breastfeeding from before the first dose of study drug until 60 days after the last dose of study drug.
33. Any other condition not specifically noted above that, in the opinion of the investigator, would preclude the participant from participating in the study or could confound interpretation of data from the study.
34. Investigational site staff members directly involved in the conduct of the study and site staff members otherwise supervised by the investigator, employees of the Sponsor or contract research organization (CRO) directly involved in the conduct of the study, or immediate family members (defined as a spouse, parent, child, or sibling, whether biological or legally adopted).
