A Safety and Efficacy Study Evaluating CTX001 in Participants With Transfusion-Dependent β-Thalassemia

A Phase 1/2/3 Study of the Safety and Efficacy of a Single Dose of Autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (hHSPCs) in Subjects With Transfusion-Dependent β-Thalassemia

This is a single-arm, open-label, multi-site, single-dose Phase 1/2/3 study in participans with transfusion-dependent β-thalassemia (TDT). 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: Hematologic Diseases; Genetic Diseases, Inborn; Hemoglobinopathies; Thalassemia; Beta-Thalassemia
• Intervention / Treatment: Biological: CTX001

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Canada
  • Toronto, Canada
    • The Hospital for Sick Children
  • Vancouver, Canada
    • British Columbia Children's Hospital
• Germany
  • Düsseldorf, Germany
    • Universitätsklinikum Düsseldorf Hospital Duesseldorf
  • Regensburg, Germany
    • Regensburg University Hospital, Clinic and Polyclinic for Paediatric and Adolescent Medicine
  • Tübingen, Germany
    • University Hospital Tübingen
• Italy
  • Rome, Italy
    • Ospedale Pediatrico Bambino Gesù, IRCCS
• United Kingdom
  • London, United Kingdom
    • University College London Hospitals Nhs Foundation Trust
  • London, United Kingdom
    • Imperial College Healthcare NHS Trust, Hammersmith Hospital
• United States
  • California
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert Lurie Children's Hospital of Chicago
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • 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
    • Nashville, Tennessee, United States, 37203
      • The Children's Hospital at TriStar Centennial Medical Center/ Sarah Cannon Center for Blood Cancers

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 31 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Diagnosis of transfusion-dependent β-thalassemia (TDT) as defined by

  1. 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
  2. History of at least 100 mL/kg/year or ≥10 units/year of packed RBC transfusions in the prior 2 years before signing the consent or the last rescreening for patients going through re-screening
• 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
• Prior allo-HSCT
• Participants with associated α-thalassemia and >1 alpha deletion or alpha multiplications
• Participants with sickle cell beta thalassemia variant
• Clinically significant and active bacterial, viral, fungal, or parasitic infection as determined by the investigator
• White blood cell (WBC) count <3 × 10^9/L or platelet count <50 × 10^9/L not related to hypersplenism

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). Participants 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
Time to neutrophil and platelet engraftment	Days post-infusion to engraftment
Frequency and severity of collected adverse events (AEs)	Signing of informed consent through Month 24 visit
Incidence of transplant-related mortality (TRM)	Baseline (pre-transfusion) to 100 days and 1 year post-CTX001 infusion
All-cause mortality	Signing of informed consent through Month 24 visit
Proportion of participants achieving transfusion independence for at least 12 consecutive months (TI12)	From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion]
Proportion of participants with engraftment (first day of 3 consecutive measurements of absolute neutrophil count [ANC] ≥500/µL on three different days)	Within 42 days after CTX001 infusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of alleles with intended genetic modification in peripheral blood leukocytes over time		Day 1 CTX001 infusion through Month 24 visit
Proportion of alleles with intended genetic modification present in CD34+ cells of bone marrow over time		Day 1 CTX001 infusion through Month 24 visit
Change in fetal hemoglobin concentration over time		Baseline (pre-transfusion) through Month 24 visit
Change in total hemoglobin concentration over time		Baseline (pre-transfusion) through Month 24 visit
Change in health-related quality of life (HRQoL) from baseline over time using EuroQol Questionnaire (5 dimensions - 5 levels of severity - 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."	Screening visit through Month 24 visit
Change in health-related quality of life (HRQoL) from baseline over time using the Functional assessment of cancer therapy-bone marrow transplant questionnaire (FACT-BMT)	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 scored; the higher the score, the better the QOL.	Screening visit through Month 24 visit
Change in patient reported outcome (PRO) over time assessed using EQ-5D-Youth (EQ-5D-Y)		Screening visit through Month 24 visit
Change in PRO over time assessed using pediatric quality of life inventory (PedsQL)		Screening visit through Month 24 visit
Changes in liver iron concentration (LIC) and cardiac iron content (CIC) and ferritin parameters of iron overload		Screening visit through Month 24 visit
Proportion of participants achieving transfusion independence for at least 6 consecutive months (TI6)		From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion
Proportion of participants achieving at least 95 percent (%), 90%, 85%, 75%, and 50% reduction from baseline in annualized volume of RBC transfusions after Month 10 after CTX001 infusion		From Month 10 up to 24 months post-CTX001 infusion
Relative reduction from baseline in annualized volume of RBC transfusions after Month 10 after CTX001 infusion		From Month 10 up to 24 months post-CTX001 infusion
Duration of transfusion free in participants who have achieved TI12		From 60 days after last RBC transfusion up to 24 months post-CTX001 infusion
Proportion of participants receiving iron chelation therapy		1 month post-CTX001 infusion through Month 24 visit

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.
• 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.
• de la Fuente J, Frangoul H, Lang P, Wall D, Meisel R, Corbacioglu S, Li AM, Shah AJ, Carpenter B, Kwiatkowski JL, Mapara MY, Liem RI, Rupprecht J, Kuo KHM, Merkeley H, Algeri M, Smith W, Kohli P, Li N, Rubin J, Zhang S, Hobbs WE, Locatelli F. Improvements in Health-Related Quality of Life in Patients with Transfusion-Dependent beta-Thalassemia After Exagamglogene Autotemcel. Blood Adv. 2025 Aug 19:bloodadvances.2025016702. doi: 10.1182/bloodadvances.2025016702. Online ahead of print.
• Locatelli F, Lang P, Wall D, Meisel R, Corbacioglu S, Li AM, de la Fuente J, Shah AJ, Carpenter B, Kwiatkowski JL, Mapara M, Liem RI, Cappellini MD, Algeri M, Kattamis A, Sheth S, Grupp S, Handgretinger R, Kohli P, Shi D, Ross L, Bobruff Y, Simard C, Zhang L, Morrow PK, Hobbs WE, Frangoul H; CLIMB THAL-111 Study Group. Exagamglogene Autotemcel for Transfusion-Dependent beta-Thalassemia. N Engl J Med. 2024 May 9;390(18):1663-1676. doi: 10.1056/NEJMoa2309673. Epub 2024 Apr 24.

Study record dates

Study Major Dates

• Study Start (Actual): September 14, 2018
• Primary Completion (Actual): November 13, 2025
• Study Completion (Actual): November 13, 2025

Study Registration Dates

• First Submitted: August 29, 2018
• First Submitted That Met QC Criteria: August 30, 2018
• First Posted (Actual): August 31, 2018

Study Record Updates

• Last Update Posted (Estimated): December 17, 2025
• Last Update Submitted That Met QC Criteria: December 11, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: CRISPR-Cas9; Beta-Thalassemia; Hemoglobinopathies
• Additional Relevant MeSH Terms: Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hemic and Lymphatic Diseases; Genetic Diseases, Inborn; Thalassemia; beta-Thalassemia; Hematologic Diseases; Hemoglobinopathies; exagamglogene autotemcel
• Other Study ID Numbers: CTX001-111; 2024-516894-57-00 (Other Identifier: EU CT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Details on Vertex data sharing criteria and process for requesting access can be found at: https://www.vrtx.com/our-science/clinical-trials-data-sharing/

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.: Yes