ISSUE1702
- Mark Abramowicz, M.D., President has disclosed no relevant financial relationships.
- Jean-Marie Pflomm, Pharm.D., Editor in Chief has disclosed no relevant financial relationships.
- Brinda M. Shah, Pharm.D., Consulting Editor has disclosed no relevant financial relationships.
- Review the efficacy and safety of exagamglogene autotemcel (Casgevy) for treatment of beta thalassemia.
Exagamglogene autotemcel (Casgevy – Vertex), a cell-based gene therapy recently approved for treatment of sickle cell disease1, has now been approved by the FDA for treatment of patients ≥12 years old with transfusion-dependent beta thalassemia. Casgevy is the first gene therapy that uses CRISPR/Cas9 gene-editing technology to be approved in the US for any disorder. Betibeglogene autotemcel (Zynteglo), an autologous lentiviral vector cell-based gene therapy, was approved in the US in 2022 for treatment of transfusion-dependent beta thalassemia.
THE DISORDER — Beta thalassemia can cause severe anemia, fatigue, shortness of breath, failure to thrive, jaundice, an enlarged spleen, liver or heart, and delayed puberty. Frequent transfusions and iron chelation therapy have been effective in many patients with transfusion-dependent beta thalassemia; iron overload is a complication of long-term transfusion therapy and can cause significant organ damage. The only definitive cure for beta thalassemia is allogeneic bone marrow transplantation.2
GENE THERAPY — Casgevy is prepared from autologous CD34+ hematopoietic stem cells obtained by mobilization and apheresis. CRISPR/Cas9 gene-editing technology is used to modify the stem cells to reduce BCL11A expression (BCL11A represses fetal hemoglobin) in erythroid lineage cells.3 The modified stem cells increase production of fetal hemoglobin in red blood cells, reducing the need for transfusions.
A CLINICAL STUDY — Approval of Casgevy for beta thalassemia was based on the results of an ongoing single-arm trial (CLIMB THAL-111) in 52 patients (only 35 had sufficient follow-up data) 12 to 35 years old with transfusion-dependent beta thalassemia. Patients were treated with myeloablative conditioning therapy followed by a single dose of Casgevy. After a median follow-up of 20.4 months, 91% of patients had achieved transfusion independence for at least 12 consecutive months. All treated patients achieved successful neutrophil and platelet engraftment.4 A trial evaluating the effects of Casgevy for up to 15 years post-infusion is ongoing.
No trials directly comparing Casgevy with Zynteglo for treatment of beta thalassemia are available, but in 2 unpublished clinical trials (summarized in the Zynteglo package insert), rates of transfusion independence achieved with Zynteglo were similar to those achieved with Casgevy.
ADVERSE EFFECTS — Casgevy has been associated with neutrophil engraftment failure, delayed platelet engraftment, mucositis, and febrile neutropenia. Myeloablative conditioning therapy can cause significant toxicity and infertility.
DOSAGE, ADMINISTRATION, AND COST — A single weight-based dose of Casgevy (a minimum of 3 x 106 CD34+ cells/kg) is infused between 48 hours and 7 days after myeloablative conditioning therapy. The wholesale acquisition cost (WAC) of a single dose is $2.2 million for Casgevy compared to $2.8 million for Zynteglo.5
- Casgevy and Lyfgenia: two gene therapies for sickle cell disease. Med Lett Drugs Ther 2024; 66:9.
- S Ali et al. Current status of beta-thalassemia and its treatment strategies. Mol Genet Genomic Med 2021; 9:e1788. doi:10.1002/mgg3.1788
- H Frangoul et al. CRISPR–Cas9 gene editing for sickle cell disease and β-thalassemia. N Engl J Med 2021; 384:252. doi:10.1056/nejmoa2031054
- F Locatelli et al. Exagamglogene autotemcel for transfusion-dependent β-thalassemia. N Engl J Med 2024 April 24 (epub). doi:10.1056/NEJMoa2309673
- Approximate WAC. WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. April 5, 2024. Reprinted with permission by First Databank, Inc. All rights reserved. ©2024. www.fdbhealth.com/drug-pricing-policy.
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