A Study to Compare Elritercept With Epoetin Alfa to Treat Anemia in Adults With Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes (MDS) Who Need Regular Blood Transfusions

Inclusion criteria

• Male or female participants aged ≥ 18 years or older at time of signing the informed consent form (ICF).
• Able to understand the purpose and risks of the trial and voluntarily sign an ICF prior to any trial-related procedures being conducted and authorization to use protected health information and personal data in accordance to national and local privacy regulations.
• Documented diagnosis of myelodysplastic syndrome(s) (MDS) according to WHO 2016 classification that meets International Prognostic Scoring System - Revised (IPSS-R) classification of very low-, low-, or intermediate-risk disease, confirmed by central laboratory independent reviewer prior to randomization. Hemoglobin (Hgb), platelet, and absolute neutrophil count (ANC) values should be collected greater than (\>) 14 days after red blood cell (RBC) transfusion or greater than (\>) 7 days after platelet transfusion, unless otherwise considered to be pretransfusion values.
• Bone marrow less than (\<) 5% blasts in an evaluable bone marrow collected at screening and confirmed by central pathology independent reviewer.
• Endogenous serum erythropoietin s (EPO) level of \<500 U/L. Should be results from blood samples collected \>14 days following an RBC transfusion to evaluate for eligibility unless considered pretransfusion values.
• Participant requires RBC transfusion, as documented by the following criteria. A transfusion requirement of 2 to 6 pRBCs units/8 weeks confirmed for a minimum of 8 weeks immediately preceding randomization. • Hgb levels at the time of or within 3 days prior to administration of a RBC transfusion must have been less than or equal to (≤) 9.0 grams per deciliter (g/dL) (5.6 millimoles per liter (mmol/L)) with symptoms of anemia (or ≤7 g/dL \[4.3 mmol/L\] in the absence of symptoms) in order for the transfusion to be counted towards meeting eligibility criteria. • RBC transfusions administered when hemoglobin (Hgb) levels were \>9.0 g/dL (or \>7 g/dL in the absence of symptoms) and/or RBC transfusions administered for elective surgery, infections or bleeding events will not qualify as a required transfusion for the purpose of meeting eligibility criteria or stratification.
• Hgb \<11.0 g/dL (6.8 mmol/L) after last RBC transfusion preceding randomization. Local laboratory is acceptable to facilitate randomization.
• Eastern Cooperative Oncology Group score of 0, 1, or 2.

Exclusion criteria

• Prior therapy with any of the following:
• Epoetin alfa • At the investigator's discretion in consultation with the medical monitor, may be allowed if received no more than 2 doses of only epoetin alfa ≥8 weeks prior to randomization. No other erythropoiesis-stimulating agent (ESA) agent is allowed.
• Darbepoetin
• Granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor administered ≤8 weeks (56 days) prior to randomization unless given for treatment of febrile neutropenia.
• Immunomodulatory drug (IMiDs) including lenalidomide • At the investigator's discretion in consultation with the medical monitor may be allowed if received ≤1 week of an IMiD ≥8 weeks prior to randomization.
• Hypomethylating agent • At the investigator's discretion, in consultation with the medical monitor may be allowed if received no more than 2 doses ≥8 weeks prior to randomization.
• Luspatercept, sotatercept, imetelstat, or elritercept
• Immunosuppressive therapy
• Hematopoeitic cell transplant
• Iron chelation if administered ≤8 weeks prior to randomization. Participants on stable doses of iron chelation therapy for ≥8 weeks are allowed Vitamin B12 or folate therapy initiated within 4 weeks prior to 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 ≤10 mg/day or corticosteroid equivalent for ≥ 4 weeks are allowed. Other disease modifying treatments for autoimmune diseases may be allowed upon medical monitor review.
• Investigational agent or any other agent intended for treatment MDS treatment
• Diagnosed to have MDS associated with del(5q) cytogenetic abnormality or MDS unclassifiable according to WHO 2016 classification or secondary MDS.
• Known history of diagnosis of acute myeloid leukemia (AML).
• Anemia due to any other known cause including but not limited to thalassemia; hypothyroidism; due to iron, vitamin B12, vitamin B6, zinc, or folate deficiencies; autoimmune or hereditary hemolytic anemia; any type of known clinically significant bleeding or sequestration or drug induced anemia, hemolytic anemia, or bleeding events.
• 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
• 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.
• Medical history of thromboembolic events within 6 months before screening, including history of cerebrovascular accident (including ischemic, embolic, and hemorrhagic cerebrovascular accident), transient ischemic attack, deep venous thrombosis (DVT; including proximal and distal), pulmonary or arterial embolism, arterial thrombosis or other venous thrombosis. Participants with prior superficial thrombophlebitis are allowed.
• Uncontrolled hypertension, defined as repeated elevations of systolic blood pressure of ≥160 millimeters of mercury (mmHg) and/or diastolic blood pressure ≥100 mmHg despite adequate treatment.
• Prior history of malignancies, other than MDS. Participants who are free of other malignant disease for ≥3 years and have completed treatment, including maintenance are allowed. 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;
• 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 antibiotics within 28 days or oral antibiotics within 14 days before randomization.
• Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B virus (HBV), or active infectious 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 square meter (kg/m\^2).
• Major surgery within 28 days before randomization.
• New-onset seizures or poorly controlled seizures within 12 weeks prior to randomization are excluded from trial participation.
• History of allergy/anaphylaxis to investigational product (including epoetin alfa) excipients (refer to the current elritercept investigator's brochure for a list of excipients) or recombination proteins.
• History of pure red cell aplasia and/or antibody against erythropoietin (EPO).
• Any of the following laboratory abnormalities:
• ANC \<500/microliter (μL) (0.5×109/L).
• Platelet count \<50,000/μL (50×109/L) or ≥450,000/μL (450×109/L).
• Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3× upper limit of the normal (ULN).
• Total bilirubin ≥2×ULN. Participants with known history of Gilbert syndrome with unconjugated bilirubin \<3×ULN are allowed. Higher levels if attributed to active RBC precursor destruction within the bone marrow (ineffective erythropoiesis) may be allowed upon medical monitor review.
• Estimated glomerular filtration rate \<30 mL/min/1.73 m\^2 as determined by the Chronic Kidney Disease Epidemiology (CKD-EPI) collaboration equation.
• Ferritin ≤50 micrograms per liter (μg/L).
• Folate ≤2.0 nanograms per milliliter (ng/mL).
• Vitamin B12 ≤200 picograms per milliliter (pg/mL).
• Ongoing participation in another interventional clinical trial.
• Participant is unwilling or in the opinion of the investigator the participant is unable to comply with the requirements of the protocol.
• Is a participant of childbearing potential (POCBP) but does not agree to use at least 1 form of highly effective contraception from the time of signing the ICF until at least 60 days after the last dose of trial intervention.
• Participants of male birth who are fertile and who have partners of childbearing potential, who do not agree to use acceptable barrier contraception, that is, a male condom during the entire trial intervention period until at least 60 days after the last dose of trial intervention.
• If applicable, participant with a positive serum pregnancy test during the screening period or known to be pregnant or a lactating participant who does not agree to forego breastfeeding during the entire trial intervention period until at least 60 days after the last dose of trial intervention.
• For Participants in France: Persons under court protection, persons not affiliated with a social security system, and protected adults.