Data will not inform further development of Voxelotor

This is a Phase 3b, randomized, double-blind, placebo-controlled, multicenter study to assess the treatment effect of voxelotor on neurocognitive function as assessed by the National Institute of Health (NIH) Toolbox Cognition Module of executive abilities in pediatric participants (8 to < 18 years) with SCD.

Eligible participants will receive daily treatment with 1500 mg voxelotor or matching placebo for 12 weeks. During screening and at the end of 12 weeks participants will undergo a series of tests to measure the change in neurocognitive functions.

Inclusion Criteria:

1. Male or female participants with confirmed diagnosis of SCD (all genotypes). Documentation of SCD genotype is required and may be based on documented history of laboratory testing or confirmed by laboratory testing during Screening.
2. Aged 8 to < 18 years.
3. Screening Hb level 5.5 to 10.5 g/dL.
4. Able to answer NIH Toolbox Module questions validated and normed based on age and maternal education on tablet.
5. If participant is receiving HU they must have been on a stable dose for at least 90 days prior to signing the ICF/AF, with no dose modifications or initiation of HU planned or anticipated by the Investigator.
6. If participant is receiving erythropoiesis-stimulating agents (ESAs) they must have been on a stable dose for at least 12 weeks before enrollment with no dose modifications planned or anticipated by the Investigator.
7. Participants, who if female and of child-bearing potential, agree to use highly effective methods of contraception from study start to 30 days after the last dose of study drug and who if male, agree to use barrier methods of contraception and refrain from donating sperm from study start to 30 days after the last dose of study drug.
8. Females of child-bearing potential must have a negative pregnancy test before the administration of study drug.
9. Parental/guardian consent and participant assent (between ≥ 12 and < 18 years) per Institutional Review Board (IRB)/Independent ethics committee (IEC) policy and requirements, consistent with International Council for Harmonisation (ICH) guidelines.
10. Capable of complying with the requirements and restrictions in the protocol, and willing to participate in the study.

Exclusion Criteria:

1. Receiving chronic transfusion therapy.

2. Red blood cell (RBC) transfusion within 3 months before initiation of study drug or receives scheduled RBC transfusion therapy (also termed chronic, prophylactic, or preventive transfusion).

3. History of overt stroke including hemorrhagic stroke or transient ischemic attack (TIA) or spinal cord injury, magnetic resonance angiography (MRA)-defined vasculopathy, or magnetic resonance imaging (MRI)/transcranial doppler (TCD)-documented silent cerebral infarcts.

4. Congenital brain malformation, previously diagnosed severe developmental disability (eg, autism and/or intelligence quotient [IQ] < 60, and/or severe attention deficit hyperactivity disorder [ADHD]), or impairment that would prevent the use of a computer tablet.

5. Participant is taking or has received voxelotor (Oxbryta®) within 90 days prior to the Screening Visit.

6. Surgery within 8 weeks before Day 1 or planned elective surgery during the study.

7. Anemia due to bone marrow failure (eg, myelodysplasia).

8. Absolute reticulocyte count (ARC) < 100 × 10^9/L.

9. Screening alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 4× upper limit of normal (ULN).

10. Severe renal dysfunction (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m^2) or is on chronic dialysis.

11. Clinically significant bacterial, fungal, parasitic, or viral infection which requires therapy.

    1. Patients with acute bacterial infection requiring antibiotic use should delay screening /enrollment until the course of antibiotic therapy has been completed.
    2. Patients with known active hepatitis A, B, or C or who are known to be human immunodeficiency virus (HIV) positive.

12. Symptomatic coronavirus disease of 2019 (COVID-19) infection.

13. Females who are breast-feeding or pregnant.

14. History of hematopoietic stem cell transplant or gene therapy.

15. Participants taking concomitant medications such as sensitive cytochrome P450 (CYP)3A4 substrates with a narrow therapeutic range, or strong CYP3A4 inducers

16. Participated in another clinical trial of an investigational product (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 product (or medical device).

17. Medical, psychological, or behavioral condition that, in the opinion of the Investigator, would confound or interfere with evaluation of safety and/or efficacy of the study drug, prevent compliance with the study protocol; preclude informed consent; or, render the participant unable/unlikely to comply with the study procedures.

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical\_trials/trial\_data\_and\_results/data\_requests.

Only one participant was enrolled. Hence, data cannot be reported due to risk of re-identification of participant.

Not applicable as adverse events were not reported.

Study was terminated and only one participant was enrolled. Hence, data cannot be reported due to risk of re-identification of participant.

The study was terminated due to slow enrollment and resource reprioritization at L-GBT. Based on the low enrolment data was not reported due to risk of re-identification of participant.