Study to Evaluate the Effects of ACE-536 in Patients With Beta-thalassemia

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 patients 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: (i) 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 patients, defined as having received < 4 units of RBCs within 8 weeks prior to Cycle 1 Day 1, or (ii) transfusion dependent, 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.
• Patients 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 (HBV) or active infectious hepatitis C (HCV).
• Known history of thromboembolic events ≥ grade 3 according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.4.0 (current active minor version).
• Ejection fraction < 50% by echocardiogram, MUGA or cardiac 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 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.
• Patients receiving or planning to receive hydroxyurea treatment. Patients 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. Patients 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/d is permitted).
• Pregnant of lactating females.
• History of severe allergic or anaphylactic reactions of hypersensitivity to recombinant proteins or excipients in the investigational drug.
• Prior treatment with sotatercept (ACE-011) or ACE-536.