On Friday, the Food and Drug Administration approved the first gene-editing therapy ever used in humans to treat sickle cell anemia, a debilitating blood disorder caused by a single mutated gene.
The agency also approved a second conventional gene therapy treatment for sickle cell disease that does not use gene editing.
For the 100,000 sick Americans, most of whom are Black, the approvals offer hope of finally living without a condition that causes unbearable pain, organ damage and strokes.
While patients, their families and their doctors welcome the FDA approvals, obtaining either therapy will be difficult and expensive.
“It is practically a miracle that this is even possible,” said Dr. Stephan Grupp, head of the division of cell therapy and transplantation at the Children’s Hospital of Philadelphia. Dr. Grupp, who consults for Vertex, said his medical center hopes to begin treating sickle cell patients next year.
But he added: “I’m very realistic about the difficulty.”
The barriers to treatment are many: there are only an extremely limited number of medical centers authorized to provide this treatment; the requirement that each patient’s cells be individually edited or gene-edited; procedures that are so complex that not everyone can tolerate them; and a multimillion-dollar price tag and potential insurance hurdles.
Sickle cell anemia experts say that, as a result, only a small proportion of patients in the United States are likely to receive the new treatment (not to mention the millions of sickle cell patients abroad, particularly in Africa, who may be completely excluded from it). not available for the time being). The F.D.A. estimates that about 20,000 patients – those 12 years old and older who have had episodes of debilitating pain – are eligible for the therapies.
The gene-editing treatment, called Exa-cel and branded Casgevy, was developed jointly by Vertex Pharmaceuticals of Boston and CRISPR Therapeutics of Switzerland. It uses CRISPR, the Nobel Prize-winning gene editing tool, to cut patients’ DNA. In a small number of subjects in clinical trials, the effects of the mutation, which causes red blood cells shaped like crescents or crescents to get caught in and clog blood vessels, were corrected.
Casgevy is the first approved treatment to use CRISPR. Patients also require expensive, intensive medical care and a long hospital stay.
The other treatment is called Lyfgenia and is made by Bluebird Bio of Somerville, Massachusetts. She uses a common gene therapy method to add a good hemoglobin gene to the patient’s DNA.
Vertex says the price of editing a patient’s genes will be $2.2 million; for Bluebird it will be $3.1 million.
But living with the disease is also extremely costly: an average of $1.7 million for those with coverage over a patient’s lifetime. Patients themselves pay an average of about $44,000 out of pocket over the course of their lives.
For patients and the doctors who treat them, the thought of being free from the complications of sickle cell anemia is tempting. Despite the many unknowns, medical centers say they are compiling lists of interested patients willing to seek treatment as it becomes available.
“We are talking about survival for the first time,” said Dr. Sharl Azar, medical director of the Comprehensive Sickle Cell Treatment Center at Massachusetts General Hospital. The patients, said Dr. Azar, who previously advised Vertex, are beginning to hope that they can live to be 70 and 80 instead of dying young.
Opportunities and obstacles
Treatment begins with hospital visits to collect patients’ bone marrow stem cells – the precursors of red blood cells, which are treated to enable the production of healthy blood cells. Stem cells must be released from the bone marrow into the blood so that they can be collected. To release them, doctors inject patients with a drug, plerixafor.
It can take months to obtain enough stem cells to be sent 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. Bluebird’s facility is located in New Jersey.
After a patient’s cells are edited with CRISPR, technicians perform a series of quality checks. About 16 weeks after the process begins, the cells are sent back to the medical center to be infused into the patient, Dr. Julie Kanter, director of the Adult Sickle Cell Anemia Center at the University of Alabama at Birmingham.
At this point, doctors must clean the patient’s bone marrow with intensive chemotherapy to make room for the new cells. Patients stay in the hospital for a month or longer while their edited stem cells repopulate their bone marrow. During this time they do not have a functioning immune system.
Provided they find a medical center that offers the new therapy. Most hospitals won’t be able to offer Casgevy even if they wanted to. So far, Vertex has only approved nine centers for treatment. The company says it will ultimately approve about 50 of them.
Bluebird has 27 authorized centers and plans to add more.
Gene editing treatment is so sophisticated and requires so many resources that leading medical centers say that even if they were authorized to do so, 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 has worked as a consultant for Vertex and Bluebird Bio in the past.
And Dr. Kanter said, “We’re really good at this,” adding that her medical center has extensive experience treating sickle cell patients and participating in the Bluebird clinical trials.
Others said the same thing. “Five to ten 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 one approved by Vertex to offer his therapy.
Vertex has not disclosed how many patient cells it can process each year, saying only that it is confident it will be able to meet demand at the time the treatment is launched.
Neither does Bluebird. But, said Dr. Grupp, Bluebird’s gene therapy for thalassemia – a genetic disorder in which the body does not produce enough hemoglobin – provides a clue. Since the drug was approved in August 2022, Bluebird has only been able to treat the cells of 50 patients per year. And that applies “to the whole country,” said Dr. Group
Another obstacle is insurance payments. Before treatment begins, the patient’s health insurance company must agree to the payment. That could 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 authorized, among other things, to carry out the Vertex and Bluebird treatments.
Most sickle cell patients are insured through Medicaid, noted Dr. John DiPersio, director of the Center for Genetic and Cellular Immunotherapy at Washington University School of Medicine in St. Louis. Dr. DiPersio advises Vertex and Bluebird.
“If every sickle cell patient in Missouri were treated, the state couldn’t afford it,” he said.
Another issue concerns unknowns about the new therapy. While an FDA panel of experts concluded that the benefits outweigh the risks, doctors remain aware of the unexpected consequences.
“We don’t yet know 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 Bluebird gene therapy causes genetic damage, they will persist.
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 to be hospitalized frequently because of the severe pain and has to take morphine. Her symptoms forced her to do distance learning. “There’s no way I could make it personal,” she said.
When she heard about Vertex Therapy, she contacted the hospital in Philadelphia and asked if she could receive it.
“God willing, I’ll keep doing it,” she said.
Among others, Children’s Hospital of Philadelphia hopes to get on Vertex’s list of approved centers and plans to admit eligible patients on a first-come, first-served basis.
Still others, like Children’s National Hospital in Washington, will prioritize the sickest patients.
Dr. Azar plans to take a different approach if Massachusetts General receives approval. He said he wanted to proceed with extreme caution, starting with just one patient and going through the entire process before taking on more.
He worries that a misstep could affect the treatment of those who could be helped.
Going forward, therapies will be provided without the extensive support that companies have provided to clinical trial participants. And it will be a test case for using CRISPR gene editing to treat other diseases. CRISPR Therapeutics is currently studying gene editing to treat cancer, diabetes and ALS, among other things.
“It’s a blessing and a curse that we go first,” said Dr. Azar. “Sickle cell anemia has never been the first disease.”
The people seeking therapy — mostly Black patients — often distrust the health care system, he added.
“We want to do this right,” said Dr. Azar. “We don’t want patients to feel like guinea pigs.”