Sickle cell gene therapy ‘benefits far outweigh the risks,’ FDA adviser says
Click Here to Manage Email Alerts
An FDA panel appeared comfortable with theoretical safety concerns during an advisory committee meeting considering the risks vs. benefits of what would be the first gene therapy for the treatment of sickle cell disease.
The Cellular, Tissue and Gene Therapies Advisory Committee convened to consider whether the gene editing technique used in exagamglogene autotemcel (CRISPR Therapeutics, Vertex Pharmaceuticals) — often called exa-cel — could cause unwanted or “off-target” gene edits in patients’ DNA.
Although the panel did not vote on any recommendations regarding the agent’s safety or efficacy, it did discuss current evidence and largely conclude that the potential benefits to patients likely outweigh any hypothetical risks caused by off-target gene edits.
Specifically, the panel considered the robustness of the manufacturer’s off-target editing analysis and whether any of them recommended additional studies to assess the risk.
“We want to be careful to not let the perfect be the enemy of the good,” panelist Scot A. Wolfe, PhD, professor of molecular, cell and cancer biology at UMass Chan Medical School, said during the discussion. "It's really exciting to see how many patients have been treated [with exa-cel] and how positive the results have been.”
Although some off-target analysis could be more precise, overall the manufacturer’s analyses use gold-standard testing to evaluate possible issues, Wolfe added.
The need for more detailed off-target analysis fell under the category of "interesting" rather than a necessity, according to Wolfe.
“There is such a huge unmet need in patients with sickle cell disease and it’s important that we think about how we can advance therapies that can help these patients,” he said. “I certainly think that [exa-cel] is one of them.”
The advisory committee meeting comes as the FDA considers a biologics license application for exagamglogene autotemcel for the treatment of sickle cell disease in patients 12 years and older with recurrent vaso-occlusive crises.
The pivotal phase 1/phase 2 CLIMB SCD-121 trial assessed the safety and efficacy of exa-cel in patients with severe sickle cell disease aged 12 to 35 years. Only of 30 patients (mean age, 22 ± 6 years; 52.3% women) in the study’s primary efficacy sample reported a vaso-occulsive event after being treated with exa-cel (duration range, 2-32.3 months) compared with 3.9 severe vaso-occlusive events (range, 2-9.5) per year during the 2 years prior to study enrollment.
The panelists generally agreed with Wolfe’s analysis, including Alexis Komor, PhD, assistant professor of chemistry and biochemistry at University of California, San Diego.
“[The manufacturer's] in silico off-target analysis was quite expansive,” she said. "The thresholds they used were quite lenient."
Although the technology exists to do a comprehensive genetic off-target analysis of each patient’s genome, such a step would not be reasonable on the part of the manufacturer at this time, according to Komor.
"Given the benefits of this treatment — or cure — and what patients are facing without it, I think the benefits far outweigh the risks,” she said.
The FDA has established a target action date of Dec. 8, 2023, for exa-cel’s sickle cell disease indication marketing request.
Collapse
Meeting of the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee. Oct. 31, 2023.
Click Here to Manage Email Alerts