FDA advisers see no roadblocks for gene-editing treatment for sickle cell disease

The Food and Drug Administration appears poised to approve the first medical therapy that uses gene-editing to treat a disease.

A committee of independent FDA advisers Tuesday praised the treatment, which uses the gene-editing technique called CRISPR to treat sickle cell disease, a devastating blood disorder

The assessment of outside advisers typically marks the final step before the agency renders a decision. The FDA has a Dec. 8 deadline to act on the therapy, known as "exa-cel."

During the hearing, Vertex Pharmaceuticals of Boston, which developed the treatment with CRISPR Therapeutics also based in Boston, reported exa-cel appears to be safe and highly effective at preventing episodes of excruciating pain that plague sickle cell disease patients.

The treatment worked in 29 of 30 patients followed for at least 18 months, and doesn't appear to cause any serious short-term safety concerns, the company reported.

"In totality, the data support the remarkable clinical benefit of exa-cel in patients with sickle cell disease," Dr. William Hobbs, Vertex's vice president, clinical development, told the committee.

Because the FDA concurred in an analysis posted Friday, the agency did not ask the advisers to take the usual step of assessing exa-cel's benefits or whether the agency should approve the therapy.

Instead, because of the high stakes of approving an entirely new kind of technology to treat people for the first time, the FDA instead asked the advisers to focus on whether sufficient research had been done to spot "off-target" effects of the treatment — unintended editing errors that missed their mark in the DNA and that could potentially cause long-term health problems.

While agreeing additional research could be helpful, several committee members expressed enthusiasm for the treatment and few concerns that theoretical issues would outweigh the clear benefits.

"It's really exciting to see how many patients have been treated and how positive the results have been," said Scot Wolfe of the UMass Chan Medical School in Worcester, Mass. "We want to be careful to not let the perfect be the enemy of the good."

First patient says the treatment changed her life

During the public comment portion of the meeting, the committee heard emotional testimony from several sickle cell patients, including Victoria Gray, 38, of Forest, Miss. Gray became the first sickle cell patient to receive the treatment in 2019. NPR has chronicled Gray's experience.

Before the treatment, Gray was tortured by pain crises that prevented her from finishing school, working or even often being able to care for herself or her children. Since the treatment, all of her symptoms have disappeared.

"I believe if you say. 'Yes,' to this treatment that it's going to change the lives positively of many people who are suffering from diseases and disorders who now feel hopeless," Gray said. "Once it comes, they can feel hope again, just like I did."

The treatment would be the first of what researchers hope will be many new medical treatments that use CRISPR. The gene-editing technology allows scientists to easily make precise changes in DNA. Researchers are studying CRISPR-based therapies for conditions including muscular dystrophy, diabetes, cancer, Alzheimer's, AIDS and heart disease.

"It's extraordinary to think that we're on the verge of an approval of the first CRISPR therapy," says Jennifer Doudna of the University of California, Berkeley, who shared a Nobel Prize for her role in discovering the technique.

"As a scientist, I think we always hope that our work will affect people in a positive way — and this is one of those moments," Doudna says. "It's kind of a landmark moment for the technology, industry and hopefully the people who will benefit from it."

A genetic illness that afflicts millions

Sickle cell disease is caused by a genetic defect that produces an abnormal form of the protein hemoglobin, which red blood cells need to carry oxygen through the body. These red blood cells become misshapen and get jammed inside blood vessels.

The jagged cells cause unpredictable attacks of intense pain and damage vital organs. Throughout their lives, sickle cell patients are repeatedly rushed to the hospital for powerful pain drugs and blood transfusions. They often can't finish school, hold jobs or care for themselves or their families. They're also prone to strokes and other serious complications. Patients usually die about 20 years prematurely.

The disease disproportionately occurs among people of African, Middle Eastern and Indian descent, affecting millions around the world and about 100,000 in the U.S. Although a rare disease, sickle cell is one of the most common genetic disorders. About 20,000 patients in the U.S. have the severe form of the disease the CRISPR treatment would initially be used to treat.

For the treatment, doctors remove cells from each patient's bone marrow, edit a gene with CRISPR and then infuse billions of the modified cells back into patients. The edited cells produce a form of hemoglobin known as fetal hemoglobin, restoring normal red blood cell function. While not a cure for the disease, the hope is exa-cel will be a one-time treatment that will alleviate symptoms for a lifetime.

In a study involving 30 patients, the treatment resolved the severe pain crises for at least 18 months for 29 of the subjects — 96.7%. That transformed the lives of Gray and the other patients, enabling them to work, go to school and care for themselves and their families. The treatment has also produced similar results for patients suffering from a related condition known as beta thalassemia.

"These results are incredible," Dr. Haydar Frangoul, director of pediatric hematology, oncology and cellular therapy at the Sarah Cannon Research Institute in Nashville, Tenn., who led the study, said in an interview before testifying at the hearing. "They are truly transformative."

People treated with exa-cel "live their lives like people who do not have their disease," Frangoul said during the advisory meeting.

Other independent experts agreed.

"The amount of change in peoples' lives is super encouraging," says Dr. Lewis Hsu, a professor of pediatric hematology at the University of Illinois Chicago and chief medical director of the Sickle Cell Disease Association of America. "It's very significant."

Cost and complexity are likely barriers

One concern, however, is the likely cost of the therapy, which could be as much as $2 million per patient. The treatment is also complex, requiring a bone marrow transplant and lengthy hospitalization. Those factors may put it out of reach for those who need it most in the U.S., as well as in less affluent countries where the disease is most common.

"I'm worried that this will be a very highly lauded technology that people will not be able to use," says Melissa Creary, an assistant professor at the University of Michigan School of Public Health who studies sickle cell. "I think the people who need this therapy the most will not be able to afford it."

Many of the countries where most sickle cells patients live don't have enough sophisticated medical centers to provide the complicated treatment, Creary notes.

"I have to ask the question: How many people are going to be able to actually benefit from the technology?" Creary says.

Vertex officials say the company is working with Medicaid and private insurance companies to pay for the treatment and developing other ways to make the treatment accessible.

University of Illinois Chicago's Hsu argues that while the price is high, it's still cost-effective given how much it costs to care for sickle cell patients their entire lives.

"There is a return on investment to the health care system," he says. "These cost savings would make it worthwhile for those upfront costs."

On the lookout for stray mutations

During the meeting, Daniel Bauer of Boston Children's Hospital described recent research showing CRISPR can cause unanticipated mutations. But Bauer added that his "guess is it's a small risk in the scheme of this risk-benefit," especially when balanced against the impact of the disease.

Dr. David Altshuler, the chief scientific officer for Vertex, argued the company's analysis found no evidence of significant off-target edits.

"To the best of our knowledge, this is the most comprehensive evaluation of off-target potential performed to date," Altshuler said.

But the FDA was "concerned" by limitations in the company's analyses, Komudi Singh of the FDA's Office of Cellular Therapy ad Human Trials told the committee. The limitations support the "need for additional studies to assess the safety of exa-cel," Singh said.

"The small number of sequencing data present in the database and lack of confirmatory testing of all off-target [possibilities] is concerning," Singh said.

The companies are planning to follow all the patients treated in the study for 15 years to see how long the benefits last, if the treatment actually helps patients live longer and watch for any signs of long-term complications.

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