The main aim of this study is to learn how safe elritercept is and how well it is tolerated when taken alone and in combination with the JAK inhibitor, ruxolitinib. Other aims are to learn about the effects of elritercept on the signs and symptoms of MF when taken with or without ruxolitinib and to learn how elritercept affects the body, how the body processes elritercept, and the effects of elritercept on anemia when taken with or without ruxolitinib The study will also check on how safe elritercept is and how well it is tolerated.

Elritercept is an investigational therapeutic protein designed to increase red blood cell and platelet production by inhibiting the signaling of a subset of the transforming growth factor beta (TGF-ß) family of proteins to promote hematopoiesis. It is being developed for the treatment of low blood cell counts, or cytopenias including anemia and thrombocytopenia in participants with Myelodysplastic Syndrome (MDS) and Myelofibrosis (MF).

Inclusion Criteria:

1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information in accordance with national and local study participant privacy regulations.

2. 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).

3. Male or female greater than equal to (≥)18 years of age, at the time of signing informed consent.

4. Eastern Cooperative Oncology Group (ECOG) performance score lesser than equal to (≤)2.

5. Life expectancy ≥12 months per Investigator assessment.

6. Confirmed diagnosis of primary myelofibrosis (PMF) (prefibrotic or overtly fibrotic) according to the 2016 World Health Organization (WHO) criteria, post-polycythemia vera myelofibrosis (PV MF), or post-essential thrombocythemia myelofibrosis (ET MF) according to the 2008 International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria.

7. Anemia, defined as:

   1. Having received ≥6 units of RBC transfusion for Hgb ≤8.5 g/dL in the 12 weeks prior to the planned C1D1, including ≥1 unit of RBC transfusion in the 28 days prior to C1D1; or

   2. Having ≥3 evaluable Hgb measurements at less than (<)10.0 g/dL including ≥1 evaluable Hgb measurement assessed 8 to 13 weeks prior to C1D1. Participants receiving RBC transfusions but not meeting criterion "a." may enroll under criterion "b." following the below parameters:

      • All pre-transfusion Hgb values (defined as a Hgb assessed within the 3 days prior to a transfusion) should be recorded, and ≥1 pre-transfusion Hgb value is required.
      • Hgb values collected within the 28 days following a transfusion will not be considered evaluable unless qualifying as a pre-transfusion Hgb; in cases where multiple transfusions are given in succession due to poor Hgb response, only the first pre-transfusion Hgb will be considered evaluable.

8. Arm-specific criteria:

   Arms 1A and 2A:

   1. Previously treated with JAK inhibitor(s) and, per the Investigator, discontinued due to one of the following reasons:

      • Relapsed disease following treatment with JAK inhibitor(s)
      • Refractory to treatment with JAK inhibitor(s)
      • Intolerance to treatment with JAK inhibitor(s)
      • Participant no longer met risk/benefit ratio to continue JAK inhibitor(s) OR
      • Participant with prognostic score of intermediate-1 or higher per Dynamic International Prognostic Scoring System (DIPSS) and is ineligible for JAK inhibitor(s) in the opinion of the Investigator

   2. Participants previously treated with JAK inhibitor(s) must have discontinued JAK inhibitor therapy ≥8 weeks before C1D1

   Arms 1B and 2B:

   1. Has been receiving ruxolitinib prescribed for a diagnosis of PMF (prefibrotic or overtly fibrotic), post-PV MF, or post-ET MF for ≥8 weeks prior to C1D1 and on a stable dose for ≥4 weeks prior to C1D1. In Arm 2B only, at least 10 participants should have been on ruxolitinib for <6 months prior to C1D1.

   2. Meets ≥1 of the following criteria in the opinion of the Investigator:

      • Current ruxolitinib treatment is considered to be providing insufficient control of the disease
      • The participant's cytopenias are limiting the participant's ruxolitinib dose intensity
      • The participant's disease is symptomatic and warrants additional therapy

   Arm 2C (Brazil only):

   1. No prior treatment with JAK inhibitor(s) and no access to JAK inhibitor therapy as determined by the Investigator

   2. Spleen volume ≥ 450 cubic centimeter (cm^3) as assessed by CT or MRI collected during the pretreatment period and/or

   3. Myelofibrosis Symptom Assessment Form Total Symptom Score (MF-SAF-TSS) meeting at least one of the following criteria during the pretreatment period:

      • 2 symptoms with average score ≥ 3
      • Average total symptom score ≥ 10

9. Females of childbearing potential and sexually active males must agree to use highly effective methods of contraception as described in the protocol.

Exclusion Criteria:

Medical History:

1. Active infection requiring parenteral antibiotic therapy within 28 days prior to C1D1 or oral antibiotics within 14 days of C1D1. Prophylactic antibiotics and/or antifungals for neutropenia are allowed.

2. Presence of the following cardiac conditions:

   1. New York Heart Association Class 3 or 4 heart failure
   2. QTcF (QT interval corrected by Fridericia's formula) >500 milliseconds (msec) on the screening or C1D1 electrocardiogram (ECG; mean of 3 measurements)
   3. Uncontrolled clinically significant arrhythmia (participants with rate-controlled atrial fibrillation are not excluded)
   4. Acute myocardial infarction or unstable angina pectoris ≤6 months prior to C1D1

3. Body mass index (BMI) ≥40 kilograms per meter square (kg/m^2).

4. Presence of uncontrolled hypertension, defined as systolic blood pressure ≥160 millimeters of mercury (mmHg) or diastolic blood pressure ≥100 mmHg despite adequate treatment.

5. History of drug or alcohol abuse (as defined by the Investigator) within the past 2 years.

6. History of stroke, deep venous thrombosis, or arterial embolism within 6 months prior to C1D1.

7. Major surgery within 28 days prior to C1D1. Participants must have completely recovered from any previous surgery prior to C1D1 in the opinion of the Investigator.

8. Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B with positive viral load (hepatitis B virus [HBV] deoxyribonucleic acid [DNA]), or active infectious hepatitis C with positive viral load (hepatitis C virus [HCV] ribonucleic acid [RNA]). Participants without a known positive history of HIV, HBV, and/or HCV do not require further testing, unless testing is mandated per local guidelines.

9. Any malignancy other than PMF, post-ET MF, or post-PV MF that has not been in remission and/or has required systemic therapy including radiation, chemotherapy, hormonal therapy, or biologic therapy, within 1 year prior to C1D1. In situ cancers, squamous cell and basal cell carcinomas, and monoclonal gammopathy of unclear significance are allowed at the discretion of the Investigator.

10. History of solid organ or hematological transplantation.

11. History of severe allergic or anaphylactic reaction(s) or hypersensitivity to recombinant proteins or excipients in the investigational drug, or ruxolitinib for participants enrolling in Arm 1B or 2B.

12. Diagnosis of hemolytic anemia, active bleeding, hemoglobinopathies, or congenital disorders as a cause of the participant's anemia.

13. History of intracranial hemorrhage (any grade).

14. National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥2 bleeding events within the 3 months prior to C1D1.

15. Receipt of an RBC or platelet transfusion for any reason(s) or combination of reasons other than underlying MF within the 12 weeks prior to C1D1. If a participant requires a transfusion for an unanticipated reason during the Pretreatment Period, a prolonged screening period may be considered after discussion with the Medical Monitor.

    Treatment History:

16. Prior treatment with luspatercept, sotatercept, or other commercially available or investigational transforming growth factor-beta (TGF-β) inhibitors (all arms).

17. Treatment within 28 days prior to C1D1 with:

    1. Erythropoiesis-stimulating agent (ESA)
    2. Granulocyte colony-stimulating factor (G-CSF)
    3. Granulocyte-macrophage colony-stimulating factor (GM-CSF)
    4. Thrombopoietin (TPO) agonists
    5. Immunomodulator imide drugs (IMiDs) (e.g., thalidomide, pomalidomide, lenalidomide)
    6. Interferon
    7. Hydroxyurea
    8. Steroids at doses exceeding corticosteroid equivalent of 10 mg/day prednisone

18. Newly initiated iron chelation therapy within the 8 weeks prior to C1D1. Stable doses of iron chelators are allowed if prescribed per label.

19. Vitamin B12 and/or folate therapy initiated within 4 weeks before randomization. Participants on stable replacement doses for ≥4 weeks and without concurrent vitamin B12 or folate deficiency are allowed.

20. Treatment with another investigational drug or device or approved therapy for the treatment of MF or anemia in MF ≤28 days prior to C1D1, or, if the half-life of the previous product is known, within 5 times the half-life prior to C1D1, whichever is longer.

21. For Arms 1B and 2B (participants receiving ruxolitinib), initiation of treatment with strong cytochrome P450 (CYP)3A4 inhibitors within 2 weeks prior to C1D1. Participants receiving CYP3A4 inhibitors/inducers as concomitant therapy with ruxolitinib in accordance with ruxolitinib local prescribing information may continue to receive such therapies in this study.

    Laboratory Exclusions (during screening):

22. Bone marrow aspirate blast percentage >5 percent (%)

    a. In the event of a non-evaluable pretreatment bone marrow aspirate expected to be due to marrow fibrosis, participants may be enrolled without bone marrow aspirate blast percentage data if all other eligibility criteria are met. Historical bone marrow data may be requested to support confirmation of diagnosis.

23. Peripheral blood blast percentage ≥10%

24. Platelet count <25 × 10^9 per liter (10^9/)L or >450 × 10^9/L

25. Persistent Hgb <7 g/dL despite RBC transfusions

26. Transferrin saturation <15%

27. Ferritin <50 nanograms per mililiters (ng/mL)

28. Folate <4.5 nanomoles per liter (nmol/L) (<2.0 picograms per liter (pg/L))

29. Vitamin B12 <148 picomoles per liter (pmol/L) (<200 picograms per milliliter (pg/mL))

30. Estimated glomerular filtration rate <30 milliliters per minute per 1.73 square meter (mL/min/1.73 m^2) (as determined by the Chronic Kidney Disease Epidemiology Collaboration equation)

31. Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) >3 × upper limit of normal (ULN)

32. Total bilirubin >2 × ULN

33. International normalized ratio (INR) >1.2 × ULN, unless participant is receiving anticoagulation, in which instance the INR must fall within the participant's designated therapeutic range.

    Miscellaneous:

34. Pregnant or lactating females.

35. Any other condition not specifically noted above that, in the opinion of the Investigator or Sponsor, would preclude the participant from participating in the study.

36. Participants who are investigational site staff members directly involved in the conduct of the study and their immediate family members, site staff members otherwise supervised by the Investigator, or participants who are Keros or contract research organization (CRO) employees directly involved in the conduct of the study. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.