Food and Drug Administration scientists are scrutinizing whether an experimental gene editing therapy for sickle cell disease makes unwanted changes to DNA as part of the agency’s closely watched review of the CRISPR-based treatment.

Documents published Friday revealed the agency plans to focus a meeting of expert advisers next week on this risk, known as “off-target” edits, and on whether there’s enough evidence to show it’s not a safety concern.

Called exa-cel and developed by partners Vertex Pharmaceuticals and CRISPR Therapeutics, the treatment is the first CRISPR medicine up for approval in the U.S., about a decade after the Nobel Prize-winning technology was described in a series of landmark papers.

Testing by Vertex and CRISPR has shown exa-cel generally eliminates the debilitating pain crises that people with sickle cell disease frequently experience. People treated in the companies’ study also had significantly higher levels of hemoglobin, the vital oxygen-carrying protein that’s disrupted by the disease.

The FDA, which is set to decide on exa-cel’s approval by Dec. 8, appears convinced the treatment does offer significant benefit. In the documents, agency staff describe Vertex and CRISPR’s supporting clinical trial data as “strongly positive” and “evidence of efficacy of exa-cel.”

FDA staff also don’t appear unduly concerned by the direct safety risks involved in receiving exa-cel, which is made from a patient’s own stem cells that are extracted and edited with CRISPR in a laboratory. Before exa-cel can be infused, patients have to undergo an arduous “conditioning” regimen of chemotherapy that can cause painful mouth sores and leave them at risk of infection.

Instead, the agency’s scientists have zeroed in on the theoretical risk that the CRISPR tools used to edit a specific gene in patient stem cells might also cut DNA in other areas of the genome.

“Since unintended edits can disrupt gene expression if present in the coding or regulatory DNA sequences, it is critical that the specificity of [exa-cel’s targeting component] be thoroughly screened to ensure off-target genome editing is minimized,” FDA staff wrote.

Vertex and CRISPR did several tests to ensure off-target edits weren’t happening. Using a computer algorithm, the companies identified stretches of the genome that are, based on their sequence, the most likely sites for any off-target CRISPR edits. Testing at those sites of edited cells from healthy donors showed no unwanted DNA changes.

Vertex and CRISPR also did another experiment with donor stem cells from six individuals who had either sickle cell or beta thalassemia, another blood disorder exa-cel is being developed for. Testing using a technique known as “GUIDE-seq” also showed no off-target edits.

The FDA raised a number of technical issues with the companies’ tests, which agency staff said might not accurately reflect genetic variations among people with sickle cell. In theory, people with rare gene variants may be at risk of off-target edits not foreseen by Vertex and CRISPR’s analysis.

Still, the documents noted the availability of donor cells from people with sickle cell disease is limited, making it harder to do more exhaustive testing.

To Luca Issi, an analyst at RBC Capital Markets, the FDA documents read “benign.” In a Friday client note, he wrote how the agency’s focus appears to be on “technology … more than the broader risk for patients receiving this therapy.”

Mizuho Securities’ Salim Syed took a similar view, describing the document as possibly a “best-case scenario.” He also noted that the FDA is only posing to the advisory committee experts a “discussion” question, rather than asking for a recorded vote.

The committee, which will meet from 9 a.m. to 5 p.m ET on Tuesday, is made up of experts in gene editing, stem cell biology, biostatistics and sickle cell disease. It’s tentatively slated to include 14 members, including industry, consumer and patient representatives.

While the FDA typically follows the advice of its committees, it’s not required to.

About PackGene

PackGene is a CRO & CDMO technology company that specializes in packaging recombinant adeno-associated virus (rAAV) vectors. Since its establishment in 2014, PackGene has been a leader in the AAV vector CRO service field, providing tens of thousands of custom batches of AAV samples to customers in over 20 countries. PackGene offers a one-stop CMC solution for the early development, pre-clinical development, clinical trials, and drug approval of rAAV vector drugs for cell and gene therapy (CGT) companies that is fast, cost-effective, high-quality, and scalable. Additionally, the company provides compliant services for the GMP-scale production of AAVs and plasmids for pharmaceutical companies, utilizing five technology platforms, including the π-Alpha 293 cell AAV high-yield platform and the π-Omega plasmid high-yield platform. PackGene's mission is to make gene therapy affordable and accelerate the launch of innovative gene drugs. The company aims to simplify the challenging aspects of gene therapy development and industrialization processes and provide stable, efficient, and economical rAAV Fast Services to accelerate gene and cell therapy development efforts from discovery phase to commercialization.

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