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FDA advisers: Benefits of new sickle cell gene therapy outweigh theoretical risks

October 31, 2023

The benefits of a new therapy for severe sickle cell disease seem to outweigh theoretical risks associated with gene editing, Food and Drug Administration (FDA) advisers said Tuesday.

While the group discussed further research that could be done on exagamglogene autotemcel (exa-cel) from Vertex Pharmaceuticals Inc., it did not recommend holding up approval of the product to do so.

“It’s really exciting to see how many patients have been treated and how positive the results have been,” said Scot A. Wolfe, Ph.D., professor in the Department of Molecular, Cell, and Cancer Biology at UMass Chan Medical School. “ … We want to be careful to not let the perfect be the enemy of the good.”

Dr. Wolfe is a member of the FDA’s Cellular, Tissues, and Gene Therapies Advisory Committee, which was tasked Tuesday with reviewing data on exa-cel, although the group did not take a vote on the therapy. Vertex is requesting FDA approval of the gene therapy for people ages 12 years and older with severe sickle cell disease.

Sickle cell disease is a disorder in which red blood cells form a C shape and become sticky and fragile. It can cause debilitating pain and organ damage and affects about 100,000 people in the U.S. About 20,000 have severe disease. Sickle cell disease is disproportionately high in people of African descent in the U.S. People of Middle Eastern, Mediterranean and Indian/Asian descent also are affected.

The only cure is hematopoietic stem cell transplantation, but fewer than 20% of patients have an appropriate donor for this option. Other treatments are only partially effective.

Exa-cel is a one-time treatment that uses the gene-editing tool CRISPR to increase patients’ levels of fetal hemoglobin, which has been shown to be therapeutic without some of the risks of traditional stem cell transplantation.

Vertex performed clinical trials with 44 patients ages 12-35 years. Before treatment, they had an average of four vaso-occlusive crisis (VOC) episodes a year. After the therapy, 97% went at least 12 consecutive months without a VOC (average 22.4 months), and all participants stayed out of the hospital for at least 12 consecutive months. Results for adolescents were similar to adults.

Trial participant Victoria Gray, 38, described the pain of sickle cell disease as “like being hit by a truck and struck by lightning at the same time” and talked about the hospital stays that dominated her life. Since receiving the gene therapy, she works full time and is able to enjoy life with her children.

“I believe if you say yes to this treatment, it’s going to change the lives positively of many people who are suffering from diseases and disorders who now feel hopeless,” she said. “But once this comes, they can feel hope again just like I did.”

About 30% of trial participants had an adverse event possibly related to exa-cel, and none were serious. The most common adverse events were nausea, stomatitis, vomiting, febrile neutropenia, abdominal pain, headache and itching, which were similar to adverse events seen with other treatment options like myeloablative conditioning with busulfan and stem cell transplant. All trial participants achieved neutrophil and platelet engraftment.

The FDA asked advisers to weigh in specifically on the issue of off-target editing in which the gene editing impacts a genetic site other than the one it was intended to impact. Depending on which genomic sites are affected, these changes could range from having no functional impact to causing cancer.

Vertex leaders said Tuesday that most human genetic variation does not impact functioning, and they designed exa-cel in a way that minimizes the risk of off-target editing. The company’s studies did not find off-target editing or safety risks. It plans to follow patients for 15 years.

The FDA questioned whether sample sizes were large enough to detect risks from off-target editing. While advisers identified additional data that could be collected, none expressed a desire to hold up approval of the product to do so.

“Given what people are dealing with right now and given that the evidence of efficacy of this treatment is overwhelming, I really wonder what would we not be able to tolerate with respect to the unknown,” said Lisa M. Lee, Ph.D., associate vice president for research and innovation at Virginia Polytechnic Institute at Virginia Tech.

Acting Committee Chair Tabassum “Taby” Ahsan, Ph.D., vice president of cell therapy operations at City of Hope cancer research and treatment organization, noted the benefit is obvious while the risk is theoretical.

“One of the words I started thinking about early on during the day was what should we know vs. what can we know because when we do all this theoretical analysis, at some point it has diminishing returns and inhibits progress,” she said.

Alexis C. Komor, Ph.D., assistant professor in the Department of Chemistry and Biochemistry at the University of California, San Diego, expressed a similar sentiment.

“I think what we see here, I think especially given the benefits of this treatment, this cure, and what these patients are dealing with without having this treatment, I think the benefits far outweigh the risks here,” she said.

The FDA will weigh the committee’s input and is expected to make a decision by Dec. 8.




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