A Study to Determine the Efficacy and Safety of Luspatercept in Adults With Non Transfusion Dependent Beta (β)-Thalassemia

Inclusion Criteria

Subjects must satisfy the following criteria to be enrolled in the study:

• Subjects must be ≥ 18 years of age at the time of signing the informed consent document (ICF).
• Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
• Subject is willing and able to adhere to the study visit schedule (eg, not scheduled to receive hematopoietic stem cell transplantation) and other protocol requirements.
• Subject must have documented diagnosis of β-thalassemia or hemoglobin E/ β-thalassemia. Concomitant alpha globin mutation and/or duplication are allowed.
• Subject must be non-transfusion dependent, defined as 0 to 5 units of RBCs received during the 24-week period prior to randomization. Note: 1 unit defined for this entry criterion as approximately 200 to 350 mL of transfused packed RBCs.
• Subject must not be on a regular transfusion program and must be RBC transfusion-free for at least ≥ 8 weeks prior to randomization
• Subject must have mean baseline hemoglobin ≤ 10 g/dL, based on a minimum of 2 measurements ≥ 1 week apart within 4 weeks prior to randomization; hemoglobin values within 21 days post-transfusion will be excluded.
• Subject must have performance status: Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 1.
• A female of childbearing potential (FCBP) for this study is defined as a female who:
• has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months). A FCBP participating in the study must:
• Have 2 negative pregnancy tests as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence* from heterosexual contact.
• Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented). If a FCBP engages in sexual activity that may result in a pregnancy, she must agree to use, and be able to comply during the study therapy (including dose interruptions), and for 12 weeks (approximately 5 times the mean terminal half-life of luspatercept based on multiple dose pharmacokinetics [PK] data) after discontinuation of study therapy.
• Male subjects must:

a. Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 12 weeks (approximately 5 times the mean terminal half-life of luspatercept based on multiple-dose PK data) following IP discontinuation, even if he has undergone a successful vasectomy

Exclusion Criteria

The presence of any of the following will exclude a subject from enrollment:

• Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
• Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
• Any condition that confounds the ability to interpret data from the study.
• Diagnosis of hemoglobin S/β-thalassemia or alpha (α)-thalassemia (eg,Hemoglobin H).
• Active hepatitis C (HCV) infection
• Deep vein thrombosis (DVT) or stroke requiring medical intervention ≤ 24 weeks prior to randomization.
• Subjects on chronic anticoagulant therapy are excluded, unless they stopped the treatment at least 28 days prior to randomization. Anticoagulant therapies for prophylaxis and for surgery or high-risk procedures as well as low