Study of Safety & PK of Luspatercept (ACE-536) in Pediatric Participants With Beta (β)-Thalassemia

Inclusion Criteria

• Participants must be 6 years to < 18 years of age at the time of signing theinformed consent form (ICF)/informed assent form (IAF).

• Participants (and when applicable, parent/legal representative) must understand andvoluntarily sign an ICF/IAF prior to conducting any study-relatedassessments/procedures.

• Participants (and when applicable, parent/legal representative) is willing and ableto adhere to the study visit schedule and other protocol requirements.

• Participants must have documented diagnosis of β-thalassemia or HemoglobinE/β-thalassemia.

• Transfusion dependence (TD): a. TD participant i. Participant is regularly transfused, defined as: ≥ 4 RBCtransfusion events in the 24 weeks prior to enrollment with no transfusion-freeperiod ≥ 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.

• Participants have Karnofsky (age ≥16 years) or Lansky (age < 16 years) performancestatus score ≥ 50 at screening.

• Female children of childbearing potential (FCCBP), individuals of childbearingpotential (IOCBP), and male (as assigned at birth) participants that have reachedpuberty (and when applicable, parent/legal representative) must agree to undergophysician-approved reproductive education and discuss the side effects of the studytherapy on reproduction.

• Female children of childbearing potential, defined as females who have achievedmenarche and/or breast development in Tanner Stage 2 or greater and have notundergone a hysterectomy or bilateral oophorectomy and individuals of childbearingpotential (IOCBP) defined as a sexually mature woman who has achieved menarche atsome point, has not undergone a hysterectomy or bilateral oophorectomy and has notbeen naturally postmenopausal for at least 24 consecutive months (ie, has had mensesat any time in the preceding 24 consecutive months) must meet the followingconditions below (Note: Secondary amenorrhea from any cause does not rule outchildbearing potential):

• Medically supervised serum pregnancy tests with a sensitivity of at least 25mIU/mL must be conducted in Female children of childbearing potential (FCCBP)/individuals of childbearing potential (IOCBP), including those who commit tocomplete abstinence. Female children of childbearing potential/ individuals ofchildbearing potential (IOCBP) must have 2 negative pregnancy tests as verifiedby the Investigator prior to starting study therapy (one of these tests shouldbe performed by central laboratory). Female children of childbearing potential/individuals of childbearing potential (IOCBP) must agree to ongoing pregnancytesting during the course of the study at the End of Treatment (EOT) visit andat the 9-week Safety Follow-up visit.

• Female participants must, as appropriate to age and at the discretion of thesite Investigator, either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis) or agree to use, and be able tocomply with, effective** contraception without interruption, 28 days prior tostarting IP, during the study therapy (including dose interruptions), and for 12 weeks (approximately 5 times the mean terminal t1/2 of luspatercept based onmultiple-dose PK data) after discontinuation of study therapy.

• Male (as assigned at birth) participants, as appropriate to age and the discretionof the study physician:

• Must practice true abstinence* (which must be reviewed on a monthly basis) oragree to use a synthetic or latex condom during sexual contact with a pregnantfemale or a Female children of childbearing potential (FCCBP)/ IOCBP whileparticipating in the study, during dose interruptions and for at least 12 weeks (approximately 5 times the mean terminal t1/2 of luspatercept based onmultiple-dose PK data) following IP discontinuation, even if he has undergone asuccessful vasectomy.

• True abstinence is acceptable when this is in line with the preferred andusual lifestyle of the participant. [Periodic abstinence (eg, calendar,ovulation, symptothermal, post-ovulation methods) and withdrawal are notacceptable methods of contraception.] ** Agreement to use highly effectivemethods of contraception that alone or in combination result in a failurerate of a Pearl index of less than 1% per year when used consistently andcorrectly throughout the course of the study. Such methods include:Combined (estrogen and progesterone/progestin containing) hormonalcontraception: Oral; Intravaginal; Transdermal; Progestogen/progestin onlyhormonal contraception associated with inhibition of ovulation: Oral;Injectable hormonal contraception; Implantable hormonal contraception;Placement of an intrauterine device (IUD); Placement of an intrauterinehormone-releasing system (IUS); Bilateral tubal occlusion; Vasectomizedpartner; Sexual Abstinence.

Exclusion Criteria:

• Participant has a diagnosis of Hemoglobin S/β-thalassemia or alpha (α)-thalassemia (eg, Hemoglobin H); β-thalassemia combined with α-thalassemia is allowed.

• Participant has of active hepatitis C (HCV) infection, as demonstrated by a positiveHCF-ribonucleic acid (RNS) test of sufficient sensitivity, or active infectioushepatitis B (as demonstrated by the presence of hepatitis B surface antigen (HBsAG)and/or hepatitis B virus (HBV)-deoxyribonucleic acid (DNA) positive, or knownpositive 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.

• Participant has deep vein thrombosis (DVT), stroke, or other thromboembolic event(s) (except clogged indwelling catheter) requiring medical intervention ≤ 24 weeks priorto enrollment.

• Participant has platelet count > 1000 x 109/L.

• Participant has treatment with another investigational drug or device ≤ 28 daysprior to enrollment.

• Participant has prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536).

• Participant underwent or is scheduled for HSCT or gene therapy.

• Participant use of iron chelation therapy (ICT), if initiated ≤ 8 weeks prior toenrollment (allowed if initiated > 8 weeks before or during treatment).

• Participant received treatment with hydroxyurea immunomodulatory drugs IMiDs (suchas thalidomide), other fetal Hb (HbF) inducers or erythropoiesis-stimulating agents (ESAs) ≤ 12 weeks prior to enrollment for NTD participants and ≤ 24 weeks for TDparticipants.

• Participant is pregnant or breastfeeding female or plan to get pregnant during thestudy.

• Participant has uncontrolled hypertension. Controlled hypertension for this protocolis considered: blood pressure value corresponding to ≤ Grade 1 according to NCICTCAE version 5.0 with or without pharmacological treatment.

• 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 requiringtreatment, or recent myocardial infarction within 6 months of enrollment

4. Lung disease, including pulmonary fibrosis or pulmonary hypertension of Grade ≥ 3 according to NCI-CTCAE version 5.0.

5. Renal insufficiency defined as:

• A serum creatinine based on age/gender based on threshold derived from Schwartzformula for estimating GFR utilizing child length and stature data published by theCenters for Disease Control.

• Participant has proteinuria ≥ Grade 3 according to NCI CTCAE version 5.0 (which isequivalent to a urine protein/creatinine ratio > 215 mg/mmol of creatinine), or aurine albumin/creatinine ratio > 129 mg/mmol of creatinine.

• Participant use of high dose long-term therapy with systemic glucocorticoids ≤ 12weeks prior to enrollment (physiologic replacement therapy for adrenal insufficiencyis allowed). Low-dose long-term (defined as ≤ 0.2 mg/kg/day or ≤ 10 mg/day ofprednisone equivalent), short treatment (eg, for prevention or treatment oftransfusion reactions) inhaled, intranasal and topical corticosteroids are allowed.

• Participant has history of severe allergic or anaphylactic reactions orhypersensitivity to recombinant proteins or excipients in the IP (refer to the IB).

• Participant use of cytotoxic agents, immunosuppressants ≤ 28 days prior toenrollment (ie, antithymocite globulin (ATG) or cyclosporine).

• Participant has history of malignancy with the exception of:

1. Curatively resected nonmelanoma skin cancer.

2. Curatively treated carcinoma in situ.

3. Other solid tumor with no known active disease in the opinion of theInvestigator.

• Participant who has extramedullary hematopoiesis (EMH) complications or requirestreatment to control the growth of EMH masse(s) during the screening period.

• Participants with any medical or psychiatric condition that in the opinion of theinvestigator would put the participant at unacceptable risk of participating in thestudy or may impact interpretation of the study results.

• Participants who use herbs or food supplements (eg: Chinese traditional medicine),if, per investigator's judgment, likely to impact the safety and efficacyassessment, for 24 weeks before initiating the study treatment for TD participants,and 12 weeks for NTD participants.