FDA approves sickle cell treatments, including one that uses CRISPR

On Friday, the Food and Drug Administration approved the first gene-editing therapy for sickle cell disease, a debilitating blood disorder caused by a single mutated gene.

The agency also approved a second treatment using conventional gene therapy for sickle cell disease, which does not use gene editing.

For the 100,000 Americans with the disease, most of whom are Black, the approvals offer hope of finally living without a condition that causes excruciating pain, organ damage and strokes.

But getting the treatments approved was the easier task. Now comes the hard part: actually getting them to patients.

“It’s practically a miracle that this is even possible,” says Dr. Stephan Grupp, chief of cell therapy and transplantation at Children’s Hospital of Philadelphia. Dr. Grupp, a consultant for Vertex, said his medical center hoped to begin treating sickle cell patients next year.

But he added: “I’m very realistic about how difficult this is.”

The obstacles to treatment are numerous: an extremely limited number of medical centers authorized to provide treatment; the requirement that each patient’s cells be edited or have a gene added individually; procedures that are so burdensome that not everyone can tolerate them; and a multimillion-dollar price tag and potential insurance barriers.

As a result, sickle cell experts say, only a small fraction of patients in the United States are expected to receive the new treatment (not to mention the millions of sickle cell patients abroad, especially in Africa, for whom it may be completely out of the question). hand is running). range for now).

The gene-editing treatment, called Exa-cel and branded CASGEVY, was jointly developed by Vertex Pharmaceuticals of Boston and CRISPR Therapeutics of Switzerland. It uses CRISPR, the Nobel Prize-winning gene-editing tool, to cut patients’ DNA. For a small number of subjects in clinical trials, it corrected the effects of the mutation, which results in red blood cells in the shape of sickles or crescents that get stuck in and block blood vessels.

CASGEVY is the first approved treatment using CRISPR. Patients will also require expensive, intensive medical care and a long hospital stay.

The other treatment, called Lyfgenia and made by Bluebird Bio of Somerville, Massachusetts, uses a common gene therapy method to add a good hemoglobin gene to patients’ DNA.

But so is living with the disease extremely expensive: Average $1.7 million for those with commercial insurance over a patient’s lifetime. On average, patients can pay about $44,000 out of pocket over the course of their lives.

It is tempting for patients and the doctors who treat them to imagine that they are free from the complications of sickle cell disease. So despite many unknowns, medical centers say they are compiling lists of interested patients willing to pursue treatment when it becomes available.

“We’re talking about survival for the first time,” said Dr. Sharl Azar, medical director of the Comprehensive Sickle Cell Disease Treatment Center at Massachusetts General Hospital. Patients, said Dr. Azar, who previously consulted for Vertex, are beginning to hope they can live into their 70s and 80s instead of dying young.

Treatment begins with hospital visits to collect patients’ bone marrow stem cells – the precursors of red blood cells that are treated to enable the production of healthy blood cells. Stem cells must be released from the bone marrow into the blood so they can be collected. To release them, doctors inject patients with a drug called plerixafor.

It can take months before there are enough stem cells to send to a central facility for treatment. And Vertex has only one gene editing facility in the United States, in Tennessee, and one in Europe, in Scotland.

After editing a patient’s cells with CRISPR, technicians perform a series of quality checks. About 16 weeks after the process begins, the cells are returned to the medical center to be infused into the patient, said Dr. Julie Kanter, director of the adult sickle cell center at the University of Alabama at Birmingham.

At that point, doctors must clear out the patient’s bone marrow with intensive chemotherapy to make room for the new cells. Patients stay in the hospital for a month or more while their edited stem cells repopulate their bone marrow, during which time they have no functioning immune system.

That is, if they can find a medical center that offers the new therapy. Most hospitals will not be able to offer Exa-cel even if they want to. So far, Vertex has only authorized nine centers to provide the treatment. The company says it will eventually authorize about 50.

The gene-editing treatment is so challenging and requires so many resources that leading medical centers say that even if they were qualified to provide it, they would likely be able to treat only a small number of patients per year.

“We can’t do more than 10 a year,” says Dr. Kanter, who in the past has consulted for Vertex and another sickle cell treatment company, Bluebird Bio.

And dr. Kanter said “we’re really good at it,” adding that her medical center had extensive experience treating sickle cell patients and participating in Vertex’s clinical trials.

Others said the same. “Five to 10 a year,” says Dr. Jean-Antoine Ribeil, clinical director of the Center of Excellence in Sickle Cell Disease at Boston Medical Center, which says it is the largest sickle cell center in New England and is approved by Vertex. to offer his therapy.

Vertex has not revealed how many patient cells it can process annually, saying only that it is confident it can meet demand when the treatment is introduced.

Neither does Bluebird Bio, which developed a gene therapy for sickle cell disease that uses a different method. The treatment is expected to be approved later this month.

But, said Dr. Grupp, Bluebird’s gene therapy for thalassemia – a genetic condition in which the body does not produce enough hemoglobin – provides a hint. Bluebird, he said, has only been able to treat cells from 50 patients a year since the drug was approved in August 2022. And that applies “to the entire country,” said Dr. Group.

Insurance benefits are another obstacle. Before treatment begins, a patient’s insurer must agree to payment. That could take months, said Dr. David Jacobsohn, chief of the blood and bone marrow transplant division at Children’s National Hospital in Washington. His medical center is one of the authorized hospitals to provide the Vertex treatment.

Most sickle cell patients are insured through Medicaid, noted Dr. John DiPersio, director of the Center for Gene and Cellular Immunotherapy at Washington University School of Medicine in St. Louis. Dr. DiPersio consults for Vertex and Bluebird.

“If every sickle cell patient in Missouri gets treated, the state can’t afford it,” he said.

Another concern concerns the unfamiliarity about the new therapy. Although a panel of FDA experts concluded that the benefits outweighed the risks, physicians remain aware of unexpected outcomes.

“We don’t know yet what the long-term effects will be,” said Dr. DiPersio. “We didn’t follow patients long enough – just a few years.” And stem cells, he added, “will live forever,” so if CRISPR or the Bluebird gene therapy causes genetic damage, it will persist.

How patients and doctors feel

Haja Sandi, a 19-year-old student at Rowan University in New Jersey, hopes to top the list at Children’s Hospital of Philadelphia.

She is regularly admitted to hospital because of pain so severe that she has to take morphine. Her symptoms have forced her to pursue remote learning. “I can’t possibly do it in person,” she said.

When she heard about the Vertex therapy, she contacted the hospital in Philadelphia to ask if she could get it.

“God willing, I’ll continue with it,” she said.

The Children’s Hospital of Philadelphia, among others, hopes to join the Vertex list of approved centers and plans to admit eligible patients on a first-come, first-served basis.

Still others, such as Children’s National Hospital in Washington, will prioritize the sickest patients if they are on Vertex’s list.

Dr. Azar plans to take a different approach if Massachusetts General is approved. He said he wanted to proceed with extreme caution, starting with just one patient and going through the entire process before accepting more.

He worries that a misstep could taint the treatment of those who can be helped.

In the future, the therapies will be offered without the extensive support that the companies provided to clinical trial participants. And it will be a test case for using CRISPR gene editing to treat other diseases. CRISPR Therapeutics is now studying gene editing for the treatment of cancer, diabetes and ALS, among others.

“It’s a blessing and a curse that we go first,” said Dr. Azar. “Sickle cell disease has never been number one in anything.”

The people who seek therapy — mostly Black patients — often distrust the health care system, he added.

“We want to get this right,” said Dr. Azar. “We don’t want patients to feel like they are guinea pigs.”