Exagamglogene autotemcel (exa-cel) has shown the potential to be a landmark therapy in preventing episodes of excruciating pain among patients with sickle cell disease.
CRISPR Therapeutics has announced the completion of the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee meeting for exagamglogene autotemcel (exa-cel) for the treatment of sickle cell disease (SCD) in patients aged 12 years and older with recurrent vaso-occlusive crises (VOCs). Exa-cel is the first potential therapy to emerge from a strategic partnership between CRISPR Therapeutics and Vertex Pharmaceuticals.1
During the committee meeting, which was held on October 31, 2023, independent FDA advisers praised the treatment. During the hearing, Vertex Pharmaceuticals, which developed the treatment with CRISPR Therapeutics, reported that exa-cel appears to be safe and highly effective at preventing episodes of excruciating pain that plague patients with SCD. The treatment worked in 29 of 30 patients who were followed for at least 18 months and doesn't appear to cause any serious short-term safety concerns, the company reported.1
"In totality, the data support the remarkable clinical benefit of exa-cel in patients with SCD," William Hobbs, MD, PhD, vice president, clinical development, Vertex told the committee.2
The FDA concurred with the potential benefits of exa-cel and did not ask advisers to take the usual step of assessing exa-cel's benefits or whether the agency should approve the therapy.2
Instead, because of the high stakes of approving an entirely new kind of technology to treat people for the first time, the FDA asked advisers to focus on whether sufficient research had been done to spot "off-target" effects of the treatment—unintended editing errors that missed their mark in the DNA and that could potentially cause long-term health problems.2
The advisers suggested that Vertex and CRISPR could assess the potential safety risks of their SCD gene therapy after approval. If the therapy is approved, Vertex has proposed a 15-year follow up of patients to evaluate the safety outcomes of exa-cel. This 15-year follow up will help generate data from real-time monitoring of the therapy, which uses the new gene editing CRISPR technology.3
Although the advisers agreed that additional research could be helpful, several members expressed enthusiasm for the treatment.
"It's really exciting to see how many patients have been treated and how positive the results have been," said Scot Wolfe of the UMass Chan Medical School. "We want to be careful to not let the perfect be the enemy of the good."2
SCD is caused by a genetic defect that produces an abnormal form of the protein hemoglobin, which red blood cells need to carry oxygen through the body. These red blood cells then get jammed inside blood vessels.2
The jagged cells cause unpredictable attacks of intense pain and damage vital organs. Throughout their lives, patients with SCD are repeatedly rushed to the hospital for powerful pain drugs and blood transfusions. This affects their ability to finish school, hold jobs, or care for themselves or their families. Patients are also prone to strokes and other serious complications.2
If approved, exa-cel could be the first genetic therapy available to approximately 20,000 patients with severe SCD in the United States. The FDA granted priority review for exa-cel in the treatment of patients with SCD and assigned a Prescription Drug User Fee Act (PDUFA) action date of December 8, 2023. Exa-cel’s Biologics License Application (BLA) for transfusion-dependent beta-thalassemia (TDT) was assigned a PDUFA date of March 30, 2024.1