Questions of Access: Gene Therapy’s Next Chapter in β-Thalassemia
Tami John, MD and Shalini Shenoy, MD, MBBS, offer insight into the clinical experience of patients treated with Casgevy and Zynteglo thus far.
β-thalassemia constitutes an inherited blood disorder that interferes with normal hemoglobin production.1 Mutations in the beta-globin gene have been identified as the root cause of the disorder, which in its most severe form can necessitate blood transfusions on a 2 to 5 week basis for the duration of a patient’s life. This severe form is referred to as transfusion-dependent β-thalassemia (TDT).
Traditionally, treatment for TDT has involved the aforementioned regular transfusions. Although, several decades ago, allogeneic hematopoietic stem cell transplantation became another treatment option for the disorder. The ideal donor for such transplantations is a matched sibling; as such, this treatment option is not a viable path for all patients. According to a 2017 paper published in Haematologica, fewer than 10% of patients on a global scale with β-thalassemia major (the most severe form of β-thalassemia) who would be eligible for allogeneic transplant are able to actually receive it, whether because of a lack of donors, cost, or other factors.2
More recently, a new treatment modality has come to TDT in the form of genomic medicine. On August 17, 2022, 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, was approved by the FDA for the treatment of adult and pediatric patients with TDT.3 Later, on January 16, 2024, Vertex Pharmaceuticals and CRISPR Therapeutics’ exagamglogene autotemcel (exa-cel; marketed as Casgevy), a CRISPR/Cas9 gene-editing cell therapy, was approved by the FDA for the treatment of patients 12 years and older with TDT.4
In the time since these approvals, the 2 gene therapy products have begun to be rolled out into commercial use. This process has been slow-going, however, and to date the gene therapy products still have availability limited to certain centers of excellence.5,6 Notably, some centers are just now beginning to provide exa-cel within the past month or so. In light of this recent progress, CGTLive® reached out to several experts to get their insight on the clinical experience of patients and treating physicians with the gene therapy products thus far.
Barriers to Access
...[W]e don't have a lot of adult centers across the country that are becoming qualified treatment centers and so I get a lot of questions about if I can treat patients aged over 30 and for TDT I've been asked if I could treat a 54-year-old at a pediatric institution."
The gene therapy products for TDT unfortunately come with a number of barriers to access. These include factors like cost (exa-cel is priced at $2.2 million for TDT and beti-cel is priced at $2.8 million) and geographic availability with regard to patients’ places of residence, as well as eligibility to receive the treatment itself.7 Notably, both gene therapy products currently require patients to undergo myeloablative chemotherapy with busulfan prior to administration. This process carries a number of risks, with one of the most notable being the potential impact on future fertility. CGTLive spoke with Tami John, MD, a clinical associate professor at Stanford Medicine, to get her insight on these factors.
John began by emphasizing the benefits of the gene therapy products despite their risks, noting that more than 90% of patients are able to become transfusion-independent following treatment, and that those patients who don’t often require less frequent transfusions after treatment. Afterwards, she stressed the need for improving access in whatever ways are possible. John stated that currently she does not prefer one gene therapy product over the other for treating patients, but pointed out that if one or the other of the 2 products is able to have its manufacturing scaled up in a way that makes it more widely available, that therapy may become the favored option.
Furthermore, she noted that because some of the centers currently providing the gene therapies specialize in pediatrics, adult patients may find even more barriers to treatment, and that some are even requesting to be treated at pediatric centers because of the lack of options. John also pointed out that the process of administering the gene therapies is quite complex, thus requiring centers to be properly equipped and skilled in order to provide the products; this further limits the number of centers currently able to treat patients.
The Importance of Long-Term Follow-Up
"We always warn them that they do need to come back for follow-up. We're not going to be in their face every month, but they need to come back initially once every 6 months; later, potentially once a year, or once every 2 years, to make sure everything's going okay..."
Although the clinical trials for exa-cel and beti-cel have provided several years of posttreatment follow-up data for a number of patients, more follow-up is still needed. This is particularly important because both gene therapies are one-time treatments intended to provide a lifelong effect on the disease. As such, it remains unclear whether the therapies will live up to this ideal outcome.
CGTLive also spoke with Shalini Shenoy, MD, MBBS, a professor of pediatrics in hematology & oncology at Washington University School of Medicine, about areas of interest where more data is needed. Shenoy stressed that although early outcomes with exa-cel have been largely positive, more follow-up is certainly needed to determine long-term efficacy. She pointed out that because of the exposure to busulfan prior to treatment, patients who receive the gene therapy and experience limited efficacy may experience higher toxicity risks if they choose to pursue allogeneic transplant, which also requires the use of conditioning chemotherapy prior to administration. In addition, she stated that after treatment with one of the gene therapy products, subsequent treatment with the same or the other gene therapy product in order to address issues with efficacy would be impossible because of the toxicity risks of another exposure to busulfan conditioning. As such, patients and their families need to consider the choice of treatment carefully prior to beginning.
Shenoy also emphasized the need for patients to undergo regular follow-up for years to come after treatment with either gene therapy product in order to check for possible malignancies. Shenoy also touched on the benefits of patients receiving gene therapy for TDT at a younger age in order to prevent organ damage that can develop over time from frequent transfusions and the underlying disease.
Additional Considerations for the Real World
"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."
CGTLive also asked John about early real-world experience with gene therapy for TDT. Although John clarified that her firsthand experience with the products 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 issue of potential infertility caused by the busulfan conditioning. For pediatric patients who may be too young to make informed decisions about this, it can present difficulties depending on the patient’s family’s values. John also discussed the limited data on manufacturing efficiency, speed, and failure rate for the gene therapy products in the real world. She additionally touched on the need to collect more long-term data on the possibility of gene therapies causing deleterious or oncogenic off-target effects.
The Big Picture and the Broader World
On the whole, gene therapy products for TDT seem to be providing promising early outcomes for patients who are able to receive them, though, more data collection will be needed to verify the long-term efficacy and safety of these products. Furthermore, a number of barriers to accessibility to the therapies still need to be addressed.
During CGTLive’s discussions with John, she noted that although TDT is a rare disorder in the United States, occurring in only about 1,300 people in the US, it occurs more commonly in some other parts of the world, such as India.8 She pointed out that because of its rarity, many patients in the US often feel like they are facing the disease alone. John emphasized the need to foster community for patients living with TDT and seeking access to treatment.
“...[I]f we can educate locally so that those populations can start to recognize that we have the therapy available, that it can be transformative, and [we] really celebrate that—I think that's a big deal,” John told CGTLive. “Actually, one of the things that I'm starting to recognize in my region is that individuals with thalassemia live with thalassemia alone. They don't know anybody else who has thalassemia, and then they come to see me, and they start to meet other people who have had a similar therapy and they can share their story, and they can help support their community... I think building that community is really important so they can share some of that information... I do think the companies really should be focusing on building community.”
