Regulatory FDA Advisors Greenlight First CRISPR-Based Therapy with Confidence in...

FDA Advisors Greenlight First CRISPR-Based Therapy with Confidence in Off-Target Tests


FDA advisers have expressed contentment with CRISPR Therapeutics and Vertex Pharmaceuticals’ comprehensive evaluation of potential off-target effects in their CRISPR-based gene therapy, exa-cel. This development alleviates the FDA’s primary concerns as the approval deadline approaches.

This favorable conclusion strengthens the position of CRISPR Tx and Vertex that the assessment of potential off-target edits has been conducted with sufficient detail to justify approval, especially given the potential benefits for patients with sickle cell disease. The FDA is scheduled to make a decision on exa-cel’s approval for sickle cell patients by December 8. For the therapy’s second indication, beta thalassemia, the decision date is March 30, 2024.

In order to address concerns regarding off-target effects, Vertex and CRISPR Tx conducted in silico and cellular-based tests to identify potential off-target edits and vulnerable areas. They utilized data from the 1,000 Genomes Project, but the sample size was reduced to 61 datasets when narrowing down to the ideal patient population.

During the meeting, a question of whether conducting in vitro testing with naked DNA, Cas9, and guide RNA protein would have revealed additional off-target edits. Scot Wolfe, Ph.D., a genomics professor at the University of Massachusetts Chan Medical School, indicated that while this process could expand the potential off-target sites, it may not be necessary at this point.

As the committee was not tasked with voting on exa-cel’s risk-benefit profile, investors had minimal concerns about the potential for the meeting to negatively impact the therapy’s prospects. RBC Capital Market researchers described the meeting as beforehand, and J.P. Morgan analysts left the meeting with a positive outlook. 

Vertex entered the meeting with plans for 15 years of follow-up on both patients who participated in the phase 1/2/3 study and those who will receive the commercial product. Committee members recommended that these follow-ups include real-time analysis of gene edits.

Overall, the committee did not identify any significant issues with the off-target assessment conducted by the companies, particularly in light of the compelling clinical evidence. Updated data presented in June indicated that 88.9% of patients treated with exa-cel achieved transfusion independence 12 months after treatment, and 94.1% of sickle cell patients experienced no vaso-occlusive crises for at least 12 months.

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