Inclusion Criteria: Participants must satisfy the following criteria to be enrolled into the study: 1. Participant must be 6 years to < 18 years of age at the time of signing the informed consent form (ICF)/informed assent form (IAF). 2. Participant (and when applicable, parent/legal representative) must understand and voluntarily sign an ICF/IAF prior to conducting any study-related assessments/procedures. 3. Participant (and when applicable, parent/legal representative) is willing and able to adhere to the study visit schedule and other protocol requirements. 4. Participant must have documented diagnosis of β-thalassemia or Hemoglobin E/β-thalassemia. 5. Transfusion dependence: a. TD participant i. Participant is regularly transfused, defined as: ≥ 4 RBC transfusion events in the 24 weeks prior to enrollment with no transfusion-free period ≥ 42 days during that period. Note: For the purpose of the study, transfusions administered over 2 or 3 consecutive days are considered as part of a single transfusion event. Participant must have a history of regular transfusions for at least 2 years. b. NTD participant (ex-US sites only) i. Participant must have received < 4 RBC transfusion events in the 24 weeks prior to enrollment. ii. Participant must not be on a regular transfusion program and must be RBC transfusion-free for at least 8 weeks prior to enrollment. iii. Participant must have mean baseline hemoglobin ≤ 10 g/dL, based on a minimum of 2 measurements ≥ 1 week apart within 4 weeks prior to enrollment; hemoglobin values within 21 days post-transfusion will be excluded. 6. Participant has Karnofsky (age ≥16 years) or Lansky (age < 16 years) performance status score ≥ 50 at screening. 7. Female children of childbearing potential (FCCBP), females of childbearing potential (FCBP), and male participants that have reached puberty (and when applicable, parent/legal representative) must agree to undergo physician-approved reproductive education and discuss the side effects of the study therapy on reproduction. 8. Female children of childbearing potential, defined as females who have achieved menarche and/or breast development in Tanner Stage 2 or greater and have not undergone a hysterectomy or bilateral oophorectomy and females of childbearing potential (FCBP)defined as a sexually mature woman who has achieved menarche at some point, has not undergone a hysterectomy or bilateral oophorectomy and has not been naturally postmenopausal for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months) must meet the following conditions below (Note: Secondary amenorrhea from any cause does not rule out childbearing potential): - Medically supervised serum pregnancy tests with a sensitivity of at least 25 mIU/mL must be conducted in Female children of childbearing potential (FCCBP)/ females of childbearing potential (FCBP), including those who commit to complete abstinence. Female children of childbearing potential/ females of childbearing potential (FCBP) must have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy (one of these tests should be performed by central laboratory). Female children of childbearing potential/ females of childbearing potential (FCBP)must agree to ongoing pregnancy testing during the course of the study at the End of Treatment (EOT) visit and at the 9-week Safety Follow-up visit. - Female participants must, as appropriate to age and at the discretion of the site Investigator, either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis) or agree to use, and be able to comply with, effective** contraception without interruption, 28 days prior to starting IP, during the study therapy (including dose interruptions), and for 12 weeks (approximately 5 times the mean terminal t1/2 of luspatercept based on multiple-dose PK data) after discontinuation of study therapy. 9. Male participants, as appropriate to age and the discretion of the study physician: - Must practice true abstinence* (which must be reviewed on a monthly basis) or agree to use a synthetic or latex condom during sexual contact with a pregnant female or a Female children of childbearing potential (FCCBP)/FCBP while participating in the study, during dose interruptions and for at least 12 weeks (approximately 5 times the mean terminal t1/2 of luspatercept based on multiple-dose PK data) following IP discontinuation, even if he has undergone a successful vasectomy - True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the participant. [Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.] ** Agreement to use highly effective methods of contraception that alone or in combination result in a failure rate of a Pearl index of less than 1% per year when used consistently and correctly throughout the course of the study. Such methods include: Combined (estrogen and progesterone/progestin containing) hormonal contraception: Oral; Intravaginal; Transdermal; Progestogen/progestin only hormonal contraception associated with inhibition of ovulation: Oral; Injectable hormonal contraception; Implantable hormonal contraception; Placement of an intrauterine device (IUD); Placement of an intrauterine hormone-releasing system (IUS); Bilateral tubal occlusion; Vasectomized partner; Sexual Abstinence. Exclusion Criteria: The presence of any of the following will exclude a participant from enrollment into the study: 1. Participant has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the participant from participating in the study. 2. Participant has any condition including the presence of laboratory abnormalities, which places the participant at unacceptable risk if he/she were to participate in the study. 3. Participant has any condition that confounds the ability to interpret data from the study. 4. Participant has a diagnosis of Hemoglobin S/β-thalassemia or alpha (α)-thalassemia (eg, Hemoglobin H); β-thalassemia combined with α-thalassemia is allowed. 5. Participant has of active hepatitis C (HCV) infection, as demonstrated by a positive HCF-ribonucleic acid (RNS) test of sufficient sensitivity, or active infectious hepatitis B (as demonstrated by the presence of hepatitis B surface antigen (HBsAG) and/or hepatitis B virus (HBV)-deoxyribonucleic acid (DNA) positive, or known positive human immunodeficiency virus (HIV). Note: Participants receiving antiviral therapies should have 2 negative HCV-RNA tests 3 months apart before ICF/IAF signature, ie, one test at the end of the antiviral therapy and the second test 3 months following the first test. 6. Participant has severe infection ≤ 28 days prior to enrollment. Additionally, in the case of prior SARS-CoV-2 infection, symptoms must have completely resolved, and based on Investigator assessment in consultation with the Clinical Trial Physician, there are no sequelae that would place the participant at a higher risk of receiving investigational treatment. 7. Participant has received a live COVID-19 vaccine ≤ 28 days prior to screening. 8. Participant has deep vein thrombosis (DVT), stroke, or other thromboembolic event(s) (except clogged indwelling catheter) requiring medical intervention ≤ 24 weeks prior to enrollment. 9. Participant has chronic anticoagulant therapy ≤ 28 days prior to enrollment (Anticoagulant therapies used for prophylaxis for surgery or high-risk procedures as well as low molecular weight [LMW] heparin for superficial vein thrombosis [SVT] and chronic aspirin are allowed). 10. Participant has platelet count > 1000 x 109/L. 11. Participant has poorly controlled diabetes mellitus within 24 weeks prior to enrollment as defined by short term (eg, hyperosmolar or ketoacidotic crisis) and/or history of diabetic cardiovascular complications (eg, stroke or myocardial infarction). 12. Participant has treatment with another investigational drug or device ≤ 28 days prior to enrollment. 13. Participant has prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536). 14. Participant underwent or is scheduled for HSCT or gene therapy 15. Participant has used an erythropoiesis-stimulating agent (ESA) ≤ 24 weeks prior to enrollment. 16. Participant use of iron chelation therapy (ICT), if initiated ≤ 8 weeks prior to enrollment (allowed if initiated > 8 weeks before or during treatment). 17. Participant use of hydroxyurea treatment ≤ 24 weeks prior to enrollment. 18. Participant is pregnant or breastfeeding female. 19. Participant has uncontrolled hypertension. Controlled hypertension for this protocol is considered ≤ Grade 1 according to NCI CTCAE version 5.0. 20. Participant has major organ damage, including: 1. Symptomatic splenomegaly 2. Liver disease with alanine aminotransferase (ALT)/aspartate aminotransferase (AST) > 3X the upper limit of normal (ULN) for age 3. Heart disease, heart failure as classified by the New York Heart Association (NYHA) classification 3 or higher, or significant arrhythmia requiring treatment, or recent myocardial infarction within 6 months of enrollment 4. Lung disease, including pulmonary fibrosis or pulmonary hypertension which are clinically significant 5. Renal insufficiency defined as: - A serum creatinine based on age/gender based on threshold derived from Schwartz formula for estimating GFR utilizing child length and stature data published by the Centers for Disease Control 21. Participant has proteinuria ≥ Grade 3 according to NCI CTCAE version 5.0 (which is equivalent to a urine protein/creatinine ratio > 215 mg/mmol of creatinine), or a urine albumin/creatinine ratio > 129 mg/mmol of creatinine. 22. Participant use of chronic systemic glucocorticoids ≤ 12 weeks prior to enrollment (physiologic replacement therapy for adrenal insufficiency is allowed). Single day glucocorticoid treatment (eg, for prevention or treatment of transfusion reactions) is allowed. 23. Participant has major surgery ≤ 12 weeks prior to enrollment (participants must have completely recovered from any previous surgery prior to enrollment). 24. Participant has history of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the IP (refer to the IB). 25. Participant use of cytotoxic agents, immunosuppressants ≤ 28 days prior to enrollment (ie, antithymocite globulin (ATG) or cyclosporine). 26. Participant has history of malignancy with the exception of: 1. Curatively resected nonmelanoma skin cancer. 2. Curatively treated cervical carcinoma in situ. 3. Other solid tumor with no known active disease in the opinion of the Investigator. 27. Participant who has EMH complications or requires treatment to control the growth of EMH masse(s) during the screening period.