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

Inclusion Criteria:

• Provision of consent

• Female patients of childbearing potential must use acceptable methods ofcontraception, 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 viaelectrophoresis]) for primary stroke prevention or due to previous stroke. Chronicred 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 secondarystroke prevention/treatment of primary stroke (initial completed overt clinicalstroke with documented infarction on brain computed tomography [CT] or magneticresonance imaging [MRI])

• Prior to screening OR at least 12 months of chronic RBC transfusions for primarystroke prevention (abnormal TCD) prior to screening

• Documented adequate monthly transfusions with average HbS ≤ 45% (the upper limit ofthe established academic community standard) for the previous 12 weeks of red bloodcell 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 24weeks 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

Exclusion Criteria:

• Female who is breast feeding or pregnant

• Hepatic dysfunction characterized by:

• Alanine aminotransferase (ALT) > 4.0 × upper limit of normal (ULN)

• Direct bilirubin > 3.0 × ULN

• History of cirrhosis

• Known human immunodeficiency virus (HIV) positivity

• Active hepatitis B or hepatitis C infection

• Severe renal dysfunction or on chronic dialysis

• History of malignancy within the past 2 years prior to treatment Day 1 requiringsystemic 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)

• History of unstable or deteriorating cardiac or pulmonary disease within 6 monthsprior to consent including but not limited to the following:

• Unstable angina pectoris or myocardial infarction or elective coronaryintervention

• Congestive heart failure requiring hospitalization

• Uncontrolled clinically significant arrhythmias

• Symptomatic pulmonary hypertension