The first cell-based gene therapies for sickle cell disease in adolescents and adults received Food and Drug Administration (FDA) approval Friday.
Casgevy (exa-cel) from Vertex Pharmaceuticals Inc. and Lyfgenia (lovo-cel) from BlueBird Bio Inc. were approved for patients 12 years and older who have experienced vaso-occlusive crises or events (VOCs or VOEs).
“Today’s approval demonstrates continued momentum of this promising new area of medicine,” Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research (CBER), said in a press conference. “The potential that these products can have to transform the lives of patients living with sickle cell disease is enormous.”
Sickle cell disease is a disorder in which red blood cells form a C shape and become sticky and fragile. It can cause debilitating pain and organ damage and affects about 100,000 people in the U.S. About 20,000 have severe disease. Sickle cell disease is disproportionately high in people of African descent in the U.S.
The only cure is hematopoietic stem cell transplantation, but fewer than 20% of patients have an appropriate donor for this option. Other treatments are only partially effective.
Both therapies approved Friday use a patient’s own blood cells, which are modified and given back in a single-dose infusion as part of a hematopoietic stem cell transplant.
“The approval of two gene therapy options gives those affected by sickle cell disease an opportunity for cure,” said Rachelle F. Nuss, M.D., FAAP, a member of the AAP Section on Hematology Oncology. “However, access will be limited due to restricted capacity to create the products and cost. Also, it will require long term follow up to assess the safety of the treatments.”
Dr. Nuss, associate director of the Colorado Sickle Cell Treatment and Research Center, was not involved in the trial for either therapy but is involved with another gene therapy trial.
Casgevy uses the gene-editing tool CRISPR to modify blood stem cells and increase patients’ levels of fetal hemoglobin, which facilitates oxygen delivery and prevents sickling of red blood cells.
Vertex performed clinical trials with 44 patients ages 12-35 years. Before treatment, they had an average of four VOC episodes a year. Among 31 patients followed for 24 months, nearly 94% were free from severe VOC episodes for at least 12 consecutive months. The most common side effects were low levels of platelets and white blood cells, mouth sores, nausea, musculoskeletal pain, abdominal pain, vomiting, febrile neutropenia, headache and itching.
In October, the FDA’s Cellular, Tissues, and Gene Therapies Advisory Committee reviewed data on Casgevy. It weighed in on the issue of off-target editing in which the gene editing impacts a genetic site other than the one it is intended to impact. Depending on which genomic sites are affected, these changes could range from having no functional impact to causing cancer.
Vertex leaders said that most human genetic variation does not impact functioning, and they designed Casgevy in a way that minimizes the risk of off-target editing. The company’s studies did not find off-target editing or safety risks, although the FDA questioned whether sample sizes were large enough to detect these risks. While advisers identified additional data that could be collected, none expressed a desire to hold up approval of the product to do so. The FDA added information to the label about the potential for off-target editing.
Lyfgenia uses a lentiviral vector for genetic modification. The patient’s blood stem cells are genetically modified to produce a hemoglobin that functions similar to hemoglobin A. Red blood cells with this hemoglobin have a lower risk of sickling. The therapy was studied in 32 patients ages 12-50 years over 24 months. About 88% achieved complete resolution of VOEs between six and 18 months after infusion.
The most common side effects were stomatitis; low levels of platelets, white blood cells and red blood cells; and febrile neutropenia. However, two patients treated with Lyfgenia died after developing acute myeloid leukemia, and another patient developed myelodysplastic syndrome, according to the FDA. A black box warning will be included on the label, and patients should have lifelong monitoring.
The FDA addressed questions about whether the cancers were caused by the chemotherapy agent given as part of the conditioning regimen.
“There’s not at this point definitive evidence to say specifically that …it is just due to the conditioning regimen,” said Nicole Verdun, M.D., director of the CBER’s Office of Therapeutic Products. “There is risk whenever you’re editing genomes.”
No malignancies have been reported among Casgevy trial participants. Both manufacturers plan to conduct follow-up studies for 15 years and monitor for malignancies.
“Our team is committed to facilitating the development of safe and effective treatments for patients with unmet medical needs,” Dr. Verdun said. “These treatments signify an important medical advancement for patients with sickle cell disease and have potentially transformative implications for the future of gene therapy.”
Resources
- AAP-endorsed Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014
- AAP clinical report Health Supervision for Children with Sickle Cell Disease
- Information for parents from HealthyChildren.org on sickle cell disease
- Information from the CDC on sickle cell disease
