This study is being done to learn about etavopivat, a once a day medicine taken by mouth in adolescents with sickle cell disease. The main goals are to study safety and how long etavopivat stays in the bloodstream, while also studying if there are benefits from taking etavopivat. Eligible participants who enter the study will start a 96-week treatment period. At the end of the 96 weeks, participants will have an end of study visit that occurs 4 weeks later. The participants will receive etavopivat every day throughout the treatment period.

Inclusion Criteria:

• Type of Participant and Disease Characteristics

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

  2. Age greater than or equal to (≥) 6 months and lesser than (<) 18 years of age at time of enrollment, according to the enrolling cohort:

     • Cohort 1: age 12 to < 18 years (adolescents)
     • Cohort 2: age 6 to < 12 years
     • Cohort 3: age 2 to < 6 years
     • Cohort 4: age 6 months to < 2 years

  3. Patient has confirmed diagnosis of SCD

     • Documentation of SCD genotype (HbSS, HbSβ0-thalassemia or other sickle cell syndrome variants) based on prior history of laboratory testing. Molecular genotyping is not required. SCD genotype may be determined from the results of Hb electrophoresis, high-performance liquid chromatography (HPLC), or similar testing. Note that Hb electrophoresis is performed by the local laboratory at Screening.

  4. Hemoglobin ≥ 5.5 and lesser than or equal to (≤) 10.5 grams per deciliter (g/dL)

  5. Pediatric patients with severe SCD, as defined by at least 1 of the following:

     • 2-15 episodes of documented VOC within the 12 months prior to screening. Documentation must exist in the patient's medical record prior to screening. Events based solely on patient recall without supporting documentation should not be counted towards eligibility.
     • Hospitalization for any SCD-related complication in the last 12 months prior to starting study treatment
     • Proteinuria, defined as an albumin:creatinine ratio (ACR) > 100 mg/g on 2 measures (separated by ≥ 1 month) as an indicator of early renal disease
     • History of a conditional TCD in the last 12 months prior to starting study treatment, but not currently being treated with chronic transfusion therapy (applicable to participants > 2 years of age). Conditional TCD is defined as a TAMMV of 170-199 cm/s by TCD or 155-184 cm/s by imaging TCD (TCDi).

  6. For participants taking hydroxyurea (HU), the dose of HU (mg/kg) must be stable (no more than a 20% change in dosing) for at least 90 days prior to start of study treatment with no anticipated need for dose adjustments during the study, in the opinion of the Investigator

  7. Patients on crizanlizumab or L-glutamine treatment at the time of consent may be eligible if they:

     • Have been on a stable dose for ≥ 12 months at the time of consent (ie, no changes to the dose except for changes to weight or for safety reasons)
     • For patients on crizanlizumab, have been ≥ 80% compliant with the planned regimen during the 12 months prior to the time of consent

  8. Female patients of childbearing potential who are using acceptable methods of contraception and agree not to donate ova from study start to 90 days after the last dose of study drug, and male patients who are willing to use acceptable methods of contraception and agree not to donate sperm, from study start to 90 days after the last dose of study drug.

Exclusion Criteria:

• Medical Conditions

  1. Female who is breastfeeding or pregnant

  2. More than 15 VOCs within the 12 months prior to starting study treatment that required a hospital, emergency room (ER), or clinic visit

  3. Hospitalized for sickle cell crisis or other vaso-occlusive event occurring in the 14 days prior to starting study treatment

  4. Abnormal TCD in the 12 months prior to starting study treatment

     Prior/Concomitant Therapy

  5. Patients receiving regularly scheduled blood (RBC) transfusion therapy (also termed chronic, prophylactic, or preventive transfusion)

  6. Received any blood products within 30 days of starting study treatment

  7. Receiving or use of concomitant medications that are strong inducers of cytochrome P450 (CYP) 3A4/5 within 2 weeks of starting study treatment

  8. Use of voxelotor within 28 days prior to starting study treatment or anticipated need for this agent during the study

  9. Receipt of erythropoietin or other hematopoietic growth factor treatment within 28 days of starting study treatment or anticipated need for such agents during the study

  10. Receipt of prior cellular based therapy (eg, hematopoietic cell transplant, gene modification therapy)