The Food and Drug Administration on Friday approved the first gene-editing therapy ever used in humans, to treat diseased cell disease, a weakening blood disorder 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 free from an affliction that causes excruciating pain, organ damage and strokes.
Even if patients, their families and their doctors welcome FDA approvals, obtaining either therapy will be difficult and expensive.
“It’s practically a miracle that this is possible,” said Dr. Stephan Grupp, chief of the cell therapy and transplantation section at Children’s Hospital of Philadelphia. Dr. Grupp, who consults for Vertex, said his medical center hopes to begin treating patients with diseased cells next year.
But, he added, “I am very realistic about how difficult this situation is.”
The obstacles to treatment are innumerable: an extremely limited number of medical centers authorized to provide it; the requirement that each patient’s cells be modified or a gene added individually; procedures so cumbersome that not everyone can tolerate them; and a multimillion-dollar price tag and potential insurance hurdles.
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, particularly in Africa, for whom it could be ruled out altogether). . out of range for now). The FDA. It is estimated that around 20,000 patients – aged 12 and over and who have had episodes of debilitating pain – will be eligible for the therapies.
The gene-editing treatment, called Exa-cel and using the Casgevy brand, 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 result in sickle- or crescent-shaped red blood cells that get trapped in blood vessels, blocking them.
Casgevy is the first approved treatment using CRISPR. Patients will also need intensive, expensive medical care and lengthy hospitalization.
The other treatment, called Lyfgenia and made by Bluebird Bio of Somerville, Mass., uses a common method of gene therapy to add a good hemoglobin gene to patients’ DNA.
But living with illness is also extremely expensive: On average, $1.7 million for those with commercial insurance over a patient’s lifetime. Patients themselves can pay about $44,000 out of pocket on average over their lifetime.
For patients and the doctors who treat them, it is tempting to think about freeing themselves from the complications linked to diseased cells. So, despite the many unknowns, medical centers say they are compiling lists of patients who are interested and ready to undergo treatment as soon as it becomes available.
“We’re talking about survivorship 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 has consulted for Vertex before, are beginning to hope they can live to be 70 or 80 rather than dying young.
Opportunities and obstacles
Treatment will begin with hospital visits to collect patients’ bone marrow stem cells, the precursors to red blood cells that are processed to allow the production of healthy blood cells. Stem cells must be released from the marrow into the bloodstream before they can be collected. To release them, doctors inject patients with a drug, plerixafor.
It can take months to obtain enough stem cells to send to a central facility for processing. And Vertex only has one gene editing center in the United States, in Tennessee, and one in Europe, in Scotland. Bluebird’s facilities are located in New Jersey.
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 returned to the medical center to be infused into the patient, said Dr. Julie Kanter, director of the Adult Diseased Cell Center at the University of Alabama at Birmingham.
At this point, doctors must clear the patient’s marrow with intensive chemotherapy to make room for the new cells. Patients stay in the hospital for a month or more while their modified stem cells repopulate their marrow, during which time their immune systems do not function.
That’s on the condition that they find a medical center offering the new therapy. Most hospitals will not be able to offer Casgevy even if they want to. So far, Vertex has only authorized nine centers to provide its treatment. The company says it will eventually authorize around fifty.
Bluebird has 27 approved centers and plans to add more as well.
Gene-editing treatment is so complex and resource-intensive that major medical centers say that even if they were allowed to offer 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 has previously consulted for Vertex and Bluebird Bio.
And, according to Dr. Kanter, “we’re really good at this,” adding that his medical center has extensive experience treating patients with diseased cells and participating in Bluebird clinical trials.
Others have said the same thing. “Five to 10 a year,” said Dr. Jean-Antoine Ribeil, clinical director of the Sickle Cell Center of Excellence at Boston Medical Center, who says it is the largest sickle cell center in New England and that it is approved by Vertex. to offer therapy.
Vertex has not revealed how many patient cells it will be able to modify each year, saying only that it is confident it can meet demand by the time the treatment is introduced.
You don’t have Bluebird. But, Dr. Grupp said, Bluebird’s gene therapy for thalassemia — a genetic disease in which the body doesn’t produce enough hemoglobin — provides an indication. Bluebird, he said, has only been able to treat cells from 50 patients per 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. It can take months, said Dr. David Jacobsohn, chief of the division of blood and marrow transplantation at Children’s National Hospital in Washington. Its medical center is one of those authorized to provide Vertex and Bluebird treatments.
Most patients with diseased cells are insured by 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 sick patient in Missouri was treated, the state couldn’t afford it,” he said.
Another concern is the unknowns surrounding the new therapy. Even though an FDA panel of experts concluded that the benefits outweigh the risks, doctors remain wary of unexpected results.
“We don’t yet know what the long-term effects will be,” Dr. DiPersio said. “We didn’t follow the patients long enough, only a few years.” And stem cells, he added, “will live forever,” so if CRISPR or Bluebird gene therapy causes genetic damage, they will remain.
What patients and doctors feel
Haja Sandi, a 19-year-old student at Rowan University in New Jersey, hopes to get to the top of the list at Children’s Hospital of Philadelphia.
She is frequently hospitalized because of pain so severe that she has to take morphine. Her symptoms forced her to do distance learning. “I can’t do it in person,” she said.
Having heard about Vertex therapy, she contacted the Philadelphia hospital to ask if she could get it.
“God willing, I will move forward,” she said.
Children’s Hospital of Philadelphia, among others, hopes to be included on Vertex’s list of approved centers and plans to accept 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 is approved. He said he wanted to proceed with extreme caution, starting with just one patient and working through the entire process before accepting others.
He worries that one misstep could ruin treatment for those who could be helped.
In the future, therapies will be provided without the extensive support that companies have provided to clinical trial participants. And it will be a test for using CRISPR gene editing to treat other diseases. CRISPR Therapeutics is currently studying gene editing to treat, among other things, cancer, diabetes and ALS.
“It’s both a blessing and a curse that we’re going there first,” Dr. Azar said. “Sickle cell has never been the first to anything. »
People who seek this 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. »