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

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

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.

Study Overview

• Status: Completed
• Conditions: Sickle Cell Disease; Hemoglobinopathies; Hematological Diseases
• Intervention / Treatment: Biological: CTX001

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium
    • Hôpital Universitaire des Enfants Reine Fabiola (HUDERF)
• Canada
  • Toronto, Canada
    • The Hospital for Sick Children
• France
  • Paris, France
    • Hopital Necker Enfants Malades
• Germany
  • Dusseldorf, Germany
    • University Hospital Duesseldorf
  • Regensburg, Germany
    • Regensburg University Hospital, Clinic and Polyclinic for Paediatric and Adolescent Medicine, Paediatric Haemotology, Oncology and Stem Cell Transplantation
• Italy
  • Rome, Italy
    • Dipartimento di Onco-Ematologia e Terapia Cellulare e Genica Ospedale Pediatrico Bambino Gesu - IRCCS
• United Kingdom
  • London, United Kingdom
    • Imperial College Healthcare NHS Trust, Hammersmith Hospital
  • London, United Kingdom
    • Royal London and St Bartholomew's Hospital, Pathology and Pharmacy Building
• United States
  • California
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital of Stanford University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert Lurie Children's Hospital of Chicago
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago Hospitals and Health Systems
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center (21+ years)
    • New York, New York, United States, 10032
      • Columbia University Medical Center (≤21 years)
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Tennessee
    • Memphis, Tennessee, United States, 38105
      • St. Jude Children's Research Hospital
    • Nashville, Tennessee, United States, 37203
      • The Children's Hospital at TriStar Centennial Medical Center/ Sarah Cannon Center for Blood Cancers
  • Texas
    • San Antonio, Texas, United States, 78229
      • Methodist Children's Hospital/Texas Transplant Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 35 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CTX001; 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; Administered by IV infusion following myeloablative conditioning with busulfan.; Other Names: Exagamglogene autotemcel; Exa-cel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Vertex Pharmaceuticals Incorporated
• Collaborators: CRISPR Therapeutics

Publications and helpful links

General Publications

• Frangoul H, Altshuler D, Cappellini MD, Chen YS, Domm J, Eustace BK, Foell J, de la Fuente J, Grupp S, Handgretinger R, Ho TW, Kattamis A, Kernytsky A, Lekstrom-Himes J, Li AM, Locatelli F, Mapara MY, de Montalembert M, Rondelli D, Sharma A, Sheth S, Soni S, Steinberg MH, Wall D, Yen A, Corbacioglu S. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and beta-Thalassemia. N Engl J Med. 2021 Jan 21;384(3):252-260. doi: 10.1056/NEJMoa2031054. Epub 2020 Dec 5.
• Modarai SR, Kanda S, Bloh K, Opdenaker LM, Kmiec EB. Precise and error-prone CRISPR-directed gene editing activity in human CD34+ cells varies widely among patient samples. Gene Ther. 2021 Feb;28(1-2):105-113. doi: 10.1038/s41434-020-00192-z. Epub 2020 Sep 1.
• Brusson M, Miccio A. Genome editing approaches to beta-hemoglobinopathies. Prog Mol Biol Transl Sci. 2021;182:153-183. doi: 10.1016/bs.pmbts.2021.01.025. Epub 2021 Mar 1.

Study record dates

Study Major Dates

• Study Start (Actual): November 27, 2018
• Primary Completion (Actual): July 7, 2025
• Study Completion (Actual): July 7, 2025

Study Registration Dates

• First Submitted: November 9, 2018
• First Submitted That Met QC Criteria: November 15, 2018
• First Posted (Actual): November 19, 2018

Study Record Updates

• Last Update Posted (Actual): August 11, 2025
• Last Update Submitted That Met QC Criteria: August 5, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Genetic Diseases, Inborn; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Anemia, Sickle Cell; Hematologic Diseases; Hemoglobinopathies
• Other Study ID Numbers: CTX001-121

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No