In December 2023, the U.S. Food and Drug Administration (FDA) approved exagamglogene autotemcel (exa-cel) for the treatment of severe sickle cell disease (SCD) in people 12 years or older who have a history of vaso-occlusive crises (VOC) on the basis of a phase III study. Full results of the study, now available in the New England Journal of Medicine, highlight the therapy’s potential.1
Exa-cel is the first therapy based on CRISPR/Cas9 technology that has received FDA approval in any therapeutic area. After a patient’s hematopoietic and progenitor cells are collected, the patient undergoes myeloablative conditioning to remove additional cells from the bone marrow. Technicians modify the collected hematopoietic cells using CRISPR gene editing to interrupt the BCL11A gene and readminister the cells to the patient.
Because BCL11A represses fetal hemoglobin (HbF) production, the edited cells increase HbF and total hemoglobin (Hb) as part of a one-time treatment. Although the patient still possesses the gene for abnormal sickled erythrocytes, a higher concentration of HbF greatly decreases the extent of sickle cell polymerization, interrupting the disease pathophysiology.
The phase III CLIMB SCD-121 trial was a single-arm, open-label study of exa-cel in patients aged 12 to 35. All 44 patients had experienced at least two severe VOCs in the two years before screening.1
Early and sustained increases in HbF and total Hb led to normal or near-normal levels by month six. The study met both its primary and secondary endpoints: of the 30 evaluable patients, 97% were free from VOCs for at least 12 consecutive months, and 100% were free from hospitalizations due to VOCs during this window. Thus, efficacy appears to be comparable to best results from allogeneic hematopoietic cell transplantation (alloHCT) in HLA-matched donors.
Stephan A. Grupp, MD, PhD, director of the Kelly Center for Cancer Immunotherapy at Children’s Hospital of Philadelphia, was the senior author and one of the principal investigators on the study, supported by Vertex Pharmaceuticals. Dr. Grupp pointed out that any safety concerns, to date, result from myeloablative chemotherapy, which poses a risk of infection from low blood counts and necessitates at least four to six weeks in the hospital.
However, Dr. Grupp noted that because exa-cel is an autologous cell therapy, it doesn’t require the depth of immune-ablation needed for alloHCT (e.g., busulfan in the exa-cel protocol vs. adding an agent like cyclophosphamide in alloHCT). Additionally, even HLA-matched donors run some risk of graft-versus-host disease with alloHCT, which is not a concern in autologous transplants, such as with exa-cel.
In December, the FDA approved another gene therapy product for SCD based on a lentiviral vector, lovotibeglogene autotemcel (lovo-cel), which also relies on autologous donation. Unlike exa-cel, lovo-cel’s label has a black box warning for malignancy. Dr. Grupp pointed out that this may influence patients’ and families’ perspectives, although at his center they are comfortable giving either product.
No cancers occurred during the exa-cel study, and Dr. Grupp noted that, to date, efficacy has not fallen off. However, Dr. Grupp and colleagues plan to continue to study the participants for an additional 15 years to identify long-term efficacy and potential safety concerns.
In January, the FDA also approved exa-cel for the treatment of beta thalassemia; theoretically, the treatment might work in any hemoglobinopathy which benefits from increases in HbF.2
Dr. Grupp explained that even after insurance approval, which may be challenging, exa-cel treatment can’t begin right away because of constraints such as the time needed to collect the cells and manufacture the product.
Another key limitation of the approach is its availability. “The good news is that patients come out of this in great shape, potentially cured of their disease,” Dr. Grupp said. “But it’s going to be some time before we’re able to do this in a lot of patients.”
Any conflicts of interest declared by the authors can be found in the original article.
References
- Frangoul H, Locatelli F, Sharma A, et al. Exagamglogene autotemcel for severe sickle cell disease. N Engl J Med. 2024;390(18):1649-1662.
- Locatelli F, Lang P, Wall D, et al. Exagamglogene autotemcel for transfusion- dependent β-thalassemia. N Engl J Med. 2024;390(18):1663-1676.
Perspectives
The FDA approval of exa-cel, the first FDA-approved therapy using CRISPR technology for any disorder, represents decades of basic science research investigating Hb switching and the protective role of HbF in SCD and the clinical application of new technology to transform a disease state.
The data reported by Frangoul et al. are clear.1 Treatment with exa-cel leads to sustained elevation of HbF with normalization of total Hb, near resolution of hemolysis, significant reduction or elimination of VOCs, and improved patient quality of life. What is not clear, however, is the durability of this therapy (median follow-up is less than two years); the clinical applicability outside of a clinical trial, including who should receive this therapy; and the long-term organ function. Can this therapy protect against stroke or other multiorgan system dysfunction? Can this therapy repair any current damage? Will real-world outcomes with an FDA label that has no contraindications be similar to the outcomes from the narrow patient population treated in this study? Without the long-term durability and understanding of end-organ function, treatment with exa-cel should be considered transformative, not curative.
The success of this therapy, in part, is due to the knowledge gained from the clinical trial of the other gene therapy product, lovo-cel. This study, initiated nearly five years before the Vertex trial, contributed significantly to how we care for individuals with SCD undergoing gene therapy to optimize treatment success, including initiation of chronic transfusions, use of peripheral blood stem cells, improved manufacturing, and optimization of myeloablation.2 Although the FDA label for lovo-cel includes a black box warning for malignancy, this risk applies to all patients with SCD who undergo genetic therapies and is why patients need to be followed for years after transplant. The two reports of acute myeloid leukemia occurred in the initial treated cohorts3,4 before optimization of therapy described above; the risk of preexisting clonal outgrowth5 theoretically remains high, regardless of product given, but not every hematopoietic cell will undergo complete genetic manipulation or correction.
The clinical data and FDA approval of exa-cel provide hope for the millions of individuals living with SCD, and yet access to this therapy where the disease burden is highest is not possible. We have much more work to do to improve the safety, access, implementation, and understanding of how best to deliver durable, effective, transformative gene therapy for individuals living with SCD. The use of exa-cel is a part of this important task.
Alexis Leonard, MD
St. Jude Children’s Research Hospital
Memphis, Tennessee
COI Disclosure: Dr. Leonard has provided consultation to Vertex Pharmaceuticals and bluebird bio, inc.
References
- Frangoul H, Locatelli F, Sharma A, et al. Exagamglogene autotemcel for severe sickle cell disease. N Engl J Med. 2024;390(18):1649-1662.
- Kanter J, Thompson AA, Pierciey FJ Jr., et al. Lovo-cel gene therapy for sickle cell disease: treatment process evolution and outcomes in the initial groups of the HGB-206 study. Am J Hematol. 2023;98(1):11-22.
- Goyal S, Tisdale J, Schmidt M, et al. Acute myeloid leukemia case after gene therapy for sickle cell disease. N Engl J Med. 2022;386(2):138-147.
- Hsieh MM, Bonner M, Pierciey FJ, et al. Myelodysplastic syndrome unrelated to lentiviral vector in a patient treated with gene therapy for sickle cell disease. Blood Adv. 2020;4(9):2058-2063.
- Jones RJ, DeBaun MR. Leukemia after gene therapy for sickle cell disease: insertional mutagenesis, busulfan, both, or neither. Blood. 2021;138(11):942-947.
