Medical director, pediatric hematology/oncology, Sarah Cannon Pediatric Transplant and Cellular Therapy Program, TriStar Centennial, and investigator, Sarah Cannon Research Institute

Haydar Frangoul, MD, MS

Exa-Cel Approval Expands to Children as Young as 2 With Haydar Frangoul, MD

The US Food and Drug Administration (FDA) has expanded approval of exagamglogene autotemcel (exa-cel; Casgevy) to children ≥ 2 years of age with sickle cell disease (SCD) and recurrent vaso-occlusive crises (VOCs) or transfusion-dependent β-thalassemia (TDT), making it the first CRISPR-based gene-editing therapy approved for children this young with either condition.

Announced on July 1, 2026, the supplemental approval lowers the minimum approved age from 12 years and expands access to a one-time gene-editing therapy earlier in the disease course. The decision was supported by efficacy and safety data in children aged 5 to younger than 12 years, with the indication extending to children aged 2 to younger than 5 years based on extrapolation from those findings. The approval was granted 53 days after filing through the FDA Commissioner's National Priority Voucher pilot program.

For Haydar Frangoul, MD, MS, director of the pediatric stem cell transplant program at Sarah Cannon Research Institute and TriStar Centennial Children's Hospital and first author of multiple landmark studies evaluating exa-cel, the expanded indication represents an opportunity to begin discussing curative therapy earlier with patients and families.

"This is a huge milestone in the field, and I hope it won't be the last milestone in the field," Frangoul told 

Earlier Intervention Before Irreversible Complications

Although the pediatric findings closely mirrored results previously reported in adolescents and adults, Frangoul said the expanded indication is most meaningful because it creates the potential to intervene before cumulative disease-related complications become irreversible.

"The striking part is that children did extremely well, which we expect them to because they don't have end organ damage," Frangoul said.

He explained that both SCD and TDT cause progressive complications that accumulate throughout childhood and adulthood.

"Individuals with sickle cell disease... can develop more chronic complications that are irreversible with any type of therapy, including transplant or gene therapy," Frangoul said.

Earlier access to gene-editing therapy, he said, may allow clinicians to intervene before permanent organ damage develops, a concept also reflected in the FDA's rationale for expanding the indication to younger children.

Pediatric Data Extend Earlier Clinical Experience

According to Frangoul, the most important finding from the pediatric studies was not that outcomes differed from older patients, but that they remained remarkably consistent across age groups.

"The biggest takeaway is that the results... mirrored the results that we previously published in those who are 12 to age 35 and adolescents as well as in adults," Frangoul said.

The FDA based the expanded approval on efficacy and safety data in children aged 5 to younger than 12 years.

Among pediatric patients with SCD, all 8 efficacy-evaluable children achieved the primary endpoint of remaining free from protocol-defined severe vaso-occlusive crises for at least 12 consecutive months within the first 24 months following exa-cel infusion. Among pediatric patients with TDT, 8 of 9 efficacy-evaluable children achieved transfusion independence for at least 12 consecutive months, with a median duration of transfusion independence of 20.1 months.

Exa-cel is an autologous CRISPR/Cas9 gene-editing therapy in which a patient's hematopoietic stem cells are edited ex vivo before reinfusion following myeloablative conditioning. By increasing fetal hemoglobin production, the therapy reduces sickling of red blood cells in SCD and can eliminate transfusion dependence in patients with TDT.

Earlier Conversations About Curative Therapy

Beyond the regulatory decision, Frangoul believes the expanded indication should prompt hematologists to begin discussing curative treatment options earlier in the disease course.

Having cared for patients with SCD and TDT for nearly three decades, he said families should understand available treatment options even if gene therapy ultimately is not the right choice.

"I believe that every child and every even adult or adolescent with these diseases need to actually know their options," Frangoul said. "It might not be for everybody, and not everybody might want to do it."

Because most patients receive their routine care from hematologists rather than transplant or gene therapy specialists, he encouraged earlier collaboration between community clinicians and centers offering curative therapies.

"I hope that hematologists... partner with their partners that do the gene therapy and do the curative therapies and discuss these options early in life," Frangoul said.

He noted that introducing these conversations before children become eligible for treatment allows families to better understand future options if disease-related complications emerge over time.

Expanding Access Beyond Bone Marrow Transplantation

Frangoul also emphasized the approval's importance for patients who historically have not had access to curative therapy.

Approximately 80% of patients with SCD or TDT do not have a matched sibling donor and therefore are not candidates for allogeneic bone marrow transplantation, historically the only established curative approach for these disorders.

"This basically opens the door to the majority of the patients to be able to receive this therapy, which is really exciting," Frangoul said.

Treatment with exa-cel requires myeloablative conditioning before reinfusion of gene-edited autologous hematopoietic stem cells. The prescribing information includes warnings for neutrophil engraftment failure, delayed platelet engraftment, hypersensitivity reactions, and the potential for off-target genome editing.

Reflecting on patients he has followed after treatment, Frangoul described seeing children and young adults return to school, pursue careers, and regain opportunities that once seemed out of reach.

"I have some of the patients who went back to college. One graduated law school recently," he said.

Looking back on nearly 30 years caring for patients with SCD and TDT, Frangoul said the pace of progress has exceeded what he imagined earlier in his career.

"We are now in 2026, a place I never dreamt of 20 years ago," Frangoul said. "It is very exciting."

FDA approves first gene therapy for young children with sickle cell disease.

Frangoul H, Locatelli F, Sharma A, et al. Exagamglogene autotemcel for severe sickle cell disease. 

 2024;390(18):1649-1662. doi:10.1056/NEJMoa2309676.

Frangoul H, et al. Exagamglogene autotemcel in children with severe sickle cell disease and transfusion-dependent β-thalassemia. 

Videos

Haydar Frangoul, MD, discusses how the expanded indication may allow earlier conversations about curative therapy and intervention before irreversible complications develop.

FDA Expands Exa-Cel (Casgevy) Approval, Bringing Gene Therapy to Younger Children

Frangoul discussed highlights from the latest data update from the CLIMB SCD-121 trial of Casgevy.

Haydar Frangoul, MD: Preventing VOCs in People With Sickle Cell Disease With Exa-Cel Gene Editing Therapy

Exagamglogene autotemcel (exa-cel; Casgevy, Vertex Pharma and CRISPR Therapeutics) is a non-viral CRISPR-Cas9 gene editing cell therapy that reactivates fetal hemoglobin (HbF), approved as a one-time treatment for patients aged at least 12 years with severe sickle cell disease (SCD). The CLIMB SCD-121 phase 3 study is ongoing and continues to assess the safety and efficacy of exa-cel in people with SCD.

The latest data from the CLIMB SCD-121 study are being presented at the

 66th American Society of Hematology (ASH) Annual Meeting and Exposition

, held December 7-10, 2024, in San Diego, California, by Haydar Frangoul, MD, MS, medical director, pediatric hematology/oncology, Sarah Cannon Pediatric Transplant and Cellular Therapy Program, TriStar Centennial, and investigator, Sarah Cannon Research Institute.

“I keep telling people that our therapy was CRISPR gene editing 1.0 and I'm pretty sure as the field evolves, we are going to potentially use safer conditioning regimen for patients that will does not cause hair loss and infertility. But we had to start somewhere… and I think that's why it's so groundbreaking, is what we did is we established the bar, and now it can only get better from here,” Frangoul told 

He shared highlights from the data update, including an over 90% rate of participants remaining vaso-occulsive event (VOC)-free, and an over 90% hospitalization prevention rate. He also noted that participants maintained fetal hemoglobin levels of over 40% sustained for up to 5 years.

“The big question that yet to be answered is, yes, we are preventing VOCs, but how is that going to impact the end organ damage that we know SCD patients will develop years and years and years down the road. So, I am very excited to see where the field goes,” Frangoul said.

Frangoul H, Locatelli F, Sharma A, et al. Durable Clinical Benefits with Exagamglogene Autotemcel for Severe Sickle Cell Disease. Presented at: Presented at: ASH Annual meeting; December 7-10; San Diego, California. Abstract 4954.

Haydar Frangoul, MD, MS

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