Potential cure for sickle cell disease raises few concerns for FDA panel

A panel of outside advisers to the Food and Drug Administration expressed few concerns Tuesday during a daylong meeting focused on the potential risks posed by a new therapy that could cure sickle cell disease using a gene editing technology called CRISPR.

If approved by the FDA, the infusion called exa-cel, from Vertex Pharmaceuticals, could be the first cure available for many patients battling severe forms of this rare and debilitating blood disease.

The FDA is expected to rule on exa-cel’s approval by Dec. 8, according to a Vertex press release.

Blood and bone marrow transplants are currently the only option for curing sickle cell disease, according to the National Institutes of Health, and are limited to a minority of patients who can obtain donors who match them genetically.

About 100,000 Americans are affected by sickle cell disease, the CDC estimates. Most are black and can trace their ancestry to parts of the world, from sub-Saharan Africa to the Mediterranean.

Patients can face serious and painful complications, including what doctors call vaso-occlusive crises, when blood flow is blocked in the body, causing this to happen. a patient described like “crushing pain”.

Adults with sickle cell disease now live longer thanks to medical advances, the FDA told the panel, but they are still likely to have “significantly shorter” lives.

Dr. Jon LaPook reported on another effort to harness gene therapy to cure sickle cell disease. Watch this story in the video below:

Exa-cel’s trials led to efficacy results that Vertex hailed as “transformational” and “unprecedented” for patients with severe sickle cell disease, eliminating hospitalizations due to these crises for patients who received single dose of exa-cel.

In documents released ahead of Tuesday’s meeting, the FDA largely expressed agreement with the company’s description of “strongly positive results” from trials of the therapy.

“This is an exciting time in the field of cell and gene therapy where we are beginning to address some of this unmet need in various diseases. Exa-cel has been studied for the treatment of sickle cell disease accompanied by severe vaso-occlusive crises and has shown its effectiveness. and safety,” Dr. Nicole Verdun, head of the FDA’s Office of Therapeutic Products, said during the meeting.

Risks of “off-target” genetic modification

The agency has not asked its Cell, Tissue and Gene Therapies Advisory Committee to vote on the broader balance between exa-cel’s benefits and risks, as it often does when weighing options. tricky approval decisions.

Instead, FDA officials asked the committee to focus only on discussing concerns that Vertex may need to do more to study the possibility that its technology could, in rare cases, accidentally alter other parts of the genome.

“If the gene plays an essential role in cellular function, then such unintended changes may be deleterious. These changes may also increase the risk of cancer,” FDA’s Komudi Singh, a bioinformatics reviewer for the agency, told the committee. .

Verdun said the FDA also has regulatory authority to require certain studies after product deployment, monitoring the risk of unintended changes. Vertex said it was also still in talks with the FDA about how a label for the treatment could address the theoretical risks it poses.

In its presentations to the committee, Vertex highlighted that it has used a number of strategies to minimize the risk of unintended genetic modification and examine potential pathways that could lead to unintended modifications.

Once blood is drawn from patients, the company said, their cells are only “briefly exposed” to the CRISPR technology it uses to modify the cells, before being infused back into patients.

“The design of exa-cel minimized the potential for off-target risk and multiple systematic evaluations have not identified evidence of off-target editing by exa-cel,” said Dr. David Altshuler, chief scientific officer of Vertex .

Targets submitted to CRISPR for editing were selected to be unique and have “no other matches elsewhere in the human genome,” Altshuler said.

Other experts the FDA asked to present to the committee also acknowledged theoretical concerns that off-target modifications could cause leukemia. However, many unintended changes might not even have an effect on patients, they said.

“In theory, is this possible? Yes. Is there any evidence to suggest that this is the case? I would say no. But it hasn’t really been done. We need to be humble and open to learning of these courageous patients who participate,” said Dr. Daniel Bauer, a researcher at Boston Children’s Hospital.

Committee members broadly expressed support for the treatment, as well as some additional steps after its deployment to study its long-term risks. The panel did not go so far as to request that more exhaustive research be done before the project could be approved.

“We want to be careful not to let the perfect be the enemy of the good,” said Dr. Gil Wolfe, one of the committee members.

Wolfe acknowledged that it was possible to do a “deeper analysis” of the samples, but said he was skeptical that much more useful information could be gleaned.

“You want to do the best job you can, but at some point you just have to try things with patients,” he said.

Aiming to cure sickle cell disease

In addition to exa-cel, other potential “gene therapies” are also in the works to treat sickle cell disease. And scientists hope this type of approach will also unlock a list of potential new cures for other diseases.

“There are 7,000 genetic diseases for which we know precisely the DNA misspellings. Couldn’t this same strategy, this same set of principles work for many of them, perhaps one day all of them? ?” Dr. Francis Collins, then director of the National Institutes of Health, told CBS News chief medical correspondent Dr. Jon LaPook. on “60 Minutes” in 2019.

At the time, Collins predicted that a gene therapy they were testing could cure sickle cell disease.

This trial, of a treatment now called lovo-cel from the company Bluebird Bio, is also expected to get a decision from the FDA on its potential approval in December.

“This is likely just the first of many discussions on this topic as products must be approved by regulatory authorities,” said Taby Ahsan, acting chair of the FDA panel.