Evaluation of Safety and Efficacy of CTX001 in Pediatric Participants With Severe Sickle Cell Disease (SCD)

Study Overview
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Brief Summary
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This is a single-dose, open-label study in pediatric participants with severe SCD and hydroxyurea (HU) failure or intolerance. The study will evaluate the safety and efficacy of autologous CRISPR-Cas9 modified CD34+ human hematopoietic stem and progenitor cells (hHSPCs) (CTX001).

Official Title
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A Phase 3 Study to Evaluate the Safety and Efficacy of a Single Dose of CTX001 in Pediatric Subjects With Severe Sickle Cell Disease

Conditions
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Sickle Cell Disease, Hydroxyurea Failure, Hydroxyurea Intolerance, Hemoglobinopathies, Hematological Diseases

Intervention / Treatment
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* Biological: CTX001


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of severe SCD as defined by: Documented SCD genotypes History of at least two severe VOCs events per year for the previous two years prior to enrollment Hydroxyurea (HU) failure unless HU intolerant Eligible for autologous stem cell transplant as per investigators judgment Key Exclusion Criteria: A willing and healthy 10/10 human leukocyte antigen (HLA)-matched related donor Prior hematopoietic stem cell transplant (HSCT). Clinically significant and active bacterial, viral, fungal, or parasitic infection Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 11 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CTX001<br>CTX001 (autologous CD34+ hHSPCs modified with CRISPR-Cas9 at the erythroid lineage-specific enhancer of the BCL11A gene). Participants will receive single infusion of CTX001 through central venous catheter. | Biological: CTX001<br>* Administered by intravenous infusion following myeloablative conditioning with busulfan.<br>* Other names: Exa-cel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants who do not Have any Severe Vaso-occlusive Crises (VOCs) for at Least 12 Consecutive Months (VF12) |  | Up to 24 Months After CTX001 Infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | From Signing of Informed Consent up to 24 Months After CTX001 Infusion | 
| Proportion of Participants With Engraftment (First day of 3 Consecutive Measurements of Absolute Neutrophil Count [ANC] ≥500 per Microliter [mcgL] on 3 Different Days) |  | Within 42 Days After CTX001 Infusion | 
| Time to Engraftment |  | Up to 24 Months After CTX001 Infusion | 
| Incidence of Transplant-related Mortality (TRM) Within 100 Days After CTX001 Infusion |  | Within 100 Days After CTX001 infusion | 
| Incidence of TRM Within 12 Months After CTX001 Infusion |  | Within 12 Months After Infusion | 
| Incidence of All-cause Mortality |  | From Signing of Informed Consent up to 24 Months After CTX001 Infusion | 
| Proportion of Participants Free from Inpatient Hospitalization for Severe VOCs for at Least 12 Months (HF12) |  | Up to 24 Months After CTX001 Infusion | 
| Relative Reduction in Annualized Rate of Severe VOCs |  | From Baseline up to 24 Months After CTX001 Infusion | 
| Duration of Severe VOC Free in Participants who Have Achieved VF12 |  | Up to 24 Months After CTX001 Infusion | 
| Relative Reduction in Annualized Rate of Inpatient Hospitalizations for Severe VOCs |  | From Baseline up to 24 Months After CTX001 Infusion | 
| Relative Reduction in Annualized Duration of Hospitalization for Severe VOCs |  | From Baseline up to 24 Months After CTX001 Infusion | 
| Proportion of Participants With Sustained Fetal Hemoglobin (HbF) ≥20 Percent (%) for at Least 3 Months |  | Up to 24 Months After CTX001 Infusion | 
| Proportion of Participants With Sustained HbF ≥20% for at Least 6 Months |  | Up to 24 Months After CTX001 Infusion | 
| Proportion of Participants With Sustained HbF ≥20% for at Least 12 Months |  | Up to 24 Months After CTX001 Infusion | 
| Proportion of Participants With Sustained HbF ≥30% for at Least 3 Months |  | Up to 24 Months After CTX001 Infusion | 
| Proportion of Participants With Sustained HbF ≥30% for at Least 6 Months |  | Up to 24 Months After CTX001 Infusion | 
| Proportion of Participants With Sustained HbF ≥30% for at Least 12 Months |  | Up to 24 Months After CTX001 Infusion | 
| Time for Participants to Reach HbF ≥20% |  | Up to 24 Months After CTX001 Infusion | 
| Time for Participants to Reach HbF ≥30% |  | Up to 24 Months After CTX001 Infusion | 
| Relative Reduction from Baseline in Annualized Volume of RBC Transfusions |  | Up to 24 Months After CTX001 Infusion | 
| HbF Concentrations Over Time |  | Up to 24 Months After CTX001 Infusion | 
| Hemoglobin (Hb) Concentrations Over Time |  | Up to 24 Months After CTX001 Infusion | 
| Change in Reticulocyte Count Over Time |  | From Baseline up to 24 Months After CTX001 Infusion | 
| Change in Indirect Bilirubin Over Time |  | From Baseline up to 24 Months After CTX001 Infusion | 
| Change in Haptoglobin Over Time |  | From Baseline up to 24 Months After CTX001 Infusion | 
| Time to First Detectable Haptoglobin |  | Up to 24 Months After CTX001 Infusion | 
| Change in Lactate Dehydrogenase (LDH) Over Time |  | From Baseline (Pre-infusion) up to 24 Months After CTX001 Infusion | 
| Time to First Normalized LDH (Defined as Within Normal Limits per Local Laboratory) |  | Up to 24 Months After CTX001 Infusion | 
| Proportion of Alleles With Intended Genetic Modification Present in Peripheral Blood Over Time |  | Up to 24 Months After CTX001 Infusion | 
| Proportion of Alleles With Intended Genetic Modification Present in CD34+ Cells of the Bone Marrow Over Time |  | Up to 24 Months After CTX001 Infusion |