FDA Approves Two Gene Therapies for Sickle Cell Disease

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FDA Approves First CRISPR-Based Therapy for Sickle Cell Disease In a transformative moment for patients with sickle cell disease, and after rigorous clinical trials that took place at Children’s Hospital of Philadelphia (CHOP) and other sites, the Food and Drug Administration (FDA) has approved CASGEVY™ (exagamglogene autotemcel) and LYFGENIA™ (lovotibeglogene autotemcel), the first two gene therapies for the treatment of sickle cell disease  in patients 12 years and older with recurrent vaso-occlusive crises (VOCs). CHOP is a Qualified Treatment Center offering LYFGENIA, manufactured by bluebird bio, and also plans to offer CASGEVY, which is manufactured by Vertex Pharmaceuticals. 

“For many years, a bone marrow transplant has been the only transformative option for treating patients with sickle cell disease, and a limited one, as not all patients have a suitable donor,” said Alexis A. Thompson, MD, MPH, Chief of the Division of Hematology at Children's Hospital of Philadelphia. “Now, after decades of limited progress in treating sickle cell disease, we have reached a historical moment with two new gene therapies.”

Sickle cell disease is a lifelong condition that causes intense pain due to deformed blood cells that can cause blockages in blood vessels. This can also lead to strokes, organ damage, and potentially shortened lives.

Researchers have been extensively studying the use of gene therapy and CRISPR technology to edit portions of DNA in people with inherited or genetic disorders, like sickle cell disease. In the case of sickle cell disease, the newly approved therapy edits DNA within the patient’s own cells and enables the patient to produce a different form of hemoglobin in their red blood cells. Clinical trials at CHOP and other sites have shown that successful gene-editing can prevent cells from taking on the distinctive crescent shape apparent in sickle cell disease and has eliminated pain episodes in almost all patients. CASGEVY is the first FDA-approved therapy developed with CRISPR technology.

In the case of LYFGENIA, the gene therapy is specifically designed to treat the underlying cause of sickle cell disease by adding a functional gene that enables production of adult hemoglobin that does not form into the crescent shape associated with the disease.

“In clinical trials with CASGEVY, we have seen elimination of painful vaso-occlusive crisis in more than 90% of patients and a complete elimination of VOC-related hospitalizations in all patients, with a safety profile generally consistent with autologous stem cell transplantation,”  said Stephan A. Grupp, MD, PhD, Section Chief of the Cellular Therapy and Transplant Section, Inaugural Director of the Susan S. and Stephen P. Kelly Center for Cancer Immunotherapy, and Medical Director of the Cell and Gene Therapy Laboratory at CHOP. Grupp is one of the principal investigators in the clinical trials that led to this historic approval and the leader of the study’s steering committee. “The impact of the treatment on these patients has been so meaningful,” he said.

“As these therapies become available outside of the landmark clinical trials, we will be sure to carefully monitor each patient’s progress and make sure each gene therapy is prescribed to the patients who will benefit from them the most,” said Janet Kwiatkowski, MD, Director of the Thalassemia Center at CHOP and one of the principal investigators involved in the clinical trial that led to the approval of LYFGENIA. “CHOP’s extensive experience in studying and treating patients with these therapies will help ensure we get the best outcomes for these patients, while also pushing forward and finding ways of improving the effectiveness of these therapies and others on the horizon.”

For almost two decades, CHOP has been at the forefront in the treatment of sickle cell disease as well as multiple gene therapies to treat other rare and complex diseases. In the mid-2000s, research began on what would become Luxturna, the first FDA-approved gene therapy for a genetic disease, in this case an inherited retinal disease. In 2012, CHOP researchers led by Dr. Grupp infused the first-ever pediatric CAR T patient, which led to the first pediatric clinical trial for CAR T-cell therapy and the FDA approval of the first CAR T treatment, called Kymriah.

The historic FDA approvals for sickle cell disease were based on the results of clinical trials across multiple sites, including CHOP.

Advancing the treatment of sickle cell disease is a priority at CHOP. Our Comprehensive Center for the Cure of Sickle Cell Disease and Other Red Blood Cell Disorders (CuRED) program provides comprehensive evaluation and cutting-edge treatment that is customized to each patient and family, and guides children from management of a chronic disease to exploring the potential for curative therapy. Sickle cell disease, as well as beta thalassemia, are devastating blood disorders that result in anemia, severe chronic pain, and premature death. CuRED was established to help take the treatment of these disorders beyond just supportive care. Patients receiving gene therapy then are treated by CHOP’s Cell Therapy and Transplant Section.

“Gene therapy requires specialized centers, and thanks to the work being done in our CuRED Program, CHOP is one such center where we not only have incredible expertise in taking care of patients with sickle cell disease but also outstanding transplant specialists and others who help us meet the needs of patients and their families,” Thompson said. “The hope is that, as we gain more experience using this technology, more centers will come online and we will reach a point where the treatment will be available not only in more communities in the United States, but potentially throughout the world.”

Additionally, CHOP is actively exploring other options for innovative treatment of sickle cell disease. Researchers from CHOP and the Perelman School of Medicine, University of Pennsylvania, have been developing a system for in vivo modification of blood stem cells by delivering gene editing tools using the same lipid nanoparticle technology used in mRNA vaccines for COVID-19. Researchers are also mapping transcriptional regulation of fetal hemoglobin to improve oxygen transfer by way of small molecules.

CHOP continues to be a global leader in cell and gene therapies. The Cell and Gene Therapy Laboratory, which has been processing cells for transplants for decades, has taken on an increasing number of experimental cellular therapy protocols since 2010. Approved therapies involving research conducted at CHOP have included Kymriah for B-cell acute lymphoblastic leukemia, Luxturna for inherited retinal dystrophy, and Zolgensma for spinal muscular atrophy.

CHOP is also home to the Raymond G. Perelman Center for Cellular and Molecular Therapeutics Clinical Vector Core, which utilizes a vast array of state-of-the-art technology for preclinical and clinical vector production and characterization used in the development of gene therapies.

Read more about the FDA approval of CASGEVY in this Vertex press release and LYFGENIA in this bluebird bio press release.

CASGEVY™is a registered trademark of Vertex Pharmaceuticals. LYFGENIA™ is a registered trademark of bluebird bio, inc.