The Food and Drug Administration (FDA) approved this Friday a powerful treatment against sickle cell anemia, a devastating disease that affects more than 100,000 Americans, most of them black.
The treatment Casgevyfrom the pharmaceutical companies Vertex Pharmaceuticals and CRISPR Therapeutics, is the first approved in the United States that uses the CRISPR gene editing tool, which awarded its inventors the Nobel Prize in Chemistry in 2020.
“I think this is a pivotal moment in the field,” said Dr. Alexis Thompson, chief of the division of hematology at Children’s Hospital of Philadelphia, who has previously consulted for Vertex. “It has been truly extraordinary how quickly we have gone from the discovery of CRISPR, to the awarding of a Nobel Prize, to the approval of a product.”
The approval marks the first of two possible advances in the treatment of this inherited blood disorder. On Friday, the FDA also gave the go-ahead to a second treatment for sickle cell anemia, called Lyfgenia, a gene therapy from the pharmaceutical company Bluebird Bio. Both genetically modify the patient’s stem cells.
Until now, the only known cure for sickle cell disease was a bone marrow transplant from a donor, which carries the risk of being rejected by the immune system, in addition to the difficult process of finding a match.
Approved for people ages 12 and older, Casgevy eliminates the need for a donor. Through the CRISPR process, the DNA of the patient’s stem cells is edited to eliminate the gene that causes the disease. “The patient is their own donor,” Thompson said.
“It’s a game changer,” said Dr. Asmaa Ferdjallah, a pediatric hematologist and bone marrow transplant physician at the Mayo Clinic in Rochester in Minnesota. “Truly reimagining and rediscussing sickle cell anemia as a curable disease and not a painful and debilitating chronic disease is hope enough with this news.”
A cure available to only a few
Still, the new therapy is expected to be extremely expensive: potentially around $2 million per patient, according to a report by the Institute for Clinical and Economic Review, a nonprofit group that helps determine drug prices.
According to experts, these costs can put it out of reach for many families. What’s more, this price does not include the amount of care associated with the treatment, such as a hospital stay or chemotherapy.
“We really have to make sure it’s accessible,” said Dr. Rabi Hanna, a pediatric hematologist-oncologist at the Cleveland Clinic who has served on Vertex’s advisory board.
How does Casgevy work?
In patients with sickle cell anemia, the red blood cells, which are usually disc-shaped, take on a crescent or sickle shape. This change can cause cells to clump together, causing clots and blockages in blood vessels, depriving tissues of oxygen.
Patients can suffer excruciating pain, breathing problems and strokes.
Casgevy works by editing the DNA of the patient’s stem cells, which are responsible for making blood cells, so that they stop producing sickle cells.
Although it is technically a one-time treatment, before the patient receives the modified stem cells, it is necessary to follow a series of steps that last months. It begins with a series of blood transfusions over three or four months, after which stem cells are extracted from the patient’s bone marrow and sent to a laboratory where they are edited, Hanna explains.
However, before reinfusing them into the patient, doctors must ensure that no defective stem cells remain in the body. To do this, chemotherapy is used to destroy the patient’s bone marrow.
Only then can the edited stem cells be reinfused into the patient, after which they must remain in the hospital for an additional month or two for the cells to grow and the patient to recover.
Hanna says he is always “cautious” when talking to family members and patients about the one-time treatment, because they may have unrealistic expectations. “There are multiple phases to this process,” she said.
Clinical trials
46 people from the US and abroad participated in the clinical trial, 30 of whom received at least 18 months of follow-up after treatment. Of them, the treatment has been successful in 29.
LaRae Morning, 29, of Phoenix, was one of the patients whose treatment was successful. Her mother lost several jobs when Morning was a child and teenager due to her frequent visits to the hospital.
In April 2021, Morning joined the clinical trial at HCA Healthcare’s Sarah Cannon Research Institute and TriStar Centennial Children’s Hospital in Nashville, Tennessee, a decision she initially regretted. Since she lived in Phoenix, she had to fly to Nashville once a month for treatment. It included several blood transfusions, each lasting eight hours, and taking a medication called plerixafor, which, as she recalls, caused intense stomach pains.
When he started chemotherapy, his hair began to fall out and his skin changed color, looking like a chemical burn. She also experienced nausea.
It took six to seven months to return to normal after the CRISPR treatment. Now, she said, she is feeling the benefits, going out to coffee shops, spending time with her friends and finishing her first semester of law in Washington, D.C.
“Now that I am at this point, I am very happy that I did it,” she said of the essay. “I’m like a normal person. I got up and ran. I lift weights. If I wanted to swim, I can swim. “I’m still trying to figure out how far I can go, what things I can do.”
That has also been the experience of several other patients in the trial, according to Dr. Monica Bhatia, chief of pediatric stem cell transplantation at NewYork-Presbyterian/Columbia University Irving Medical Center. Bhatia is a principal investigator at one of the clinical trial sites in New York.
After treatment, most patients returned to school, the gym or resumed other activities — “things that many people take for granted,” he said — within about three or four months.
“They can really live without restrictions,” Bhatia said.
Dr. Haydar Frangoul, medical director of pediatric hematology-oncology at the Sarah Cannon Research Institute, said he hopes the therapy will bring relief to more patients.
“I think this is a great moment for patients with sickle cell anemia,” said Frangoul, the clinical trial’s principal investigator and who treated Morning.
Long term questions
Although Casgevy has proven effective, experts still do not know the possible long-term effects, since the trial will only last two years.
At a meeting in October, an FDA advisory committee discussed the risk of “off-target” effects—that is, when the gene-editing tool makes cuts to stretches of DNA other than the intended target—and how agency should take these risks into account in the future.
It’s unclear what effects off-target editing would have on a patient, but there are fears it could have unintended health consequences in the future, according to Thompson. “To date, there don’t appear to be any measurable consequences,” she said.
