The Effect of Voxelotor on Cerebral Perfusion and Oxygenation (ESR-C005)

1. Documented SCD genotype (HbSS, HbSC, HbS-β thalassemia or other sickle cell syndrome variants) which may be based on history of laboratory testing or must be confirmed by laboratory testing during screening.
2. Age 18 and above.
3. Hemoglobin (Hb) ≤10.5 g/dL.
4. For participants taking hydroxyurea (HU), the dose of HU (mg/kg) must be stable for at least 90 days prior to participation and with no anticipated need for dose adjustments.
5. Participants, who if female and of child bearing potential, are using highly effective methods of contraception from study start to 30 days after the last dose of study drug, and who if male are willing to use barrier
methods of contraception, from study start to 30 days after the last dose of study drug.
6. Participant has provided documented informed consent or assent (the informed consent form [ICF] must be reviewed and signed by each participant; the participant's legal representative or legal guardian, and the
participant's assent must be obtained).

1. No informed consent has been given.
2. Contra-indication for MRI or acetazolamide.
3. Female who is breast feeding or pregnant.
4. Patients who are receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic, or preventive transfusion) or have received a RBC transfusion for any reason within 90 days before
participation.
5. Hospitalized for sickle cell crisis or other vaso-occlusive event within 14 days prior participation.
6. Hepatic dysfunction characterized by alanine aminotransferase (ALT) >4 × ULN.
7. Participants with clinically significant bacterial, fungal, parasitic or viral infection which require therapy:
• Participants with acute bacterial infection requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed.
• Participants with known active hepatitis A, B, or C or who are known to be human immunodeficiency virus (HIV) positive.
8. Severe renal dysfunction (estimated glomerular filtration rate <30mL/min).
9. History of malignancy within the past 2 years prior to participation requiring chemotherapy and/or radiation (with the exception of local therapy for non-melanoma skin malignancy).
10. 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.
11. Any condition affecting drug absorption, such as major surgery involving the stomach or small intestine (prior cholecystectomy is acceptable).
12. Participated in another clinical trial of an investigational agent (or medical device) within 30 days or 5 half-lives of date of informed consent, whichever is longer, or is currently participating in another trial of an
investigational agent (or medical device).
13. Medical, psychological, or behavioral conditions, which, in the opinion of the investigator, may preclude safe participation, confound study interpretation, interfere with compliance, or preclude informed consent.
14. Receipt of erythropoietin or other hematopoietic growth factors within 28 days of signing ICF or anticipated need for such agents during the study.