A Safety and Efficacy Study Evaluating CTX001 in Subjects With Severe Sickle Cell Disease

Study Overview
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Brief Summary
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This is a single-arm, open-label, multi-site, single-dose Phase 1/2/3 study in subjects with 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
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A Phase 1/2/3 Study to Evaluate the Safety and Efficacy of a Single Dose of Autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (CTX001) in Subjects With Severe Sickle Cell Disease

Conditions
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Sickle Cell Disease, Hematological Diseases, Hemoglobinopathies

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 sickle cell disease as defined by: Documented severe sickle cell disease genotype History of at least two severe vaso-occlusive crisis events per year for the previous two years prior to enrollment Eligible for autologous stem cell transplant as per investigators judgment Key Exclusion Criteria: An available 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: 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: CTX001<br>CTX001 (autologous CD34+ hHSPCs modified with CRISPR-Cas9 at the erythroid lineage-specific enhancer of the BCL11A gene). Subjects will receive a single infusion of CTX001 through a central venous catheter. | Biological: CTX001<br>* Administered by IV 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 subjects who have not experienced any severe vaso-occlusive crisis (VOC) for at least 12 consecutive months (VF12) |  | From 60 days after last RBC transfusion up to 2 years after CTX001 infusion | 
| Proportion of subjects with engraftment (first day of three consecutive measurements of absolute neutrophil count [ANC] ≥500/µL on three different days) |  | Within 42 days after CTX001 infusion | 
| Time to engraftment |  | From CTX001 infusion up to 2 years after CTX001 infusion | 
| Frequency and severity of collected adverse events (AEs) |  | From screening to 2 years 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 1 year after CTX001 infusion |  | Within 1 year after CTX001 infusion | 
| All-cause mortality |  | 2 years after mobilization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects free from inpatient hospitalization for severe VOCs sustained for at least 12 months (HF12) |  | From 60 days after last RBC transfusion up to 2 years after CTX001 infusion | 
| Proportion of subjects who have not experienced any severe VOC for at least 9 consecutive months (VF9) any time after CTX001 infusion |  | From 60 days after last RBC transfusion up to 2 years after CTX001 infusion | 
| Proportion of subjects with 90 percent (%), 80%, 75% or 50% reduction in annualized rate of severe VOCs |  | From 60 days after last RBC transfusion up to 2 years after CTX001 infusion | 
| Relative change from baseline in annualized rate of severe VOCs |  | From 60 days after last RBC transfusion up to 2 years after CTX001 infusion | 
| Duration of severe VOC free in subjects who have achieved VF12 |  | From 60 days after last RBC transfusion up to 2 years after CTX001 infusion | 
| Relative Change from baseline in rate of inpatient hospitalization for severe VOCs |  | From 60 days after last RBC transfusion up to 2 years after CTX001 infusion | 
| Relative change from baseline in annualized duration of hospitalization for severe VOCs |  | From 60 days after last RBC transfusion up to 2 years after CTX001 infusion | 
| Proportion of subjects with sustained HbF ≥20% for at least 3 months |  | From 60 days after last RBC transfusion up to 2 years after CTX001 infusion | 
| Proportion of subjects with sustained HbF ≥20% for at least 12 months |  | From 60 days after last RBC transfusion up to 2 years after CTX001 infusion | 
| Proportion of subjects with sustained HbF ≥20% for at least 6 months |  | From 60 days after last RBC transfusion up to 2 years after CTX001 infusion | 
| Change in number of units of RBC transfused for SCD-related indications |  | 6 months up to 2 years after CTX001 infusion | 
| HbF concentration over time |  | 1 month up to 2 years after CTX001 infusion | 
| Hb concentration over time |  | From the time of CTX001 up to 2 years after CTX001 infusion | 
| Change from baseline in indirect bilirubin over time |  | From baseline (pre-infusion) up to 2 years after CTX001 infusion | 
| Change from baseline in reticulocyte count over time |  | From baseline (pre-infusion) up to 2 years after CTX001 infusion | 
| Change from baseline in haptoglobin over time |  | From baseline (pre-infusion) up to 2 years after CTX001 infusion | 
| Change from baseline in lactate dehydrogenase over time |  | From baseline (pre-infusion) up to 2 years after CTX001 infusion | 
| Proportion of alleles with intended genetic modification present in peripheral blood leukocytes over time |  | 1 month up to 2 years after CTX001 infusion | 
| Proportion of alleles with intended genetic modification present in CD34+ cells of bone marrow over time |  | 6 months up to 2 years after CTX001 infusion | 
| Change in patient-reported outcome (PRO) over time assessed using weekly pain-scale (11-point numerical rating scale [NRS]) | The NRS is a 1-dimensional measure of reporting intensity of pain. The score of NRS ranges from 0 to 10 points, with higher values indicating a higher level of pain. | 3 months up to 2 years after CTX001 infusion | 
| Change in PRO over time assessed using EuroQol quality of life scale (EQ-5D-5L) | The EQ-5D-5L Questionnaire consists of the EQ-5D descriptive system and the EQ visual analogue scale (VAS). The EQ-5D comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression, and 5 levels: no problems to extreme problems. The subject marks the most appropriate statement in each dimension, resulting in a 1-digit number for that dimension. The digits can be combined in a 5-digit number describing the subject's health state. The EQ VAS records the subject's self-rated health on a 100-point VAS, endpoints labelled the best health you can imagine and the worst health you can imagine | 3 months up to 2 years after CTX001 infusion | 
| Change in PRO over time assessed using EQ-5D-Youth (EQ-5D-Y) |  | 3 months up to 2 years after CTX001 infusion | 
| Change in PRO over time assessed using functional assessment of cancer therapy-bone marrow transplant (FACT-BMT) questionnaire | The FACT-BMT Questionnaire includes physical, social, family, emotional, and functional well-being, and treatment specific concerns of bone marrow transplantation. Each statement has a 5-point Likert-type response scale ranging from 0=not at all to 4=very much. The subject marks one number per line as it applies to the past 7 days. Questionnaires are then scored; the higher the score, the better the quality of life. | 3 months up to 2 years after CTX001 infusion | 
| Change in PRO over time assessed using adult sickle cell quality of life measurement system (ASCQ-Me) | ASCQ-Me comprises measures to assess physical, mental and social health along with information on severity of disease. It includes the following domains: emotional impact, pain impact, pain episodes, sleep impact, social functioning impact, stiffness impact and SCD medical history checklist. ASCQ-Me domains are scored using T-score metric with mean of 50 for reference population and SD of 10. Higher scores indicate healthier status. | 3 months up to 2 years after CTX001 infusion | 
| Change in PRO over time assessed using pediatric quality of life inventory (PedsQL) |  | 3 months up to 2 years after CTX001 infusion | 
| Change in PRO over time assessed using PedsQL sickle cell disease module |  | 3 months up to 2 years after CTX001 infusion |