Evaluation of Efficacy and Safety of a Single Dose of Exa-cel in Participants With Severe Sickle Cell Disease, βS/βC Genotype

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the efficacy and safety of CTX001 (exa-cel) in adolescent and adult participants with severe sickle cell disease (SCD), βS/βC genotype (HbSC).

Official Title
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A Phase 3 Study to Evaluate Efficacy and Safety of a Single Dose of Exa-cel in Subjects With Severe Sickle Cell Disease, βS/βC Genotype

Conditions
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Sickle Cell Disease

Intervention / Treatment
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* Biological: Exa-cel


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Participants with documented βS/βC (HbSC) genotype Participants must be eligible for autologous stem cell transplant as per investigator's judgment Key Exclusion Criteria: A willing and healthy 10/10 human leukocyte antigen (HLA)-matched related donor is available per investigator's judgement Participants with prior hematopoietic stem cell transplant (HSCT) Treatment with regular RBC transfusions that, in the opinion of the investigator, cannot be interrupted after engraftment. Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 35 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: Exa-cel<br>Participants will receive a single infusion of exa-cel (autologous CD34+ hHSPCs modified with CRISPR-Cas9 at the erythroid lineage-specific enhancer of the BCL11A gene) through a central venous catheter. | Biological: Exa-cel<br>* Administered by intravenous (IV) infusion following myeloablative conditioning with busulfan.<br>* Other names: CTX001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants with an Average Fetal Hemoglobin (HbF) Greater Than or Equal To (>=) 20 percent (%) on or After 6 Months |  | From 60 Days after Last Red Blood Cell (RBC) transfusion up to 24 Months after exa-cel 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 exa-cel Infusion | 
| Proportion of Participants With Neutrophil Engraftment (First day of 3 Consecutive Measurements of Absolute Neutrophil Count (ANC) >=500 per Microliter [mcgL] on 3 Different Days) |  | Within 42 Days After exa-cel Infusion | 
| Time to Neutrophil Engraftment |  | Up to 24 months After exa-cel Infusion | 
| Time to Platelet Engraftment |  | Up to 24 months After exa-cel Infusion | 
| Incidence of Transplant-Related Mortality (TRM) |  | Up to 100 Days After exa-cel Infusion | 
| Incidence of Transplant-Related Mortality (TRM) |  | Within 12 Months After exa-cel Infusion | 
| Incidence of All-cause Mortality |  | From Signing of Informed Consent up to 24 Months After exa-cel Infusion | 
| Proportion of Participants With No Severe Vaso-Occlusive Crises (VOCs) for At least 12 Months (VF12) |  | From 60 Days after Last RBC transfusion up to 24 Months After exa-cel Infusion | 
| Proportion of Participants Free from Inpatient Hospitalization For Severe VOCs Sustained for At least 12 Months (HF12) |  | From 60 Days after Last RBC transfusion up to 24 Months After exa-cel Infusion | 
| Relative Reduction in Annualized Rate of Severe VOCs |  | From Baseline up to 24 Months After exa-cel Infusion | 
| Duration of Severe VOC Free in Participants who Have Achieved VF12 |  | From 60 Days after Last RBC transfusion up to 24 Months After exa-cel Infusion | 
| Relative Reduction in Rate of Inpatient Hospitalizations for Severe VOCs |  | From Baseline up to 24 Months After exa-cel Infusion | 
| Relative Reduction in Annualized Duration of Hospitalization for Severe VOCs |  | From Baseline up to 24 Months After exa-cel Infusion | 
| Proportion of Participants With Sustained HbF >= 20 % for At least 3, 6, or 12 months |  | From 60 Days after Last RBC transfusion up to 24 Months After exa-cel Infusion | 
| Relative Reduction in Annualized Volume of RBC Transfusions |  | From Baseline Up To 24 Months After exa-cel Infusion | 
| HbF Concentration Over Time |  | Up To 24 Months After exa-cel Infusion | 
| Total Hemoglobin (Hb) Concentration Over Time |  | Up To 24 Months After exa-cel Infusion | 
| Change In Reticulocyte Count Over Time |  | From Baseline Up To 24 Months After exa-cel Infusion | 
| Change in Indirect Bilirubin Over Time |  | From Baseline Up To 24 Months After exa-cel Infusion | 
| Change in Haptoglobin Over Time |  | From Baseline Up To 24 Months After exa-cel Infusion | 
| Change in Lactate dehydrogenase (LDH) Over Time |  | From Baseline Up To 24 Months After exa-cel Infusion | 
| Time to First Detectable Haptoglobin |  | Up to 24 Months After exa-cel Infusion | 
| Time to First Normalized LDH |  | Up to 24 Months After exa-cel Infusion | 
| Proportion of Alleles With Intended Genetic Modification Present in Peripheral Blood Over Time |  | Up To 24 Months After exa-cel Infusion | 
| Proportion of Alleles With Intended Genetic Modification Present in CD34+ Cells of the Bone Marrow Over Time |  | Up To 24 Months After exa-cel Infusion | 
| Change in Pain Scale (11-point numerical rating scale (NRS)) Assessment Over Time In Adults (>=18 Years) |  | From Baseline Up To 24 Months After exa-cel Infusion | 
| Change in Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) Over Time In Adults (>=18 Years) |  | From Baseline Up To 24 Months After exa-cel Infusion | 
| Change in Adult Sickle Cell Quality of Life Measurement System (ASCQ-Me) |  | From Baseline Up To 24 Months After exa-cel Infusion | 
| Change in Pain Scale (11-point NRS) Assessment Over Time In Adolescents (12 to <18 years of age) |  | From Baseline Up To 24 Months After exa-cel Infusion | 
| Change in Pediatric Quality of Life Inventory (PedsQL; self-report and parent proxy versions) Generic Core In Adolescents (12 to <18 years of age) |  | From Baseline Up To 24 Months After exa-cel Infusion | 
| Change in PedsQL SCD module (self-report and parent proxy versions) In Adolescents (12 to <18 years of age) |  | From Baseline Up To 24 Months After exa-cel Infusion |