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Exagamglogene Autotemcel for Severe Sickle Cell Disease.
- Source :
-
The New England journal of medicine [N Engl J Med] 2024 May 09; Vol. 390 (18), pp. 1649-1662. Date of Electronic Publication: 2024 Apr 24. - Publication Year :
- 2024
-
Abstract
- Background: Exagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis by means of ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) at the erythroid-specific enhancer region of BCL11A .<br />Methods: We conducted a phase 3, single-group, open-label study of exa-cel in patients 12 to 35 years of age with sickle cell disease who had had at least two severe vaso-occlusive crises in each of the 2 years before screening. CD34+ HSPCs were edited with the use of CRISPR-Cas9. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was freedom from severe vaso-occlusive crises for at least 12 consecutive months. A key secondary end point was freedom from inpatient hospitalization for severe vaso-occlusive crises for at least 12 consecutive months. The safety of exa-cel was also assessed.<br />Results: A total of 44 patients received exa-cel, and the median follow-up was 19.3 months (range, 0.8 to 48.1). Neutrophils and platelets engrafted in each patient. Of the 30 patients who had sufficient follow-up to be evaluated, 29 (97%; 95% confidence interval [CI], 83 to 100) were free from vaso-occlusive crises for at least 12 consecutive months, and all 30 (100%; 95% CI, 88 to 100) were free from hospitalizations for vaso-occlusive crises for at least 12 consecutive months (P<0.001 for both comparisons against the null hypothesis of a 50% response). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No cancers occurred.<br />Conclusions: Treatment with exa-cel eliminated vaso-occlusive crises in 97% of patients with sickle cell disease for a period of 12 months or more. (CLIMB SCD-121; ClinicalTrials.gov number, NCT03745287.).<br /> (Copyright © 2024 Massachusetts Medical Society.)
- Subjects :
- Adolescent
Adult
Child
Female
Humans
Male
Young Adult
Antigens, CD34
Busulfan therapeutic use
CRISPR-Cas Systems
Gene Editing
Hematopoietic Stem Cells
Repressor Proteins
Transplantation Conditioning
Cell- and Tissue-Based Therapy methods
Myeloablative Agonists therapeutic use
Europe
North America
Anemia, Sickle Cell complications
Anemia, Sickle Cell genetics
Anemia, Sickle Cell therapy
Fetal Hemoglobin biosynthesis
Fetal Hemoglobin genetics
Hematopoietic Stem Cell Transplantation
Subjects
Details
- Language :
- English
- ISSN :
- 1533-4406
- Volume :
- 390
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- The New England journal of medicine
- Publication Type :
- Academic Journal
- Accession number :
- 38661449
- Full Text :
- https://doi.org/10.1056/NEJMoa2309676