A Study to Compare Elritercept to Placebo in Adults With Myelofibrosis and Anemia Who Are Taking Ruxolitinib

Prior treatment

• Prior treatment with luspatercept, sotatercept, or other transforming growth factor beta inhibitors or activin receptor ligand traps.
• Systemic treatment within 28 days before randomization with any of the following:
  • Androgens (including danazol). Participants on stable androgen dosing for hypogonadism for ≥8 weeks are allowed.
  • erythropoiesis-stimulating agents.
  • granulocyte colony stimulating factor or granulocyte-macrophage colony stimulating factor.
  • High dose corticosteroids. Participants on stable chronic steroid doses of prednisone ≤10 mg/day or corticosteroid equivalent for ≥4 weeks are allowed. Other treatments for autoimmune diseases may be allowed upon medical monitor review.
  • Hydroxyurea.
  • Immunomodulatory drugs (for example, thalidomide, pomalidomide, or lenalidomide).
  • Interferon.
  • Thrombopoietin receptor agonists.
  • Any investigational drug, including antihemojuvelin antibody. If the half-life of the investigational product is known, the exclusionary period prior to randomization is equal to 5 half-lives of the investigational product or 28 days, whichever is longer.
• Initiation of new iron chelation therapy or dose adjustments to existing iron chelation therapy ≤8 weeks prior to randomization. Participants on stable doses of iron chelation therapy for ≥8 weeks are allowed.
• Receipt of RBC transfusion for any reason(s) other than underlying MF within 12 weeks before randomization.
• 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 (including proximal and distal), pulmonary or arterial embolism, arterial thrombosis, or other venous thrombosis. Participants with prior superficial thrombophlebitis are allowed.
• Active infection requiring intravenous antibiotics within 28 days or oral antibiotics within 7 days before randomization. Prophylactic antibiotics and/or antifungals for neutropenia are allowed.
• Major surgery within 28 days before randomization.
• History of allergy/anaphylaxis to recombinant proteins, investigational product, or excipients (refer to the current elritercept investigator's brochure for a list of excipients), or ruxolitinib.

Other illness

• Clinically significant anemia that is due to causes other than MF or Janus kinase (JAK) inhibitor therapy (for example, thalassemia, iron deficiency, vitamin B12 and/or folate deficiencies, autoimmune or hemolytic anemia, infections, or any active clinically significant bleeding or sequestration).
• Uncontrolled hypertension, defined as repeated elevations of systolic blood pressure of ≥160 millimetres of mercury (mmHg) and/or diastolic blood pressure ≥100 mmHg despite adequate treatment.
• History of solid organ or bone marrow transplantation.
• Known positivity for Human Immunodeficiency Virus (HIV), active hepatitis B virus (HBV), or active hepatitis C virus (HCV). Participants without known history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines.

Lab values

• Clinically significant cardiovascular disease, defined as:
  • New York Heart Association heart disease Class III or IV;
  • Fridericia corrected QT interval \>500 millisecond (ms) during screening;
  • Uncontrolled arrhythmia, myocardial infarction, or unstable angina within 6 months before screening.
• Any of the following local laboratory abnormalities:
  • Absolute neutrophil count \<500/microliter (μL) (0.5×109/ liter (L)).
  • Platelet count \<50,000/μL (50×109/L) or \>1,000,000/μL (1000×109/L).
  • Blasts \>5% as assessed in peripheral blood at screening or ≥10% in any historical bone marrow assessments. Participants with isolated transient elevations of peripheral blood blasts may be eligible after discussion between the investigator and medical monitor to confirm the blast count is not indicative of disease progression.
  • Serum aspartate aminotransferase or alanine aminotransferase ≥3× the upper limit of normal (ULN).
  • Total bilirubin ≥2×ULN. Participants with known history of Gilbert syndrome with unconjugated bilirubin less than (\<) 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 milliliters per minute per 1.73 square meters (mL/min/1.73 m\^2) as determined by the Chronic Kidney Disease Epidemiology 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).
• 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 treatment period until at least 60 days after the last dose of elritercept or placebo.

Age

• Prior history of malignancies, other than MF. Participants who are free of other malignant disease for ≥2 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; and/or
  • Incidental histologic finding of prostate cancer (T1a or T1b using the Tumour, Node, and Metastasis (TNM) staging system);
  • Early papillary thyroid cancer (stage I \[T1-T2, N0, M0\]).

Other

• Life expectancy \<12 months per investigator's judgment.
• Body mass index ≥40 kilograms per square meter (kg/m\^2).
• 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 person of childbearing potential 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 elritercept or placebo.
• 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 treatment period until at least 60 days after the last dose of elritercept or placebo.
• For participants in France: Persons under court protection, persons not affiliated with a social security system, and protected adults.

• Aged ≥18 years at the time of signing the informed consent form (ICF).
• Able to understand the purpose and risks of the trial and voluntarily sign an ICF.
• Diagnosed with primary myelofibrosis (PMF), post-essential thrombocythemia (post-ET MF) or post-polycythemia vera (post-PV MF) according to the 2022 WHO criteria (WHO Classification of Tumours Editorial Board 2024), confirmed by local pathology report.
• Transfusion status as assessed in the 12 weeks immediately preceding randomization classified as Transfusion Dependent: 3 to 8 RBC units over 12 weeks.
• Receiving ruxolitinib (as approved in the country of the trial site) as the standard of care treatment for MF for at least 12 consecutive weeks, and on a stable daily dose for at least the 8 weeks immediately preceding the date of randomization.
• Eastern Cooperative Oncology Group score less than or equal to (≤) 2.