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

Official Summary

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.

Eligibility Requirements

• Minimum Age: 12 Years
• Maximum Age: 35 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NA
• Model: SINGLE_GROUP
• Masking: NONE
• Enrollment: 63 participants

Study Arms

• CTX001 (EXPERIMENTAL)
  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.

Interventions

• BIOLOGICAL: CTX001 — Administered by IV infusion following myeloablative conditioning with busulfan.

Primary Outcomes

• 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)

Secondary Outcomes

• 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)

Eligibility Criteria

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

Trial Locations

• Lucile Packard Children's Hospital of Stanford University, Palo Alto, California, United States
• Ann & Robert Lurie Children's Hospital of Chicago, Chicago, Illinois, United States
• University of Illinois at Chicago Hospitals and Health Systems, Chicago, Illinois, United States
• Columbia University Medical Center (21+ years), New York, New York, United States
• Columbia University Medical Center (≤21 years), New York, New York, United States
• Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
• St. Jude Children's Research Hospital, Memphis, Tennessee, United States
• The Children's Hospital at TriStar Centennial Medical Center/ Sarah Cannon Center for Blood Cancers, Nashville, Tennessee, United States
• Methodist Children's Hospital/Texas Transplant Institute, San Antonio, Texas, United States
• Hopital Universitaire des Enfants Reine Fabiola (HUDERF), Brussels, Belgium
• ...and 7 more locations

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