The Efficacy and Safety of Elritercept in Adult Participants With Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes (MDS) With Anemia (RENEW)

Inclusion criteria

• Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information and/or protected personal data in accordance with national and local study participant data protections and privacy regulations.
• Male or female greater than or equal to (≥)18 years of age at the time of signing informed consent.
• Diagnosis of MDS with or without RS (as determined in an evaluable bone marrow aspirate, read by an independent central reader to confirm diagnosis at Screening) according to the World Health Organization 2016 classification that meets the International Prognostic Scoring System-Revised (IPSS-R) classification of very low, low, or intermediate risk disease.
• Transfusion dependence assessed in the 16 weeks immediately preceding randomization in two 8-week blocks, classified as either: a. Low-transfusion burden (LTB), defined as 4 to 7 red blood cells (RBC) units per 16 weeks; or b. High-transfusion burden (HTB), defined as ≥8 RBC units per 16 weeks; and c. For all participants: i. Only transfusion events for a pretransfusion hemoglobin (Hgb) lesser than (\<)10 grams per deciliter (g/dL) are counted toward eligibility; ii. At least 1 transfusion event in each 8-week period and a minimum of 2 transfusion events separated by ≥7 days within the 16-week period immediately preceding randomization; and iii. No consecutive 56-day period can be RBC transfusion-free during the 16-week period immediately preceding randomization.
• Refractory or intolerant to prior erythropoiesis-stimulating agent (ESA) treatment (discontinued ≥4 weeks before randomization), 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defined as follows: a. Refractory to prior ESA treatment: documentation of nonresponse or a response that was no longer maintained with a prior ESA-containing regimen, either as a single agent or combination (e.g., with granulocyte colony-stimulating factor \[G-CSF\]); ESA regimen must have been either: i. Recombinant human erythropoietin (EPO) ≥40,000 international units per week (IU/week) for ≥8 doses or equivalent; or ii. Darbepoetin alpha ≥500 micrograms (μg) 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 (e.g., 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 greater than (\>)200 units per liter (U/L).
• Less than 5% blasts in an evaluable bone marrow aspirate collected at Screening, read by an independent central reader.
• Eastern Cooperative Oncology Group performance status of 0 to 2.
• Females of childbearing potential and sexually active males must agree to use highly effective methods of contraception.
• In the opinion of the Investigator, the participant is able and willing to comply with the requirements of the protocol (e.g., all study procedures, return for follow-up visits).

Exclusion criteria

• Del(5q) MDS or therapy-related (secondary) MDS.
• Anemia due to any other known cause (e.g., thalassemia, hemolytic anemia, bleeding events, or deficiency of iron, B12, and/or folate).
• Receipt of RBC transfusion for any reason(s) other than underlying MDS within 16 weeks before randomization.
• Clinically significant cardiovascular disease defined as:
• New York Heart Association heart disease class III or IV;
• Fridericia corrected QT (QTcF) interval \>500 milliseconds during Screening;
• Presence of uncontrolled hypertension defined as mean systolic blood pressure ≥160 millimeters of mercury (mm Hg) or diastolic blood pressure ≥100 mm Hg during Screening; or
• Uncontrolled arrhythmia, myocardial infarction, or unstable angina within 6 months before Screening.
• Known ejection fraction \<35%, confirmed by a local echocardiogram performed during Screening, or a previously performed echocardiogram if collected within 6 months before Screening.
• Child-Pugh class C hepatic impairment.
• Stroke, deep vein thrombosis, or pulmonary embolism within 6 months before Screening.
• Any known history of acute myeloid leukemia (AML).
• Prior history of malignancies, other than MDS, unless 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:
• Basal or squamous cell carcinoma of the skin;
• Carcinoma in situ of the cervix;
• Carcinoma in situ of the breast; and/or
• Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, node, metastasis \[TNM\] clinical staging system).
• History of solid organ or bone marrow transplantation.
• Active infection requiring intravenous treatment (e.g., antibiotics, antifungals, or antivirals) within 28 days, or oral treatment within 14 days before randomization.
• History of or known active chronic infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV). Participants without known positive history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines.
• Body mass index ≥ 40 kilograms per meter square (kg/m\^2).
• Major surgery within 28 days before randomization.
• History of allergy/anaphylaxis to investigational medicinal product (IMP) excipients (refer to the current elritercept IB for a list of excipients) or recombinant proteins.
• Prior use of elritercept, luspatercept, or sotatercept.
• Prior use of hypomethylating agents (HMAs), isocitrate dehydrogenase inhibitor, lenalidomide, imetelstat, or immunosuppressive therapy given for treatment of MDS.
• Iron chelation therapy initiated within 8 weeks before randomization. Participants on stable doses of iron chelation therapy for ≥ 8 weeks are allowed.
• Vitamin B12 or folate therapy initiated within 4 weeks before randomization. Participants on stable replacement doses for ≥ 4 weeks and without ongoing concurrent vitamin B12 or folate deficiency are allowed.
• Androgen use within 8 weeks before randomization. Participants on stable androgen dosing for hypogonadism for ≥ 8 weeks are allowed.
• High-dose corticosteroid use within 4 weeks before randomization. Participants on stable chronic steroid doses of prednisone lesser than or equal to (≤) 10 mg/day or corticosteroid equivalent for ≥ 4 weeks are allowed.10 mg/day or corticosteroid equivalent for ≥ 4 weeks are allowed.
• 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.
• Ongoing participation in another interventional clinical study.
• Serum EPO level \>500 U/L.
• Platelet count ≥450 × 10\^9/L or ≤25 × 10\^9/L.
• Absolute neutrophil count ≤ 500/µL.
• Serum aspartate aminotransferase or alanine aminotransferase ≥3 × the upper limit of normal (ULN).
• Total bilirubin ≥2 × ULN unless attributable to Gilbert's syndrome.
• Ferritin ≤ 50 micrograms per litre (μg/L).
• Folate ≤2.0 nanograms per milliliter (ng/mL).
• Vitamin B12 ≤200 picograms per milliliter (pg/mL).
• Estimated glomerular filtration rate \<30 milliliters per minute per 1.73 meter square (mL/min/1.73m\^2) as determined by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Collaboration equation.
• Pregnant or lactating female.
• 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.
• 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).
• For Participants in France: Persons under court protection, persons not affiliated with a social security system, and protected adults (per applicable French law \[Art. L. 1121-6, Art. L. 1121-8, Art. L. 1121-8-1\]).