Study to Evaluate the Safety and Efficacy of Luspatercept (ACE-536) in Participants With Beta-thalassemia (A536-04/MK-6143-002)

The purpose of this study is to evaluate the efficacy, safety, and pharmacokinetics, of ascending doses of luspatercept in participants with β-thalassemia.

The primary objective of this study is to evaluate erythroid response, defined as:

1. a hemoglobin increase of ≥ 1.5 g/dL from baseline for ≥ 14 days (in the absence of red blood cell \[RBC\] transfusions) in non-transfusion dependent participants, or
2. a ≥ 20% reduction in RBC transfusion burden compared to pretreatment in transfusion dependent participants.


Eligibility Criteria:
Key Inclusion Criteria:

* Men or women ≥18 years of age
* For the dose escalation phase of the study: documented diagnosis of β-thalassemia intermedia (transfusion dependent participants must not have begun regular transfusions at age \<4.0 years). For the expansion cohort: documented diagnosis of β-thalassemia (including β-thalassemia major or β-thalassemia intermedia)
* Prior splenectomy or spleen size \<18 cm in the longest diameter by abdominal ultrasound (dose escalation cohorts only)
* Anemia, defined as: (1) mean hemoglobin concentration \<10.0 g/dL of 2 measurements (one performed within one day prior to Cycle 1 Day 1 and the other performed during the screening period \[Day -28 to Day -1\]) in non-transfusion dependent participants, defined as having received \< 4 units of RBCs within 8 weeks prior to Cycle 1 Day 1, or (2) transfusion dependent participants, defined as requiring ≥ 4 units of RBCs every 8 weeks (confirmed over 6 months prior to Cycle 1 Day 1)
* Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \<3 x upper limit of normal (ULN)
* Serum creatinine ≤1.5 x ULN
* Adequate pregnancy avoidance measures
* Participants are able to adhere to the study visit schedule, understand, and comply with all protocol requirements
* Understand and able to provide written informed consent

Key Exclusion Criteria:

* Any clinically significant pulmonary (including pulmonary hypertension), cardiovascular, endocrine, neurologic, hepatic, gastrointestinal, infectious, immunological (including clinically significant allo- or auto-immunization) or genitourinary disease considered by the investigator as not adequately controlled prior to Cycle 1 Day 1
* Folate deficiency
* Symptomatic splenomegaly
* Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B virus (HBV) or active infectious hepatitis C virus (HCV)
* Known history of thromboembolic events ≥Grade 3 according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 (current active minor version)
* Ejection fraction \<50% by echocardiogram, multi-gated acquisition scan (MUGA), or cardiac magnetic resonance imaging (MRI)
* Uncontrolled hypertension defined as systolic blood pressure (BP) ≥150 mm Hg or diastolic BP ≥95 mm Hg
* Heart failure class 3 or higher (New York Heart Association \[NYHA\])
* QTc \>450 msec on screening electrocardiogram (ECG)
* Platelet count \<100 x10\^9/L or \>1,000 x10\^9/L
* Proteinuria ≥Grade 2
* Any active infection requiring parenteral antibiotic therapy within 28 days prior to Cycle 1 Day 1 or oral antibiotics within 14 days of Cycle 1 Day 1
* Treatment with another investigational drug or device, or approved therapy for investigational use ≤28 days prior to Cycle 1 Day 1, or if the half-life of the previous investigational product is known, within 5 times the half-life prior to Cycle 1 Day 1, whichever is longer
* Transfusion event within 7 days prior to Cycle 1 Day 1
* Participants receiving or planning to receive hydroxyurea treatment. Participants must not have had hydroxyurea within 90 days of Cycle 1 Day 1
* Splenectomy within 56 days prior to Cycle 1 Day 1
* Major surgery (except splenectomy) within 28 days prior to Cycle 1 Day 1. Participants must have completely recovered from any previous surgery prior to Cycle 1 Day 1
* Iron chelation therapy initiated within 56 days prior to Cycle 1 Day 1
* Cytotoxic agents, systemic corticosteroids, immunosuppressants, or anticoagulant therapy such as warfarin or heparin within 28 days prior to Cycle 1 Day 1 (prophylactic aspirin up to 100 mg/day is permitted)
* Pregnant or lactating women
* History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational drug
* Prior treatment with sotatercept (ACE-011) or luspatercept (ACE-536)