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

A Phase 2, Open-Label, Ascending Dose Study to Evaluate the Effects of ACE-536 in Patients With β-Thalassemia

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.

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)