A Study of TAK-226 for Anemia in Japanese Patients With Lower-Risk Myelodysplastic Syndromes

The main aim of the study is to evaluate how TAK-226 improves symptoms of transfusion-dependent anemia in Japanese patients with lower-risk myelodysplastic syndromes. The study consists of Screening Period (up to 6 weeks), Treatment Period, Safety Follow-Up Period (8 weeks), and Long-Term Follow-Up Period (approximately 5 years from the first dose of the study treatment). Participants of this study will be administered TAK-226 during Treatment Period. Subsequently, the participants will be monitored for side effects related to the study treatment during Safety Follow-Up Period and Long-Term Follow-Up Period. The approximate duration of participation for a participant is up to approximately 6 years. During the study period, participants will visit the study clinic/hospital multiple times as per the study schedule. During Treatment Period, the participants will come to the clinic/hospital approximately every two to four weeks.

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 greater than or equal to (\>=) 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 sample 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 red blood cell (RBC) transfusion and platelet count obtained within 7 days following a platelet transfusion cannot be used for IPSS-R eligibility, unless considered pretransfusion values. 4. Transfusion dependent (TD) 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. High-transfusion burden (HTB), defined as \>=8 RBC units per 16 weeks; and 3. For all participants: i. Only transfusion events for a pretransfusion Hgb \=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. Non-transfusion dependent (NTD) cohort: NTD, defined as 0 to 1 RBC units per 8 weeks immediately preceding enrollment. Note: RBC transfusions administered when Hgb levels were \=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) \>=30,000 IU/week for \>=8 doses or equivalent; or ii. Darbepoetin alpha \>=500 mcrg every 3 weeks for \>=3 doses, \>=120 mcrg every week for \>=8 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, unless considered pretransfusion values. NTD cohort: Hgb \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 \=2 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). 5. Early papillary thyroid cancer (stage I \[T1-T2, N0, M0\]). 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. Active 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. 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 or decreasing 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 systemic corticosteroid use within 4 weeks before enrollment. Participants on stable chronic steroid doses of prednisone/prednisolone \=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, unless considered pretransfusion values. 24. Platelet count \>=800\*10\^3/mcrL or \=2\*ULN. Participants with known history of Gilbert syndrome with unconjugated bilirubin \