A Study of Etavopivat in Patients With Thalassemia or Sickle Cell Disease

Prior treatment

• History of unstable or deteriorating cardiac or pulmonary disease within 6 months prior to consent including but not limited to the following:
  • Unstable angina pectoris or myocardial infarction or elective coronary intervention
  • Congestive heart failure requiring hospitalization
  • Uncontrolled clinically significant arrhythmias
  • Symptomatic pulmonary hypertension

Other illness

• Known human immunodeficiency virus (HIV) positivity
• Active hepatitis B or hepatitis C infection
• History of malignancy within the past 2 years prior to treatment Day 1 requiring systemic chemotherapy and/or radiation.
  • Patients with malignancy considered surgically cured are eligible (eg, non- melanoma skin cancer, cancer of the cervix in-situ, ductal carcinoma in situ \[Stage 1\], Grade 1 endometrial cancer)

Lab values

• Hepatic dysfunction characterized by:
  • Alanine aminotransferase (ALT) \> 4.0 × upper limit of normal (ULN)
  • Direct bilirubin \> 3.0 × ULN
  • History of cirrhosis

Other

• Female who is breast feeding or pregnant
• Severe renal dysfunction or on chronic dialysis

• Provision of consent
• Female patients of childbearing potential must use acceptable methods of contraception, male patients are willing to use barrier methods of contraception
  • Cohort A (Sickle Cell Disease Transfusion Cohort)
• Confirmed diagnosis of sickle cell disease
• Chronically red blood cell transfused (sample or exchange \[manual or via electrophoresis\]) for primary stroke prevention or due to previous stroke. Chronic red blood cell transfusion is defined as: ≥ 6 red blood cell units in the previous 24 weeks before the first dose of study treatment and no transfusion-free period for \> 35 days during that period
• At least 24 months of chronic monthly red blood cell transfusions for secondary stroke prevention/treatment of primary stroke (initial completed overt clinical stroke with documented infarction on brain computed tomography \[CT\] or magnetic resonance imaging \[MRI\])
• Prior to screening OR at least 12 months of chronic RBC transfusions for primary stroke prevention (abnormal TCD) prior to screening
• Documented adequate monthly transfusions with average HbS ≤ 45% (the upper limit of the established academic community standard) for the previous 12 weeks of red blood cell transfusions before the first dose of study treatment
  • Cohort B (Thalassemia Transfusion Cohort)
• Documented diagnosis of β-thalassemia, Hemoglobin E/ β-thalassemia or Hemoglobin H (α-thalassemia), or other thalassemia variant
• Chronically transfused, defined as: ≥ 6 red blood cell units in the previous 24 weeks before the first dose of study treatment and no transfusion-free period for \> 35 days during that period
  • Cohort C (Thalassemia Non-transfused Cohort)
• Documented diagnosis of β-thalassemia, Hemoglobin E/ β-thalassemia or Hemoglobin H (α-thalassemia), or other thalassemia variant
• Hemoglobin ≤ 10 g/dL