Evaluation of Efficacy and Safety of a Single Dose of CTX001 in Participants With Transfusion-Dependent β-Thalassemia and Severe Sickle Cell Disease

Study Overview
=================
Brief Summary
-----------------
This is a single-dose, open-label study in participants with transfusion-dependent β-thalassemia (TDT) or severe sickle cell disease (SCD). The study will evaluate the safety and efficacy of autologous CRISPR-Cas9 modified CD34+ human hematopoietic stem and progenitor cells (hHSPCs) using CTX001.

Official Title
-----------------
A Phase 3b Study to Evaluate Efficacy and Safety of a Single Dose of Autologous CRISPR Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (CTX001) in Subjects With Transfusion-Dependent β-Thalassemia or Severe Sickle Cell Disease

Conditions
-----------------
Beta-Thalassemia, Thalassemia, Hematologic Diseases, Genetic Diseases, Inborn, Hemoglobinopathies, Sickle Cell Anemia, Sickle Cell Disease

Intervention / Treatment
-----------------
* Biological: CTX001


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Participants with TDT and SCD: Eligible for autologous stem cell transplant as per investigator's judgment. Participants with TDT: Diagnosis of TDT as defined by: Documented homozygous β-thalassemia or compound heterozygous β-thalassemia including β-thalassemia/hemoglobin E (HbE). Participants can be enrolled based on historical data, but a confirmation of the genotype using the study central laboratory will be required before busulfan conditioning History of at least 100 milliliter (mL)/kilograms (kg)/year or 10 units/year of packed red blood cells (RBC) transfusions in the prior 2 years before signing the consent or the last rescreening for patients going through re-screening Participants with SCD: 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 Key Exclusion Criteria: Participants with TDT and SCD: A willing and healthy 10/10 human leukocyte antigen (HLA)-matched related donor is available per investigator's judgement Prior hematopoietic stem cell transplant (HSCT) Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator Participants with TDT: Participants with associated α-thalassemia and >1 alpha deletion, or alpha multiplications Participants with sickle cell β-thalassemia variant Participants with SCD: History of untreated moyamoya syndrome or presence of moyamoya syndrome at screening Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 12 Years
Maximum Age: 35 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 a single infusion of CTX001 through a central venous catheter. | Biological: CTX001<br>* Administered by intravenous (IV) infusion following myeloablative conditioning with busulfan.<br>* Other names: Exa-cel;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fetal Hemoglobin (HbF) Concentration Over Time |  | Up to 12 Months After CTX001 Infusion | 
| Total Hemoglobin (Hb) Concentration Over Time |  | Up to 12 Months After CTX001 Infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TDT and SCD: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | From Signing of Informed Consent up to 12 Months After CTX001 Infusion | 
| TDT and SCD: 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 | 
| TDT and SCD: Time to Engraftment |  | Up to 12 Months After CTX001 Infusion | 
| TDT and SCD: Incidence of Transplant-Related Mortality (TRM) Within 100 Days After CTX001 Infusion |  | Within 100 Days After CTX001 Infusion | 
| TDT and SCD: Incidence of TRM Within 12 Months After CTX001 Infusion |  | Within 12 Months After CTX001 Infusion | 
| TDT and SCD: Incidence of All-cause Mortality |  | From Signing of Informed Consent up to 12 Months After CTX001 Infusion | 
| TDT and SCD: Relative Reduction in Annualized Volume of RBC Transfusions |  | From Day 60 up to 12 Months After CTX001 Infusion | 
| TDT and SCD: Proportion of Alleles With Intended Genetic Modification Present in Peripheral Blood Over Time |  | Up to 12 Months After CTX001 Infusion | 
| TDT and SCD: Proportion of Alleles With Intended Genetic Modification Present in CD34+ Cells of the Bone Marrow Over Time |  | Up to 12 Months After CTX001 Infusion | 
| TDT: Duration Transfusion Free in Participants |  | Up to 12 Months After CTX001 Infusion | 
| SCD: Relative Reduction in Annualized Rate of Severe Vaso-Occlusive Crises (VOCs) |  | From Baseline up to 12 Months After CTX001 Infusion | 
| SCD: Relative Reduction in Annualized Rate of Inpatient Hospitalizations for Severe VOCs |  | From Baseline up to 12 Months After CTX001 Infusion | 
| SCD: Relative Reduction in Annualized Duration of Hospitalization for Severe VOCs |  | From Baseline up to 12 Months After CTX001 Infusion | 
| SCD: Relative Reduction in Haptoglobin |  | From Baseline up to 12 Months After CTX001 Infusion | 
| SCD: Relative Reduction in Lactate dehydrogenase |  | From Baseline up to 12 Months After CTX001 Infusion | 
| SCD: Relative Reduction in Total Bilirubin |  | From Baseline up to 12 Months After CTX001 Infusion | 
| SCD: Relative Reduction in Indirect Bilirubin |  | From Baseline up to 12 Months After CTX001 Infusion |