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Ten Patients treated with CRISPR-based gene editing therapy for inherited sickle cell and beta thalassemia blood disorders showed a consistent and sustained response with manageable side effects, according to interim results from two clinical trials reported on Saturday.
Vertex Pharmaceuticals and CRISPR Therapeutics are jointly developing the unique gene-editing treatment called CTX001. After receiving the infusion therapy, not all of the patients in the two studies showed symptoms of the disease and did not require blood transfusions. Although the follow-up is still relatively short, the encouraging results give hope that punctual cures of the two blood disorders could be possible.
CTX001 is the first and most advanced effort to use Nobel Prize-winning CRISPR / Cas9 technology to provide functional cures for inherited diseases.
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The CTX001 data is presented Sunday at the plenary session of the American Society of Hematology annual meeting. In addition, Bluebird Bio presents updated clinical trial results on its sickle cell gene therapy at the ASH meeting. The same gene therapy gained approval in Europe last year to treat beta thalassemia.
“We made the pivot that we expected. There should be no doubt that the ability to offer patients long-term disease control using genetic tools is here, ”said Alexis Thompson, head of the hematology section at the Ann and Robert H. Lurie Children’s Hospital of Chicago, referring to both. approaches to treat blood disorders.
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The sickle cell patient community is looking at the potential of genetically modified remedies with “cautious optimism,” said Beverley Francis-Gibson, president of the Sickle Cell Disease Association of America. “The possibility that there may be a cure for sickle cell disease is what turns everyone on, obviously, but at the same time, patients want to see what’s going to happen. They ask for more information and transparency on the process. What impact will this have on my quality of life? What is the cost?”
Both sickle cell anemia and beta thalassemia are caused by mutations in the gene responsible for the production of oxygen-carrying hemoglobin. In sickle cell disease, the mutation causes red blood cells to deform and clump together. When these “sickle-shaped” red blood cells become blocked in the blood vessels, they experience episodes of extreme pain called vaso-occlusive crises which can lead to organ damage, stroke, and premature death. In beta thalassemia, a series of different mutations each produce the same result: too low production of hemoglobin, severe anemia and organ damage.
The goal of Vertex / CRISPR therapy is to functionally cure both disorders by increasing the production of fetal hemoglobin – the healthy, oxygen-carrying form of hemoglobin produced during fetal development but which normally stops soon after birth. Higher levels of fetal hemoglobin in people with sickle cell anemia and beta thalassemia are associated with reduced symptoms and better outcomes.
To do this, hematopoietic (blood-producing) stem cells are collected from patients and sent to a lab, where researchers genetically edit the cells using CRISPR / Cas9 to produce fetal hemoglobin.
Patients then undergo treatment with busulfan, a chemotherapy drug, to clear any mutated stem cells that might remain in their bone marrow. Once prepared, patients are given an infusion of CRISPR-edited cells – CTX001 – which graft into the bone marrow and, if all goes well, begin to produce healthy, normal red blood cells.
The Vertex / CRISPR clinical trial, called CLIMB-111, has so far enrolled 13 patients with beta thalassemia, seven of whom have been followed long enough to assess response. Five of the seven patients are women. A breakdown of patients by race was not provided. Prior to entering the study, patients had undergone a median of 15 blood transfusions per year.
After CTX001 infusion, all seven patients did not receive a transfusion, with a follow-up ranging from three to 18 months.
Five of the seven patients were followed for six months, during which their total hemoglobin levels were in the normal range – almost all of them being the fetal hemoglobin produced by CRISPR’d cells.
The second paired study, called CLIMB-121, enrolled six patients with sickle cell disease. Data on three evaluable patients are reported at the ASH meeting. Two patients are black women, one is a black man.
Prior to treatment with CTX-001, the three patients had an average of six vaso-occlusive pain attacks per year. After treatment, all three were seizure-free, with follow-up times ranging from three to 15 months.
In the two sickle cell patients followed for at least six months, their total hemoglobin was in the normal range, with just under half composed of fetal hemoglobin. It is believed that a fetal hemoglobin level of 25% to 30% is sufficient to “cure” a patient with sickle cell disease.
A beta-thalassemia patient presented a severe inflammatory immune response considered possibly related to CTX-001, but which resolved. Most of the side effects reported in the two studies – fever, infections, liver toxicity, inflammation of the colon and sepsis – were related to the toxicity caused by the chemotherapy with busulfan used to prepare patients for CTX-001. All the side effects were manageable.
“In our presentation, we caution that this data is preliminary, but it is also simply excellent,” said Haydar Frangoul, medical director of pediatric hematology and oncology at the Sarah Cannon Research Institute in Nashville, in Tennessee. Haygar presents the Data CTX001 at the ASH meeting on Sunday.
Frangoul treated the first sickle cell patient to enter study CTX001 – Victoria Gray, a mother of three from Mississippi. Gray’s story was told in a series of National Public Radio reports.
“For Victoria, it was a great success,” said Frangoul. “Her life has really changed because she is now able to be a full time mother who doesn’t have to leave her children with her family when she is hospitalized. She doesn’t have to run to the ER, she doesn’t get tired often like before, so she leads a normal and happy life. Taking the stress of sickle cell disease out of her life has been extremely satisfying for her and her family.
The results are “early but impressive,” said Biree Andemariam, founding director of the New England Sickle Cell Institute at the University of Connecticut.
“These are pretty sick patients. They didn’t just choose young, healthy patients. They have chosen patients who are really confronted with their disease, ”she added. “It’s a practical application of gene therapy in a post-approval period. These are the types of patients with sickle cell disease that clearly have an impact on their lives, likely contributing to progressive underlying organ damage over time. And this is the type of patient who will eventually want and be referred for gene therapy. Andemariam did not participate in the CTX001 studies, but reviewed the data prior to the ASH presentation at the request of STAT.
Vertex and CRISPR continue to enroll patients with sickle cell anemia and beta thalassemia in clinical trials. The companies have not disclosed a timeline for when studies could be completed or when submissions for approval in the US and Europe could take place, assuming the data continues to be positive.
Bluebird Bio is developing competing gene therapies for these two blood diseases that use a redesigned virus to deliver a different functional form of hemoglobin to the bone marrow of patients. One of the Bluebird products gained approval for beta thalassemia in Europe in 2019 and a US filing for the same disease is expected in the middle of next year. The company’s sickle cell program, using related gene therapy, has been delayed due to manufacturing issues and is not expected to be filed for approval until late 2022.
CTX001 is the first gene editing treatment to emerge from CRISPR Therapeutics’ pipeline with clinical data in patients. The first results from two patients were announced a year ago. In October, the company advanced another program, showing the first data from a study of CRISPR-activated cell therapy for patients with advanced B-cell lymphoma.
Vertex is best known for its line of highly effective drugs that treat almost all forms of cystic fibrosis. More recently, through partnerships with CRISPR Therapeutics and Moderna, and through an acquisition of Semma Therapeutics, Vertex is focusing more of its research effort on curative therapies.
“When we looked at this data and recently had the opportunity to get the latest update, there was a moment of silence,” said David Altshuler, Scientific Director of Vertex. “You realize that you are seeing for the first time the use of CRISPR in a human genetic disease that is actually taking place in a significant number of patients, and not only considering what that means for these sickle cell and beta patients? -thalassemia, but the potential of CRISPR for many more patients in the future.
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