A Phase 2 Open-label Study to Evaluate the Activity of Etavopivat on Transcranial Doppler Velocities in Pediatric Patients With Sickle Cell Disease Who Are at Increased Risk for Primary Stroke

Inclusion Criteria:

1. Patient's parent, legal guardian, or legal representative has provided documentedinformed consent and patients have provided age-appropriate assent Age:

2. 12 to 16 years of age (inclusive) at time of screening Type of Participant and Disease Characteristics:

3. Confirmed diagnosis of SCD

• Documentation of any SCD genotype (e.g. HbSS, HbSβ0 -thalassemia) based on priorhistory of laboratory testing. Molecular genotyping is not required. SCD genotypemay be determined from the results of Hb electrophoresis, high-performance liquidchromatography, or similar testing.

4. TAMMV greater than or equal to (≥) 170 cm/s in the ICA and/or MCA during theScreening Period and confirmed on 2 occasions and without history of primaryischemic or hemorrhagic stroke, transient ischemic attack, or severe central nervoussystem (CNS) vasculopathy on magnetic resonance angiography (MRA). This includespatients with cTCD (170-199 centimeter per second [cm/s]) or aTCD (≥ 200 cm/s).Patients with aTCD cohort must have refused transfusion therapy.

5. Hb ≥ 6 grams per deciliter (g/dL) and lesser than or equal to (≤) 9 g/dL atscreening

6. For participants with aTCD and cTCD and already taking HU, the dose of HU milligramper kilogram (mg/kg) must be stable (no more than a 20% change in dosing except forweight-based changes) for at least 90 days prior to start of study treatment with noanticipated need for dose adjustments except for weight-based changes during thestudy, in the opinion of the Investigator. Sex and Contraceptive Requirements

7. Patients, who if female and of childbearing potential, are using acceptable methodsof contraception and agree not to donate ova from study start to 90 days after thelast dose of study drug, and who if male, are willing to use acceptable methods ofcontraception and agree not to donate sperm, from study start to 90 days after thelast dose of study drug

Exclusion Criteria:

Medical Conditions

1. Female who is breast feeding or pregnant

2. History of seizure disorder

3. Prior overt stroke (a focal neurological deficit of acute onset) by history orsignificant concerns for history of overt stroke based on Screening MRL, history oftransient ischemic attack, focal neurological deficit on standardized neurologicalexamination, or concern for moderate or severe neurological deficit (which could bedue to stroke) based on a positive "10 questions" screening. Patients withsignificant or suggestive severe CNS vasculopathy (ie, moya moya) of Grade 4 orhigher based on MRA read locally.

4. Significant cytopenias (absolute neutrophil count [ANC] < 1.5 × 10^3/microliter (µL), platelets < 150,000/µL, reticulocytes < 80,000/µL)

5. Severe renal dysfunction (estimated glomerular filtration rate at the Screeningvisit; calculated by the local laboratory < 30 mL/min/1.73 m^2) or on chronicdialysis

6. Hepatic dysfunction characterized by alanine aminotransferase (ALT) > 4 × upperlimit of normal (ULN) and/or direct bilirubin > 3 × ULN

7. Patients with clinically significant bacterial, fungal, parasitic, or viralinfection requiring systemic therapy or history of such infections leading tosignificant neurological impairment:

• Patients with acute bacterial, fungal, parasitic, or viral infection requiringsystemic therapy should delay screening/enrollment until active therapy hasbeen completed.

• Patients with acute viral infections (eg, coronavirus disease 2019 [COVID-19])should delay screening/enrollment until the acute infection has resolved.

• Patients enrolled in areas where malaria is prevalent must be on malariaprophylaxis based on regional guidance and resistance results. Note: Infectionprophylaxis is allowed (see concomitant medication restrictions).

8. Known human immunodeficiency virus (HIV) positivity

9. Known infection with hepatitis B virus (hepatitis B surface antigen [HepBsAg] andhepatitis B core antibody [HepBcAb] positive.