Experts Weigh In on Exa-cel's FDA Approval for Transfusion-Dependent Thalassemia


In light of this major decision by the agency, CGTLive™ decided to reach out to several experts to get their thoughts on how exa-cel could impact the landscape of care for TDT.

On January 16, 2024, Vertex Pharmaceuticals’ and CRISPR Therapeutics’ exagamglogene autotemcel (exa-cel; marketed as Casgevy), an autologous CRISPR-based gene-edited cell therapy, was approved by the FDA for the treatment of patients 12 years and older with transfusion-dependent beta thalassemia (TDT).1 The decision was the second FDA approval garnered by exa-cel, which had previously been approved for the treatment of severe sickle cell disease (SCD) in patients aged 12 years and older with recurrent vaso-occlusive crises.2 The new approval in TDT was based on data from the phase 1/2/3 CLIMB-111 clinical trial (NCT03655678) in patients with TDT and the phase 3 long-term follow-up study CLIMB-131 (NCT04208529), which includes both patients with SCD and patients with TDT.1

In light of this major decision by the FDA, CGTLive™ decided to reach out to several experts to get their thoughts on how exa-cel could impact the landscape of care for TDT. Those reached out to included Akshay Sharma, MBBS, a bone marrow transplant physician at St. Jude Children’s Research Hospital; Janet Kwiatkowski, MD, MSCE, the director of the Thalassemia Center at Children's Hospital of Philadelphia (CHOP); Stephan Grupp, MD, PhD, the section chief of the Cellular Therapy and Transplant Section at CHOP; and Mark Walters, MD, the division chief of Hematology at UCSF Benioff Children’s Hospitals. Their initial reactions are reproduced below.

Akshay Sharma, MBBS

Akshay Sharma, MBBS

Akshay Sharma, MBBS: Thalassemia is an inherited disorder wherein the patients require regular blood transfusions, every 2-6 weeks, depending upon the severity of their disease, for their entire lives. In high resource settings, these blood transfusions are a burden and while they are resource intensive, most patients can be managed easily. These autologous genetic therapies provide a way to potentially reduce or eliminate that transfusion burden and associated side effects. Patients would then not have to go to their hematologist every few weeks, which would be remarkable. But I am most excited about the potential of these therapies to change the lives of patients in low resource settings where these blood transfusions are essentially a lifeline, and not easily accessible. If one-time gene therapies can be implemented in Southeast Asia—where the burden of thalassemia is probably the highest in the world, and where blood transfusion supply is not consistent—that in my opinion would be a game changer for these patients. These one-time autologous genetic therapies are not only desired but are urgently needed in such areas and we must do better for their equitable distribution outside North America and Europe.

Janet Kwiatkowski, MD, MSCE: Individuals with TDT have a tremendous treatment burden and are at risk of health problems related to their necessary blood transfusions and iron chelation treatments. As a clinician and investigator in the clinical trial that led to the approval of Casgevy, I am excited that the FDA has approved this treatment, which now offers another potentially curative treatment option.

Stephan Grupp, MD, PhD: It’s been exciting to see “early” FDA action in the space, with Lyfgenia getting FDA approval prior to its Prescription Drug User Fee Act (PDUFA) date, and now we’re seeing the same thing with Casgevy for the TDT indication well ahead of its PDUFA date. I think this is a great sign for the field, and I look forward to the next 1-2 years when we see issues of access, uptake, and manufacturing addressed in this new therapeutic area. I’m especially interested in the ability of the US healthcare system to address access in an equitable fashion. The study data look great, but now is our opportunity to learn how these products perform in the real world.

Mark Walters, MD

Mark Walters, MD, the division chief of Hematology at UCSF Benioff Children’s Hospitals

Walters, MD: It was gratifying to learn about the FDA approval of this new therapy with curative intent for TDT, which uses a person’s own stem cells as donor for a transplant that replaces thalassemia-producing with gene-modified blood stem cells that produce healthy red blood cells with high fetal hemoglobin content. This treatment uses CRISPR technology that extended a benefit of no longer needing RBC transfusions in roughly 90% of participants in a pivotal Vertex Pharmaceuticals-sponsored clinical trial.

Transcript edited for clarity.

1. Vertex Announces US FDA Approval of CASGEVY™ (exagamglogene autotemcel) for the Treatment of Transfusion-Dependent Beta Thalassemia. News release. January 16, 2024.
2. FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease. News release. FDA. December 7, 2023. Accessed December 7, 2023.
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