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An FDA advisory committee meeting on Tuesday did nothing to dispel expectations that the investigational agent exagamglogene autotemcel (exa-cel) will become the first approved gene therapy for sickle cell disease (SCD).

Members of the were not asked to vote on the agent's efficacy or safety, but instead directed to discuss whether it has been adequately proven that exa-cel won't produce off-target genetic changes, and it became clear that most panelists believe that the benefits of the therapy far outweigh the theoretical risks of off-target editing.

"There seem to be a lot of unknowns, a lot of uncertainty about what those off-target changes mean," said panelist Lisa Lee, PhD, of the Virginia Polytechnic Institute and State University in Blacksburg. "Are those unknowns more harmful than not allowing this to go forward? Given that the efficacy of this treatment is overwhelming, I really wonder what we would not be willing to tolerate with respect to the unknowns."

"There seems to be a strong sense of benefit, and the risk is theoretical," agreed committee chair Tabassum Ahsan, PhD, of City of Hope in Duarte, California.

The FDA called the meeting specifically to discuss the use of in silico and cell-based assays by developers Vertex Pharmaceuticals and CRISPR Therapeutics in evaluating off-target editing for exa-cel in the target population of SCD patients.

FDA staff identified several potential issues with exa-cel's off-target analysis. They noted that in silico off-target analysis was performed using the 1000 Genomes Project database to account for heterogeneity. However, they pointed out:

• The database contains a small amount of sequencing data from the target population of exa-cel
• Sampling of variants may be inadequate
• Confirmatory testing was performed in samples harboring a fraction of the variants nominated

Regarding cellular off-target analysis, agency staffers questioned the adequacy of the sample size, which consisted of a limited number of healthy and SCD donors. But they were convinced of the therapy's efficacy.

In the pivotal clinical study (), 29 of 30 evaluable patients (96.7%) achieved the primary efficacy endpoint of the absence of severe vaso-occlusive crises (VOCs) for at least 12 consecutive months. Of those 29 patients, 28 remained free of VOCs for a mean duration of 22.3 months, with a maximum of 45.5 months.

Vertex called the magnitude of this effect "transformational," considering that the patients in this analysis had a mean of almost four VOCs per year in the 2 years prior to screening.

All 30 evaluable subjects met the key secondary endpoint of freedom from inpatient hospitalization for severe VOCs for at least 12 consecutive months. In addition, all six adolescents included in the primary efficacy analysis achieved absence of severe VOCs for at least 12 consecutive months.

The compelling efficacy data, along with emotional testimony provided by 10 self-described sickle cell "warriors" during an open public hearing, seemed to leave panelists pondering how much more can be done to mitigate the potential risks of off-target editing.

"We ought to be careful to not let perfect be the enemy of the good," said Scot Wolfe, PhD, of the UMass Chan Medical School in Worcester, Massachusetts. "You can do a lot of in-depth analysis ... prior to the introduction to the patient, and you want to do as good a job as you possibly can, but at some point you just have to try things out on the patient."

"There is a huge unmet need for individuals with sickle cell disease, and it's important that we think about how we can advance therapies that can potentially help them," he added. "And I certainly think this is one of them."

"Each individual on the planet has several million genetic variants in their genome," said Alexis Komor, PhD, of the University of California San Diego. "The perfect off-target analysis would be to sequence the patient, use that as a reference genome, and then individually validate every single off-target. Do we have the technology to do that? Probably, but is that reasonable to expect?"

"Given the benefits of this treatment -- or this cure -- and what these patients are dealing with without having this treatment, I think the benefits far outweigh the risks," she added.

What Is the Risk?

As for what the risk of off-target editing might mean for patients, Lee asked guest speaker Daniel Bauer, MD, PhD, director of the gene therapy program at Boston Children's Hospital and the Dana-Farber Cancer institute, how he would characterize the consequences of off-target edits.

"I would emphasize to patients there is often uncertainty about the functional significance of off-target edits," Bauer said.

"Only a small part of the human genome actually codes for genes -- most of the human genome is non-coding. It's likely that many places in the human genome can tolerate an off-target edit and not have a functional consequence."

"The challenge is that we don't really know for sure, and the only way to know that is careful follow-up," he added. "My guess is that it's a relatively small risk in the scheme of this risk-benefit, but it's new, it's unknown."

However, said Bauer, it's easily measurable: "One of the goals of doing this under very careful circumstances is to try to learn what that risk is so that we can continue to improve those therapies."

Lee then asked if the consequences could be potentially catastrophic.

"In theory, these cell products have lots of cells in them, and any one cell that goes awry could cause leukemia," Bauer answered, and added that while theoretically an off-target effect of gene editing could cause leukemia, there is no evidence that it does.

But, he reminded the advisors that "this really hasn't been done very much. We need to be humble and open to learning from these brave patients who are participating" in these studies.

The ongoing long-term, open-label trial, CLIMB-131, is designed to evaluate the safety and efficacy of exa-cel in patients who received exa-cel in CLIMB-111, CLIMB-121, CLIMB-141, CLIMB-151, or CLIMB-161. The trial is designed to follow participants for up to 15 years after exa-cel infusion.

The agency is expected to decide by December 8 on whether to grant exa-cell an indication in sickle cell disease. While the FDA is not required to follow the advice of its advisors, it typically does.

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