Exa-cel a ‘first step’ in gene therapy for sickle cell disease, beta-thalassemia
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Key takeaways:
- Exagamglogene autotemcel helped patients with beta-thalassemia achieve transfusion independence.
- The drug also reduced how many vaso-occlusive crises patients with sickle cell disease.
Exagamglogene autotemcel gave most patients with beta-thalassemia transfusion independence and drastically reduced the number of vaso-occlusive crises in those with sickle cell disease in a pair of phase 3 trials.
More than 90% of participants in each trial met researchers’ primary endpoints, according final study data published in The New England Journal of Medicine.
“We are thrilled about the results,” Haydar Frangoul, MD, medical director of pediatric hematology/oncology at Sarah Cannon Research Institute and HCA Healthcare’s TriStar Centennial Children’s Hospital, told Healio. “When you are doing a study initially, you are hopeful to see results like this.”
Exagamglogene autotemcel (CRISPR Therapeutics, Vertex Pharmaceuticals), also known as exa-cel, is a nonviral cell therapy that reactivates production of fetal hemoglobin with gene editing of autologous CD34-positive hematopoietic stem and progenitor cells, according to information in both studies.
Healio previously reported on the phase 1/phase 2 trials using exa-cel — CLIMB THAL-111, for patients with beta-thalassemia, and CLIMB-SCD-121, for individuals with sickle cell disease. The FDA approved exa-cel as the first gene-editing treatment for sickle cell disease in December, and the first for beta-thalassemia in January.
“Everybody in the field is quite optimistic and excited about these results,” Frangoul said. “I’m hopeful that physicians treating patients with sickle cell and beta-thalassemia will talk to them about these therapies and refer them to somebody who is an experienced physician or a transplant program that is able to do these therapies. It’s a huge milestone.”
Sickle cell disease trial
In CLIMB-SCD-121, patients had to be between ages 12 and 35 years and have at least two severe vaso-occlusive crises in the previous 2 years.
Study participants received pharmacokinetic-adjusted busulfan myeloablation prior to treatment.
The open-label study had 44 patients (55% men; 86% Black; 73% aged 18-35 years) receive exa-cel with a median follow-up of 19.3 months.
All patients had neutrophil and platelet engraftment, 97% did not have vaso-occlusive crises for at least 1 year (95% CI, 83-100) and no patients had hospitalizations due to vaso-occlusive crises for at least 1 year (P < .001).
“Our fetal hemoglobin in individuals we enroll continue to be very stable over 2, 3, 4, 5 years, which is indicative that our editing really was effective in the hematopoietic stem cells, not in cells that will eventually fade and go away,” Frangoul said.
All patients had at least one adverse event. Researchers categorized most adverse events as grade 1 or 2, but 95% of patients experienced a grade 3 or 4 toxicity.
The most common grade 3 and above adverse events included stomatitis (55%), febrile neutropenia (48%), and decreased platelet count (48%) and appetite (41%).
Neither graft failure nor cancer developed in any patients.
“The adverse events with this study were very similar to what you expect in an autologous transplant,” Frangoul said. “When you give high-dose [chemotherapy] to individuals with a sickle cell disease, they’re going to lose their hair. They’re going to drop their white count. They are going to drop their platelets. They are going to get fever, neutropenia. All of these adverse events were compatible with what you see with high-dose chemotherapy in an autologous transplant.”
Beta-thalassemia trial
In CLIMB THAL-111, patients also had to be between ages 12 and 35 years. They had to have transfusion-dependent beta-thalassemia and specific genotypes.
Participants had the same conditioning as the individuals in the beta-sickle cell disease trial.
The open-label study had 52 participants (52% men; 42% Asian; 65% aged 18-35 years) receive exa-cel with a median follow-up of 20.4 months.
As in the other trial, all patients had neutrophil and platelet engraftment, and 91% achieved transfusion independence for at least 1 year (95% CI, 77-98).
Hemoglobin levels increased shortly after infusion and remained elevated.
All patients had at least one adverse event. Researchers categorized most of the adverse events as grade 1 or 2, but 88% of patients experienced a grade 3 or 4 toxicity.
The most common grade 3 and above adverse events included febrile neutropenia (54%), stomatitis (40%), anemia (38%), decreased platelet count (35%) and thrombocytopenia (35%).
Serious adverse events occurred in 33% of patients, the most common being veno-occlusive liver disease (five patients). Researchers believe busulfan conditioning caused them.
Next steps
The studies have follow-up protocols that last for 15 years, and Frangoul hopes they can produce answers about exa-cel’s impact on the body.
“The average life expectancy of an individual with sickle cell disease is 45 years,” he said. “The reason why is because they get end-organ damage — kidney damage, brain damage, lung damage. The key is to see if these therapies that are so effective early on actually can prevent end-organ damage long term.”
Joseph M. McCune, MD, PhD, professor at University of California, San Francisco, and HansPeter Kiem, MD, PhD, deputy director of translational science and therapeutics division at Fred Hutch Cancer Center, wrote an accompanying editorial in praising the success of the trials, but hoping future research could look into in vivo gene therapy, which could help reduce the need for high-dose chemotherapy for preparation, as well as ways to reduce cost and expand the availability away from specialized centers.
Frangoul hopes exa-cel’s approvals can be the start of that.
“Those two [studies] are basically the first step, [like Neil] Armstrong’s foot on the moon,” he said. “There are many other steps in the future. Hopefully, we showed that gene editing is safe and effective in humans, not only in the Petri dish and the lab.”
For more information:
Haydar Frangoul, MD, can be reached at haydar.frangoul@hcahealthcare.com.
References:
- Frangoul H, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2309676.
- Locatelli F, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2309673.
- McCune JM, et al. N Engl J Med. 2024;doi:10.1056/NEJMe2403104.
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