By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The U.S. Food and Drug Administration has approved the first treatment for sickle cell disease (SCD) using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR associated protein 9) genome editing technology.1,2 Exagamglogene autotemcel was given an accelerated, fast-track, priority review and orphan drug and regenerative medicine advanced therapy designations. The approval was granted to Vertex Pharmaceuticals and CRISPR Therapeutics as Casgevy.
INDICATIONS
Exagamglogene autotemcel is indicated for the treatment of SCD in patients 12 years of age and older with recurrent vaso-occlusive crises (VOC).3
DOSAGE
The minimum recommended dose is 3 × 106 CD34+ cells per kg of body weight, which may be harvested over several cycles of mobilization and apheresis.3 The treatment is a one-time, single dose intravenous administration. The use of hydroxyurea, voxelotor, and crizanlizumab should be discontinued at least eight weeks prior to start of the mobilization cycle. An antihistamine and an antipyretic are administered prior to exagamglogene infusion.3 Immunosuppressive agents are not required after initial myeloablative conditioning.3
POTENTIAL ADVANTAGES
Exagamglogene autotemcel provides a one-time, potentially curative treatment and appears to eliminate vaso-occlusive episodes and the need for transfusions.
POTENTIAL DISADVANTAGES
Most common Grade 3 or 4 laboratory abnormalities (≥ 50%) were neutropenia, thrombocytopenia leukopenia, anemia, and lymphopenia.3 Non-laboratory adverse events (≥ 25%) include mucositis, febrile neutropenia, and decreased appetite. Neutrophil engraftment failure (not achieving neutrophil engraftment after exagamglogene infusion) also may occur, as well as prolonged time to platelet engraftment.3 Hypersensitivity reaction, including anaphylaxis, can occur as a result of dimethyl sulfoxide or dextran 40 in the cryopreservative solution.3 Exagamglogene may remain active and cut genomes other than the target site (i.e., off-target mutations).4
COMMENTS
Sickle cell hemoglobin is the result of a point mutation in the hemoglobin β subunit gene (HBB) with valine replaced with glutamic acid. This results in deoxygenated sickle hemoglobin and deformed erythrocytes, hemolysis, anemia, and painful vaso-occlusive episodes. Exagamglogene autotemcel treatment requires harvesting of the patient’s own CD34+ cells, which are modified ex vivo, then given back as a one-time infusion. The patient must undergo myeloablative conditioning with high-dose chemotherapy prior to re-infusion. CRISPR/Cas9 technology allows genetic editing of the target gene (BCL11A), deactivating the expression of defective hemoglobin and reactivating the production of functioning fetal hemoglobin.
The efficacy and safety of exagamglogene autotemcel was evaluated in an ongoing single-arm study. Study participants had a history of at least two protocol-defined severe vaso-occlusive events during each of the two years prior to screening. Forty-four participants (> 90% βsβs) received the infusion and 31 had adequate follow-up to allow for evaluation of the primary efficacy. This is defined as not experiencing any protocol-defined severe VOC for at least 12 consecutive months within the first 24 months consecutive after infusion (VF12) and the proportion of participants who did not require hospitalization because of severe VOC for at least 12 consecutive months within the 24 months (HF12). The VF12 response rate was 29/31 (93.5%), with a median follow-up of 22.2 months at the time of the interim analysis. The HF12 response rate was 100% (one participant was not evaluable).
CLINICAL IMPLICATIONS
SCD is a rare, debilitating, and life-threatening disorder affecting about 100,000 individuals in the United States.1 It is characterized by acute and chronic pain, hemolytic anemia, and increased incidence of stroke, nephropathy, and retinopathy.4 In addition to the morbidity of the disease, life expectancy is about 20 years less than the general population.4 Hydroxyurea generally is first-line therapy with L-glutamine, crizanlizmab, and voxelotor as secondary options.4,5 Hematopoietic stem cell transplant with a match sibling donor is standard of care for severe disease.4
Exagamglogene potentially is a “cure” for SCD. A second treatment, lovotibeglogene autotemcel (Lyfgenia), using a different technology (lentiviral vector gene delivery) also was approved on the same day as exagamglogene. Exagamglogene is estimated to cost $2.2 million per patient.4
REFERENCES
- U.S. Food and Drug Administration. FDA approves first gene therapies to treat patients with sickle cell disease. Published Dec. 8, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease
- Reardon S. FDA approves first CRISPR gene editing treatment for sickle cell disease. Scientific American. Published Dec. 8, 2023. https://www.scientificamerican.com/article/fda-approves-first-crispr-gene-editing-treatment-for-sickle-cell-disease/
- Vertex Pharmaceuticals Inc. Casgevy prescribing information. December 2023. https://www.casgevyhcp.com/sickle-cell-disease/sites/default/files/uspi-ppi_exagamglogene_autotemcel.pdf
- Kavanagh PL, Fasipe TA, Wun T. Sickle cell disease: A review. JAMA 2022;328:57-68.
- Brandow AM, Liem RI. Advances in the diagnosis and treatment of sickle cell disease. J Hematol Oncol 2022;15:20.
