Clinical trial findings showed both treatments could reduce pain from vaso-occlusive events, hallmarks of sickle cell disease.
On Friday, the U.S. Food and Drug Administration (FDA) approved CRISPR and lentiviral vector-based gene therapies for treating sickle cell disease in patients aged 12 years or older.
“Today’s actions follow rigorous evaluations of the scientific and clinical data needed to support approval,” said Dr. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research.
The two therapies are Casgevy, a CRISPR-based gene therapy manufactured by Vertex, and Lyfgenia from Bluebird Bio, which does not use CRISPR but lentiviral vectors to edit genes.
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Clinical trial findings showed both treatments could reduce pain from vaso-occlusive events, hallmarks of sickle cell disease.
Vaso-occlusive events are instances where blood vessels become blocked, which can cause organ damage and severe pain.
“We know they transform people’s lives; they significantly—if not completely—eradicate and get rid of these horrible, painful events that take over people’s lives with sickle cell … What we don’t know is what happens with organ function,” Dr. Julie Kanter, co-director of the Lifespan Comprehensive Sickle Cell Center at the University of Alabama, said in an interview with the university.
What Is Sickle Cell Disease?
Sickle cell disease is an inherited blood disorder.
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Mutations in a hemoglobin gene cause the body to form deformed hemoglobin, proteins on red blood cells responsible for carrying oxygen.
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When hemoglobin is deformed, it becomes stickier and unable to carry oxygen. Additionally, red blood cells become misshapen, forming a crescent or “sickle” shape.
“So normally, red blood cells aren’t sticky. They easily flow through the blood vessels like water through pipes. But in people with sickle cell disease, in the tiny, tiny pipes, they can get stuck,” Dr. Kanter said in the interview.
“That’s one of the main reasons people end up having pain or organ damage associated with sickle cell disease.”
People with sickle cell disease inherited the mutation in both their genes. On average, they live up to 52 years, with their time marred by anemia, episodes of pain, infections, blood transfusions, and more.
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Stem cell transplants from a donor have successfully treated sickle cell disease in children, with some studies reporting an over 80 percent success rate. The operation is a lot riskier as a patient ages.
Gene Therapies: New Treatment Options
Currently, there are limited treatment options for patients with sickle cell disease who would like to be cured of the condition, particularly if they don’t have a matched sibling who can donate their stem cells to the patient.
Casgevy and Lyfgenia are both autologous therapies and use cells extracted from the patient receiving the treatment, “so the patients don’t need to have a donor. Theoretically, everybody can be their own donor,” Dr. Akshay Sharma, pediatric hematologist and transplanter, at the Department of Bone Marrow Transplantation & Cellular Therapy at St. Jude Children’s Research Hospital, wrote to The Epoch Times via email.
The newly approved gene therapies aim to correct the mutation by replacing the defective gene.
Blood stem cells would be harvested, screened for defects, edited, and returned to the patient.
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Casgevy, using CRISPR technology, could replace the mutated section in the cells with the correct gene sequences. The other treatment, Lyfgenia, uses a lentiviral vector to add a good hemoglobin gene to a patient’s cellular DNA.
Before treatment, patients must undergo chemotherapy to remove other stem cells from the bone marrow to replace them with the modified cells. The whole process can take several months.
Data Supporting Casgevy and Lyfgenia
Casgevy’s effectiveness and safety were assessed in an ongoing single-arm trial with 44 children and adults. Patients were followed for 24 months and had to have achieved at least one year without severe vaso-occlusive crises (VOC).
At the time of FDA submission, only 31 patients could be evaluated. After treatment, 29 of these were VOC-free for at least one year.
Common side effects among the 44 participants were “low levels of platelets and white blood cells, mouth sores, nausea, musculoskeletal pain, abdominal pain, vomiting, febrile neutropenia (fever and low white blood cell count), headache, and itching,” according to the FDA’s press release.
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Lyfgenia, on the other hand, was assessed over 24 months in 32 patients. Twenty-eight, or 88 percent, patients achieved a complete resolution of vaso-occlusive events six to 18 months after infusion.
Lyfgenia shares similar side effects with Casgevy.
Dr. David Williams, the chief of hematology and oncology at Boston Children’s Hospital, wrote to The Epoch Times that his team plans to offer both of these new treatments to their patients.
Dr. Sharma, on the other hand, said he would be more cautious in prescribing treatment to his pediatric patients.
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“Both these therapies have been approved based on a small number of patients followed for a relatively short period of time. This is a very limited follow-up in a very limited population of patients for a life-altering therapy. While the short-term results are impressive, I am looking for long-term durability and safety—which will become available with time.”
Black Box Warning for Lyfgenia
The trial for Casgevy is ongoing, and long-term risks are unknown.
“The unknown risks are relevant,” Dr. Williams wrote. “These are genetic therapies and permanently change the genome. It may take many years for us to see long-term side effects.”
Meanwhile, the Lyfgenia trial detected two cases of blood cancer among seven patients. The company initially halted the study in February 2021 but resumed after concluding that the more recent cancer case was unlikely to be related to the gene therapy.
Nevertheless, “a black box warning is included in the label for Lyfgenia with information regarding this risk. Patients receiving this product should have lifelong monitoring for these malignancies,” the FDA wrote.
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“The risk is there and still pretty undefined … But the severe form of sickle cell disease is devastating, and the current life expectancy in the United States is around 45 years, so many patients will opt for this treatment,” Dr. Williams wrote.
CRISPR Technology Suggestive of Cancer Risks
There are also concerns about CRISPR gene therapy.
A 2022 study on CRISPR technology showed that the technology can cause large rearrangements of DNA through a process called retrotransposition, known to trigger cancer.
Retrotransposition events caused by CRISPR occur 5 percent to 6 percent of the time, according to a press release on the study. The authors did not study this technology in blood stem cells but instead in human embryonic and cancer cells in the lab, so it is unknown if the same effects may be observed in real-world settings.
“We need to determine how often retrotransposition happens in clinical trials of CRISPR gene therapies,” study author Dr. Robert Chiarle said in the media release.
