Exagamglogene Autotemcel for Severe Sickle Cell Disease

N Engl J Med. 2024 May 9;390(18):1649-1662. doi: 10.1056/NEJMoa2309676. Epub 2024 Apr 24.


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.

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.

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.

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.).

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't
  • Clinical Trial, Phase III
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Anemia, Sickle Cell* / complications
  • Anemia, Sickle Cell* / genetics
  • Anemia, Sickle Cell* / therapy
  • Antigens, CD34
  • Busulfan / therapeutic use
  • CRISPR-Cas Systems
  • Cell- and Tissue-Based Therapy / methods
  • Child
  • Europe
  • Female
  • Fetal Hemoglobin* / biosynthesis
  • Fetal Hemoglobin* / genetics
  • Gene Editing
  • Hematopoietic Stem Cell Transplantation*
  • Hematopoietic Stem Cells
  • Humans
  • Male
  • Myeloablative Agonists / therapeutic use
  • North America
  • Repressor Proteins
  • Transplantation Conditioning
  • Young Adult


  • BCL11A protein, human

Associated data

  • ClinicalTrials.gov/NCT03745287