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

Key Inclusion Criteria:

• Documented diagnosis of beta-thalassemia intermedia, with anemia requiring at least 1, but no more than 6 transfusion events in the last year, with no transfusion events for 56 days prior to Cycle 1 Day 1.
• Prior splenectomy or spleen size < 18 cm in the longest diameter by abdominal ultrasound.
• 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 7-28 days prior, not influenced by RBC transfusion within 7 days of measurement).
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN).
• Serum creatinine ≤ 1.5 x ULN.
• Females of child bearing potential (defined as sexually mature women who have not undergone hysterectomy or bilateral oophorectomy, or are not naturally postmenopausal ≥ 24 consecutive months) must have negative urine or blood pregnancy test prior to enrollment and use adequate birth control methods (abstinence, oral contraceptives, barrier method with spermicide, or surgical sterilization) during study participation. Males must agree to use a latex condom during any sexual contact with females of child-bearing potential while participating in the study and for 12 weeks following the last dose of ACE 536, even if he has undergone a successful vasectomy. Patients must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of ACE-536.

Key Exclusion Criteria:

• Any clinically significant pulmonary (including pulmonary hypertension), cardiovascular, endocrine, neurologic, hepatic, gastrointestinal, infectious or genitourinary disease considered by the investigator as not adequately controlled prior to Cycle 1 Day 1.
• Folate deficiency.
• 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, Appendix 1).
• QTc > 450 msec on screening ECG.
• Platelet count < 100 x109/L or > 1,000,000 x109/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.
• Patients receiving or planning to receive hydroxyurea treatment. Patients must not have had hydroxyurea within 56 days of Cycle 1 Day 1.
• Splenectomy with 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 if 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 or lactating females.
• History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational drug.