The Food and Drug Administration on Friday approved the first gene-editing therapy ever used in humans for sick cell disease, a blood-weakening disease caused by a single mutated gene.
The agency also approved a second treatment using conventional gene therapy for diseased cells that does not use gene editing.
For the 100,000 Americans with the disease, most of them Black, the approvals offer hope of finally living without a disease that causes excruciating pain, organ damage and stroke.
While patients, their families, and their doctors welcome the FD A approvals, obtaining both therapies will be difficult and expensive.
“It’s practically a miracle that this is possible,” said Dr. Stephan Grupp, chief of cell therapy and transplantation at the Children’s Hospital of Philadelphia. Dr. Grupp, a consultant for Vertex, said his medical center hopes to begin treating patients with diseased cells next year.
But, he added, “I’m very realistic about how difficult it is.”
There are many obstacles to treatment: an extremely limited number of medical centers authorized to provide it; the requirement that each patient’s cells be edited or a gene added individually; procedures so burdensome that not everyone can tolerate them; and a multimillion-dollar price tag and potential insurance hurdles.
As a result, sickle cell experts said, 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, particularly in Africa, for which could be completely excluded). handy for now). Both treatments were approved for patients 12 years of age and older who have experienced recurrent episodes of excruciating pain due to the disease.
The gene-editing treatment, called Exa-cel and using the brand name 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 causes sickle- or crescent-shaped red blood cells to get caught in blood vessels, blocking them.
CASGEVY is the first treatment to be approved that uses CRISPR. Patients will also need expensive, intensive medical care and lengthy hospitalization.
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: On average, $1.7 million for those with commercial insurance over the patient’s lifetime. Patients themselves may pay an average of about $44,000 out of pocket over their lifetime.
It is tempting for patients and the doctors who treat them to think that they are free from the complications of the diseased cell. So despite the many unknowns, medical centers say they are compiling lists of interested patients who are ready 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 treatment center at Massachusetts General Hospital. Patients, said Dr. Azar, who previously served as a consultant for Vertex, are starting to hope that they can live into their 70s and 80s rather than die young.
Opportunities and obstacles
Treatment will begin with hospital visits to collect patients’ bone marrow stem cells, the precursors of red blood cells that are processed to enable the production of healthy blood cells. Stem cells must be released from the marrow into the blood in order to be collected. To release them, doctors inject patients with a drug, plerixafor.
It can take months to get enough stem cells to send to a central facility for treatment. And Vertex only has 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 sequence of quality checks. About 16 weeks after the process begins, the cells will be shipped back to the medical center to be infused into the patient, said Dr. Julie Kanter, director of the adult disease cell center at the University of Alabama at Birmingham .
At that point, doctors must clean the patient’s marrow with intensive chemotherapy to make room for the new cells. Patients remain in hospital for a month or more while their modified stem cells repopulate their marrow, during which time they have no functioning immune system.
That’s if they can find a medical center that offers the new therapy. Most hospitals won’t be able to offer CASGEVY even if they want to. So far, Vertex has authorized only nine centers to provide its treatment. The company says it will eventually license about 50 of them.
The gene-editing treatment is so challenging and requires so many resources that major medical centers say that even if they were licensed to provide it, they would likely only be able to treat a small number of patients per year.
“We can’t do more than 10 a year,” said Dr. Kanter, who previously served as a consultant for Vertex and Bluebird Bio.
And, Dr. Kanter said, “we’re really good at this,” adding that his medical center has extensive experience treating patients with diseased cells and participating in Vertex clinical trials.
Others said the same. “Five to 10 a year,” said Dr. Jean-Antoine Ribeil, clinical director of the Sickle Cell Center of Excellence 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 did not reveal how many patient cells it will be able to edit each year, saying only that it is confident it can meet demand when the treatment is introduced.
And not even Bluebird Bio. But, Dr. Grupp said, Bluebird’s gene therapy for thalassemia — a genetic disease in which the body doesn’t make enough hemoglobin — gives a clue. Bluebird, he said, has been able to treat cells from only 50 patients a year since the drug was approved in August 2022. And that’s “for the entire country,” Dr. Grupp said.
Insurance payments are another obstacle. Before treatment begins, the patient’s insurer must agree to pay. That can take months, said Dr. David Jacobsohn, chief of the division of blood and marrow transplants at Children’s National Hospital in Washington. His medical center is among those authorized to provide the Vertex treatment.
Most diseased 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 is a consultant for Vertex and Bluebird.
“If every sick patient in Missouri was treated, the state couldn’t afford it,” he said.
Another concern concerns the unknowns about the new therapy. Although an FDA panel concluded that the benefits outweighed the risks, doctors remain aware of the unexpected results.
“We don’t know yet what the long-term effects will be,” Dr. DiPersio said. “We didn’t follow the patients long enough, only a couple of years.” And stem cells, he added, “will live forever,” so if CRISPR or Bluebird gene therapy causes genetic damage, they will remain.
How patients and doctors feel
Haja Sandi, a 19-year-old student at Rowan University in New Jersey, hopes to be at the top of the list at Children’s Hospital of Philadelphia.
He has frequent hospitalizations for pain so intense that he has to take morphine. Her symptoms forced her to attend school remotely. “There’s no way we can do this in person,” she said.
Hearing about the Vertex therapy, he contacted the Philadelphia hospital and asked if he could get it.
“God willing, I will move forward,” he said.
Children’s Hospital of Philadelphia, among others, hopes to make Vertex’s list of approved centers and is planning to welcome eligible patients on a first-come, first-served basis.
Still others, like 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 others.
He fears a misstep could tarnish the treatment of those who could be helped.
In the future, therapies will be delivered without the extensive support that companies have provided to clinical trial participants. And it will be a test bed for using CRISPR gene editing to treat other diseases. CRISPR Therapeutics is now studying gene editing to treat cancer, diabetes and ALS, among others.
“It’s a blessing and a curse that we’ll be the first,” Dr. Azar said. “Sickle cell disease was never the first.”
People seeking therapy — mostly Black patients — often distrust the health care system, he added.
“We want to get it right,” Dr. Azar said. “We don’t want patients to feel like guinea pigs.”