European Commission Approves Exa-Cel for SCD and TDT

The European Commission has approved CRISPR Therapeutics and Vertex Pharma’s exagamglogene autotemcel (exa-cel; Casgevy) CRISPR-edited gene therapy for the treatment of patients who are 12 years of age and older with severe sickle cell disease (SCD) characterized by recurrent vaso-occlusive crises (VOCs) or transfusion-dependent beta thalassemia (TDT), for whom hematopoietic stem cell (HSC) transplantation is appropriate and a human leukocyte antigen matched related HSC donor is not available.¹

“The approval by the European Commission is yet another important regulatory milestone underscoring the potentially transformative benefit of CASGEVY for patients with severe SCD and TDT,” Samarth Kulkarni, Chairman and Chief Executive Officer, CRISPR Therapeutics, said in a statement.¹ “There is a significant burden of these diseases across Europe, and we look forward to bringing this therapy to these patients in need.”

The European approvals follow the 2 separate United States FDA approvals of exa-cel: for SCD in December 2023 alongside bluebird bio’s lovotibeglogene autotemcel (Lygenia; lovo-cel) and for TDT in January 2024.^2,3

CASGEVY is an ex vivo CRISPR/Cas9 gene-edited cell therapy in which autologous hematopoietic cells are edited at the erythroid specific enhancer region of the BCL11A gene through a precise double-strand break resulting in the restored production of fetal hemoglobin in red blood cells.

READ MORE: After Exa-Cel: Exploring the Next Wave of CRISPR Gene Editing Strategies

“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,” Janet Kwiatkowski, MD, MSCE, Thalassemia Center at Children's Hospital of Philadelphia, told CGTLive after the US approval.

Exa-cel's approvals are based off data from the phase 1/2/3 CLIMB-121 clinical trial (NCT03745287), which was conducted exclusively in patients with SCD, and the phase 3 long-term follow-up study CLIMB-131 (NCT04208529), which includes both patients with SCD and patients with TDT. Among 30 evaluable patients with SCD, 29 (97%) achieved the primary end point of freedom from VOCs for at least 12 consecutive months. Furthermore, among the 30 patients, all 30 (100%) achieved a key secondary end point for freedom from inpatient hospitalization for VOCs for at least 12 consecutive months. Six adolescent patients achieved both of these end points; the patient who did not achieve the primary end point was also an adolescent patient.³

Exa-cel was reported to be generally safe and well-tolerated in the clinical trials with a safety profile consistent with what would be anticipated in patients receiving myeloablative busulfan conditioning and hemopoietic stem cell transplantation. The only risk specific to exa-cel identified in the clinical safety data was delayed platelet engraftment.

“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,” Akshay Sharma, MBBS, an investigator on the exa-cel trials, said.

REFERENCES

1. European Commission Approves First CRISPR/Cas9 Gene-Edited Therapy, CASGEVY™ (exagamglogene autotemcel), for the Treatment of Sickle Cell Disease (SCD) and Transfusion-Dependent Beta Thalassemia (TDT). News release. CRISPR Therapeutics. February 13, 2024. https://www.globenewswire.com/news-release/2024/02/13/2827965/0/en/European-Commission-Approves-First-CRISPR-Cas9-Gene-Edited-Therapy-CASGEVY-exagamglogene-autotemcel-for-the-Treatment-of-Sickle-Cell-Disease-SCD-and-Transfusion-Dependent-Beta-Thal.html
2. Vertex Announces US FDA Approval of CASGEVY™ (exagamglogene autotemcel) for the Treatment of Transfusion-Dependent Beta Thalassemia. News release. January 16, 2024. https://news.vrtx.com/news-releases/news-release-details/vertex-announces-us-fda-approval-casgevytm-exagamglogene
3. FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease. News release. FDA. December 7, 2023. Accessed December 7, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease