FDA advisers wave through first CRISPR-based therapy, satisfied with off-target tests

FDA advisers appear satisfied with CRISPR Therapeutics and Vertex Pharmaceuticals’ assessment of potential off-target effects from their CRISPR-based gene therapy exa-cel, quelling the top concern from the FDA as an approval deadline nears. 

Acting chair of the Cellular, Tissue, and Gene Therapies Advisory Committee Taby Ahsan, Ph.D., summarized Tuesday's meeting by noting that there was a “robust approach using multiple methods to try to identify these off-targets.”

The conclusion bolsters CRISPR Tx and Vertex’s stance that the potential—or lack thereof—for off-target edits has been studied in enough detail to warrant approval given the potential benefit for patients with sickle cell disease. The FDA is set to decide by December 8 on whether exa-cel will be approved for sickle cell patients. The decision date for the companies' second indication, beta thalassemia, is March 30, 2024. 

To assuage off-target concerns, Vertex and CRISPR Tx performed in sillico and cellular-based tests to find where off-target edits could’ve been made or areas that would’ve been susceptible to changes. The company relied on data from the 1,000 Genomes Project but when whittling down to the ideal patient population, the sample size dwindled to 61 datasets. 

Ahsan posed whether a third option, testing naked DNA with Cas9 and guide RNA protein in vitro, would’ve uncovered additional off-target edits. Scot Wolfe, Ph.D., a genomics professor at the University of Massachusetts Chan Medical School, said that while the process does increase the breadth of potential off-target sites, it may not be warranted. 

“It’s a valid way to go,” he said. “I don’t know if it’s worth the effort at this point given the analysis that they’ve already done.” 

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

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

Given the fact that the committee was not tasked with actually voting on exa-cel’s risk-benefit profile, investors had few concerns about the potential for the meeting to knock the therapy down a few pegs. RBC Capital Market researchers called the meeting “pretty benign” beforehand and J.P. Morgan analysts walked away from the meeting “incrementally more positive” on exa-cel’s approval potential.