The US Food and Drug Administration gave the green light last week to the first gene editing therapy to be used in humans – for sickle cell disease, the 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, reports The New York Times.
However, while patients, their families and their doctors welcome the FDA’s approvals, getting either therapy will be difficult, and expensive.
“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. Grupp, who consults for Vertex, said his medical centre 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 centres authorised to provide it; the requirement that each patient’s cells be edited or have a gene added individually; procedures that are so onerous 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 US 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 FDA estimates that about 20 000 patients, aged 12 and older and have had episodes of debilitating pain, will be eligible for the therapies.
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 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 hospitalisation.
The other treatment, called Lyfgenia and made by Bluebird Bio in Massachusetts, uses a common gene therapy method to add a good haemoglobin gene to patients’ DNA.
Understand sickle cell disease
The rare blood disorder, which can cause debilitating pain, strokes and organ failure, affects 100 000 Americans and millions of people globally, mostly in Africa.
Vertex says its price to edit a patient’s genes will be $2.2m; for, Bluebird it will be $3.1m.
For patients and the doctors who treat them, it is tantalising to think of being free from the complications of sickle cell. So despite the many unknowns, medical centres 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 centre at Massachusetts General Hospital. Azar, who previously consulted for Vertex, said patients are starting to hope they can live into their 70s and 80s rather than dying young.
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. Bluebird’s facility is in New Jersey.
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 centre to be infused into the patient, said Dr Julie Kanter, director of the adult sickle cell centre 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 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 centre that offers the new therapy.
Most hospitals will not be able to offer Casgevy even if they want to. So far, Vertex has authorised only nine centres to provide its treatment. The company says it will eventually authorise about 50.
Bluebird has 27 authorised centres and also plans to add more.
The gene editing treatment is so challenging and requires so many resources that leading medical centres say that even if they are authorised 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 Kanter, who has, in the past, consulted for Vertex and Bluebird Bio.
And, she added: “We’re really good at it,” adding that her medical centre had extensive experience treating sickle cell patients and participating in the Bluebird clinical trials.
Others said the same. “Five to 10 a year,” said Dr Jean-Antoine Ribeil, clinical director of the Centre of Excellence in Sickle Cell Disease at Boston Medical Centre, which says it is the largest sickle cell centre 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. But, Grupp said, Bluebird’s gene therapy for thalassaemia – a genetic disorder in which the body does not make enough haemoglobin – 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”.
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 centre is among those authorised to provide the Vertex and the Bluebird treatments.
Most sickle cell patients are insured through Medicaid, noted Dr John DiPersio, director of the Centre for Gene and Cellular Immunotherapy at the Washington University School of Medicine.
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 FDA 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,” 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.
The Children’s Hospital of Philadelphia, among others, is hoping to get on Vertex’s list of approved centres 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.
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 ALS, among others.
“It is a blessing and curse that we are going first,” 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. We don’t want patients to feel as if they are guinea pigs.”
See more from MedicalBrief archives:
UK first to approve CRISPR-based treatment for sickle cell disease
FDA advisers debate sickle cell gene therapy safety
Sickle cell disease 11 times more deadly than thought – global study
Call for guidelines and ethical boundaries in genetic editing therapies