Tami John, MD, on Considerations for β-Thalassemia Gene Therapy in the Real World

This is the second part of an interview with Tami John, MD. For the first part, click here.

"I have heard through the real world that people are having some difficulty, either with volumes or with some of the requirements with manufacturing. But so far, for both products, we haven't seen numbers that indicate one is more difficult or problematic than the other."

bluebird bio’s betibeglogene autotemcel (beti-cel; marketed as Zynteglo), an autologous, lentiviral gene-addition therapy that delivers a modified form of the β-globin gene into patients’ hematopoietic stem cells ex vivo before reinfusion into the patient, and Vertex Pharmaceuticals and CRISPR Therapeutics’ exagamglogene autotemcel (exa-cel; marketed as Casgevy), a CRISPR/Cas9 gene-editing cell therapy, were approved by the FDA for the treatment of transfusion-dependent β-thalassemia (TDT) in 2022 and early 2024, respectively.^1,2 Since then, these therapies have been in the process of slowly being rolled out to patients in the real world.

In March of this year, CGTLive® spoke with Tami John, MD, a clinical associate professor at Stanford Medicine, about the real world experience with TDT gene therapy thus far. Although John clarified that her firsthand experience with the products so far comes from working on clinical trials, she explained several factors that will have to be considered in the real-world setting. One point she emphasized is the potential for infertility being caused by the busulfan conditioning regimens that must be used prior to the administration of the therapies. John pointed out that for pediatric patients who may be too young to make informed decisions about this risk, it can present difficulties depending on the patient’s family’s values. She also noted that more data will need to be gathered on the manufacturing efficiency, speed, and failure rate for beti-cel and exa-cel in order to determine whether either of these products has an advantage in these regards. John also discussed the possibility of gene therapy products causing deleterious or oncogenic off-target effects, stating that more long-term data will need to be collected in order to assess these risks in exa-cel and beti-cel.

REFERENCES
1. FDA approves first cell-based gene therapy to treat adult and pediatric patients with beta-thalassemia who require regular blood transfusions. News release. FDA. August 17, 2022. Accessed June 24, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-treat-adult-and-pediatric-patients-beta-thalassemia-who?utm_medium=email&utm_source=govdelivery
2. Vertex Announces US FDA Approval of CASGEVY™ (exagamglogene autotemcel) for the Treatment of Transfusion-Dependent Beta Thalassemia. News release. January 16, 2024. Accessed June 24, 2025. https://news.vrtx.com/news-releases/news-release-details/vertex-announces-us-fda-approval-casgevytm-exagamglogene