On Friday, the Food and Drug Administration approved the first gene editing therapy ever to be used in humans, a debilitating blood disorder caused by a single mutated gene.
The agency also approved a second treatment using conventional gene therapy for sickle cell that does not use gene editing.
For the 100,000 Americans with the disease, most of them Black, the approvals offer hope for finally living without an affliction that causes excruciating pain, organ damage and strokes.
But getting the treatments approved was the easier effort. Now comes the hardest part: actually getting them to patients.
“It is practically a miracle that this is even possible,” said Dr. Stephan Grupp, chief of the cellular therapy and transplant section at Children’s Hospital of Philadelphia. Dr. Grupp, who consults for Vertex, said his medical center was hoping to begin treating sickle cell patients next year.
But, he added, “I am very realistic about how hard this is.”
The obstacles to treatment are myriad: an extremely limited number of medical centers authorized to provide it; the requirement that each patient’s cells be edited or have a gene added individually; procedures that are so onerous that not everyone can tolerate them; and a multimillion-dollar price tag and potential insurance obstacles.
As a result, sickle cell experts said, only a small fraction of patients in the United States are expected to receive the new treatment (to say nothing of the millions of sickle cell patients overseas, particularly in Africa, for whom it may be completely out of reach for now).
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 snip patients’ DNA. For a small number of subjects in clinical trials, it corrected the effects of the mutation, which results in red blood cells that are shaped like sickles or crescents that become 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 a long hospitalization.
The other treatment, called Lyfgenia and made by Bluebird Bio of Somerville, Mass., uses a common gene therapy method to add a good hemoglobin gene to patients’ DNA.
But living with the disease is also extremely costly: On average, $1.7 million for those with commercial insurance over a patient’s lifetime. Patients themselves may pay about $44,000 out of pocket on average over the course of their lives.
For patients and the doctors who treat them, it is tantalizing to think of being free from the complications of sickle 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 are talking for the first time about survivorship,” 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 starting to hope they can live into their 70s and 80s rather than dying young.
Opportunities and Obstacles
Treatment will start 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 marrow into the blood so they can 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 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 do 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 sickle cell center at the University of Alabama at Birmingham.
At that point, doctors must clear the patient’s marrow with intensive chemotherapy to make way for the new cells. Patients remain in the hospital for a month or more while their edited stem cells repopulate their marrows, 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 authorized only nine centers to provide its 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 are authorized to provide it they would probably only be able to treat a small number of patients a year.
“We can’t do more than 10 a year,” said Dr. Kanter, who has in the past consulted for Vertex and another company working on sickle cell treatments, 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 the Vertex clinical trials.
Others said the same. “Five to 10 a year,” said 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 one approved by Vertex to offer its therapy.
Vertex has not revealed how many patients’ cells it will be able to edit each year, saying only that it is confident it can meet the demand at the time the treatment is introduced.
Nor has Bluebird Bio. But, Dr. Grupp said, Bluebird’s gene therapy for thalassemia — a genetic disorder in which the body does not make enough hemoglobin — gives a hint. Bluebird, he said, has only been able to treat the cells of 50 patients a year since the drug was approved in August 2022. And that is “for the entire country,” Dr. Grupp said.
Insurance payments pose another obstacle. Before treatment starts, a patient’s insurer has to agree to pay. That can take months, said Dr. David Jacobsohn, chief of the division of blood and marrow transplantation at Children’s National Hospital in Washington. His medical center is among those authorized 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 the 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 couldn’t afford it,” he said.
Another concern involves unknowns about the new therapy. While a panel of F.D.A. experts concluded that the benefits outweighed the risks, doctors remain mindful of unexpected outcomes.
“We don’t know yet what the long-term effects will be,” Dr. DiPersio said. “We haven’t followed patients long enough — just a couple of years.” And stem cells, he added, “will live forever,” so if CRISPR or the Bluebird gene therapy does genetic damage, it 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 the Children’s Hospital of Philadelphia.
She has frequent hospitalizations for pain so intense she has to take morphine. Her symptoms have forced her into remote schooling. “There is no way I could do it in person,” she said.
Hearing about the Vertex therapy, she contacted the hospital in Philadelphia asking if she could get it.
“God willing, I will go forward with it,” she said.
The Children’s Hospital of Philadelphia, among others, is hoping to get on Vertex’s list of approved centers and is planning to take eligible patients on a first-come-first-served basis.
Still others, like Children’s National Hospital in Washington, will give priority to the sickest patients if they are on Vertex’s list.
Dr. Azar intends 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 sully the treatment for those who could be helped.
Going forward, the therapies will be provided without the extensive support that the companies gave 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 to treat cancer, diabetes, and A.L.S., among others.
“It is a blessing and curse that we are going first,” Dr. Azar said. “Sickle cell disease has never been first for anything.”
The people seeking the therapy — mostly Black patients — often mistrust the health care system, he added.
“We want to do this right,” Dr. Azar said. “We don’t want patients to feel like they are guinea pigs.”