A significant milestone in the pharmaceutical industry is on the horizon as an FDA advisory committee prepares to review the first-ever CRISPR gene editing-based therapy developed by Vertex Pharmaceuticals and CRISPR Therapeutics. The therapy, known as exagamglogene autotemcel, targets sickle cell disease (SCD). However, the critical hurdle to clear for the therapy’s approval is demonstrating that it does not cause off-target effects.
The FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee is focused on one key question: the evaluation of off-target analysis for exa-cel and whether additional studies are necessary to assess the associated risks. To support their case, Vertex and CRISPR Therapeutics have submitted data from in silico and cellular assays. However, the FDA has expressed concerns regarding the adequacy of these methods in capturing potential off-target editing specific to SCD patients.
In response, the FDA recommended the use of a more diverse data tool called CRISPRme, which could provide insights into potential off-target effects with gene editing. The companies face a challenge due to the small sample size of the target population in the available data.
To defend the therapy’s off-target effect analysis, Vertex emphasized the lack of effective treatment options for SCD, particularly for vaso-occlusive crises (VOCs). They are seeking approval to address this unmet medical need. Patients with severe SCD often rely on allogeneic hematopoietic stem cell transplants, which come with limitations and risks. Exa-cel offers an alternative with a positive benefit-risk profile that aligns with hematopoietic stem cell transplant outcomes.
While the FDA’s primary focus is on off-target effects, analysts and experts consider the agency’s inquiry to be relatively benign. The pivotal question remains whether additional studies will be required to investigate potential off-target effects and whether these studies must be completed before approval. The companies have already planned a post-marketing study to address long-term safety and monitoring.
Importantly, the FDA has not raised concerns about the therapy’s efficacy or safety profile. Given the positive data generated to date, experts believe the AdComm meeting will support exa-cel’s therapeutic profile and could act as a catalyst for the stock.
Although the chances of approval appear favorable, questions remain about market uptake, long-term studies, and potential side effects following treatment with exa-cel. Building the necessary infrastructure to support the therapy’s commercial use is another challenge.
Despite the potential obstacles, the pharmaceutical industry is on the verge of a groundbreaking moment as CRISPR-based therapy advances through the FDA approval process.
