A Study of Elritercept Alone or Together With Ruxolitinib in Adults With Myelofibrosis

Inclusion Criteria:

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

2. In the opinion of the Investigator, the participant is able and willing to complywith the requirements of the protocol (e.g., all study procedures, return forfollow-up visits).

3. Male or female greater than equal to (≥)18 years of age, at the time of signinginformed 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-polycythemiavera myelofibrosis (PV MF), or post-essential thrombocythemia myelofibrosis (ET MF)according to the 2008 International Working Group-Myeloproliferative NeoplasmsResearch and Treatment (IWG-MRT) criteria.

7. Anemia, defined as:

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

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

• All pre-transfusion Hgb values (defined as a Hgb assessed within the 3days prior to a transfusion) should be recorded, and ≥1 pre-transfusionHgb value is required.
• Hgb values collected within the 28 days following a transfusion will notbe considered evaluable unless qualifying as a pre-transfusion Hgb; incases where multiple transfusions are given in succession due to poor Hgbresponse, only the first pre-transfusion Hgb will be considered evaluable.

8. Arm-specific criteria: Arms 1A and 2A:

9. 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 DynamicInternational Prognostic Scoring System (DIPSS) and is ineligible for JAKinhibitor(s) in the opinion of the Investigator

2. Participants previously treated with JAK inhibitor(s) must have discontinuedJAK inhibitor therapy ≥8 weeks before C1D1 Arms 1B and 2B:

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

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

• Current ruxolitinib treatment is considered to be providing insufficientcontrol of the disease
• The participant's cytopenias are limiting the participant's ruxolitinibdose 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 therapyas determined by the Investigator

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

3. Myelofibrosis Symptom Assessment Form Total Symptom Score (MF-SAF-TSS) meetingat 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 highlyeffective methods of contraception as described in the protocol.

Exclusion Criteria:

Medical History:

1. Active infection requiring parenteral antibiotic therapy within 28 days prior toC1D1 or oral antibiotics within 14 days of C1D1. Prophylactic antibiotics and/orantifungals for neutropenia are allowed.

2. Presence of the following cardiac conditions:

3. New York Heart Association Class 3 or 4 heart failure

4. QTcF (QT interval corrected by Fridericia's formula) >500 milliseconds (msec)on the screening or C1D1 electrocardiogram (ECG; mean of 3 measurements)

5. Uncontrolled clinically significant arrhythmia (participants withrate-controlled atrial fibrillation are not excluded)

6. Acute myocardial infarction or unstable angina pectoris ≤6 months prior to C1D1

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

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

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

10. History of stroke, deep venous thrombosis, or arterial embolism within 6 monthsprior to C1D1.

11. Major surgery within 28 days prior to C1D1. Participants must have completelyrecovered from any previous surgery prior to C1D1 in the opinion of theInvestigator.

12. Known positive for human immunodeficiency virus (HIV), active infectious hepatitis Bwith positive viral load (hepatitis B virus [HBV] deoxyribonucleic acid [DNA]), oractive 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 localguidelines.

13. Any malignancy other than PMF, post-ET MF, or post-PV MF that has not been inremission 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 unclearsignificance are allowed at the discretion of the Investigator.

14. History of solid organ or hematological transplantation.

15. History of severe allergic or anaphylactic reaction(s) or hypersensitivity torecombinant proteins or excipients in the investigational drug, or ruxolitinib forparticipants enrolling in Arm 1B or 2B.

16. Diagnosis of hemolytic anemia, active bleeding, hemoglobinopathies, or congenitaldisorders as a cause of the participant's anemia.

17. History of intracranial hemorrhage (any grade).

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

19. Receipt of an RBC or platelet transfusion for any reason(s) or combination ofreasons other than underlying MF within the 12 weeks prior to C1D1. If a participantrequires a transfusion for an unanticipated reason during the Pretreatment Period, aprolonged screening period may be considered after discussion with the MedicalMonitor. Treatment History:

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

21. Treatment within 28 days prior to C1D1 with:

22. Erythropoiesis-stimulating agent (ESA)

23. Granulocyte colony-stimulating factor (G-CSF)

24. Granulocyte-macrophage colony-stimulating factor (GM-CSF)

25. Thrombopoietin (TPO) agonists

26. Immunomodulator imide drugs (IMiDs) (e.g., thalidomide, pomalidomide,lenalidomide)

27. Interferon

28. Hydroxyurea

29. Steroids at doses exceeding corticosteroid equivalent of 10 mg/day prednisone

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

31. Vitamin B12 and/or folate therapy initiated within 4 weeks before randomization.Participants on stable replacement doses for ≥4 weeks and without concurrent vitaminB12 or folate deficiency are allowed.

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

33. For Arms 1B and 2B (participants receiving ruxolitinib), initiation of treatmentwith strong cytochrome P450 (CYP)3A4 inhibitors within 2 weeks prior to C1D1.Participants receiving CYP3A4 inhibitors/inducers as concomitant therapy withruxolitinib in accordance with ruxolitinib local prescribing information maycontinue to receive such therapies in this study. Laboratory Exclusions (during screening):

34. Bone marrow aspirate blast percentage >5 percent (%) a. In the event of a non-evaluable pretreatment bone marrow aspirate expected to bedue to marrow fibrosis, participants may be enrolled without bone marrow aspirateblast percentage data if all other eligibility criteria are met. Historical bonemarrow data may be requested to support confirmation of diagnosis.

35. Peripheral blood blast percentage ≥10%

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

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

38. Transferrin saturation <15%

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

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

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

42. Estimated glomerular filtration rate <30 milliliters per minute per 1.73 squaremeter (mL/min/1.73 m^2) (as determined by the Chronic Kidney Disease EpidemiologyCollaboration equation)

43. Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) >3 × upper limitof normal (ULN)

44. Total bilirubin >2 × ULN

45. International normalized ratio (INR) >1.2 × ULN, unless participant is receivinganticoagulation, in which instance the INR must fall within the participant'sdesignated therapeutic range. Miscellaneous:

46. Pregnant or lactating females.

47. Any other condition not specifically noted above that, in the opinion of theInvestigator or Sponsor, would preclude the participant from participating in thestudy.

48. Participants who are investigational site staff members directly involved in theconduct of the study and their immediate family members, site staff membersotherwise supervised by the Investigator, or participants who are Keros or contractresearch organization (CRO) employees directly involved in the conduct of the study.Immediate family is defined as a spouse, parent, child, or sibling, whetherbiological or legally adopted.