A Study to Determine the Efficacy and Safety of Luspatercept in Adult Participants and to Evaluate the Safety and Pharmacokinetics in and Adolescent Participants With Alpha (α)-Thalassemia

Key Inclusion Criteria:

• Adult participant≥ 18 years with documented diagnosis of A-Thal HbH disease withTransfusion dependence defined as:.

1. TD participant: ≥ 6 RBC units during the 24 weeks prior to randomization.

2. NTD participant:< 6 RBC units during the 24 weeks prior torandomization(transfusion due to conditions other than A-Thal will not beconsidered)and, RBC transfusion-free during at least 8 weeks prior torandomization(unless transfusion was required to treat an acute medicalcondition other than A-Thal) and, mean baseline Hb ≤ 10 g/dL, based on aminimum of 2 measurements ≥ 1 week apart within 4 weeks prior to randomization;hemoglobin values within 21 days post-transfusion will be excluded.

• Adult participant has Eastern Cooperative Oncology Group (ECOG) 34 score of 0 or 1.

• Adolescent participant 12 years to < 18 years with documented diagnosis of A-ThalHbH disease with transfusion dependence defined as:.

1. TD participant: ≥ 4 RBC events during the 24 weeks prior to enrollment and, notransfusion-free period for > 56 days during the 24 weeks prior to enrollment.Participants must have a history of regular transfusions for at least 2 years.

2. NTD participant:< 4 RBC events during the 24 weeks prior to enrollment and RBCtransfusion-free during at least 8 weeks prior to enrollment and, mean baselineHb ≤ 10 g/dL, based on a minimum of 2 measurements ≥ 1 week apart within 4weeks prior to enrollment, hemoglobin values within 21 days post-transfusionwill be excluded.

3. Participant has Karnofsky (age ≥16 years) or Lansky (age < 16 years)performance status score ≥ 50 at screening.

Key Exclusion Criteria:

• Medical Conditions: Diagnosis of A-ThalTrait, Hb Bart hydrops, ATRx A-Thal,hemoglobin S/β-thalassemia, myelodysplasia subtype anemia, or with HbE homozygousbeta gene mutation. Anemia related to nutritional deficiency, anemia of chronicdisease, autoimmune hemolytic anemia, or any other hemolytic anemias. Undergoneepisodes of hemolysis not related to A-Thal within the 8 weeks prior torandomization.

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

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

• Reproductive Status: Women who are pregnant, plan to get pregnant during the study,or who are breastfeeding.

• Prior/Concomitant: Undergone HSCTs or gene therapy (candidates for HSCT or genetherapy with waiting period of ≥ 12 months are eligible).

• Use of hydroxyurea treatment ≤ 12 weeks prior to enrollment for NTD participants and ≤ 24 weeks for TD participants.

• Participant who has extramedullary hematopoiesis (EMH) complications requiringtreatment to control the growth of EMH mass(es) during the screening period.

• Any medical or psychiatric condition (including active infections, recent surgery,sequelae of diseases or interventions, clinically significant laboratoryabnormalities or concurrent treatment) that in the opinion of the investigator wouldput the participant at unacceptable risk of participating in the study or that couldaffect interpretability of data.

• Other protocol-defined inclusion/exclusion criteria apply.