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Graphical representation of normal red blood cells and sickled red blood cells with normal and mutant hemoglobin chains in them.
Sickle cell disease is a group of inherited blood disorders affecting approximately 100,000 people in the US.

FDA Approves First Gene Therapies for Sickle Cell Disease

The FDA granted the approval of Casgevy to Vertex Pharmaceuticals Inc., and Lyfgenia to Bluebird Bio Inc.

U.S. Food and Drug Administration
Published:Dec 08, 2023
|4 min read
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The U.S. Food and Drug Administration approved two milestone treatments, Casgevy and Lyfgenia, representing the first cell-based gene therapies for treating sickle cell disease (SCD) in patients 12 years and older. Additionally, Casgevy is the first FDA-approved treatment to utilize the CRISPR gene-editing technology, signaling an innovative advancement in the field of gene therapy. 

The primary cause of SCD is a mutation in the hemoglobin molecule that results in red blood cells developing a crescent or “sickle” shape. These sickled red blood cells restrict the flow in blood vessels and limit oxygen delivery to the body’s tissues, leading to severe pain and organ damage, called vaso-occlusive events (VOEs) or vaso-occlusive crises (VOCs). The recurrence of these events or crises can lead to life-threatening disabilities and/or early death. 

“Sickle cell disease is a rare, debilitating, and life-threatening blood disorder with significant unmet need, and we are excited to advance the field, especially for individuals whose lives have been severely disrupted by the disease by approving two cell-based gene therapies today,” said Nicole Verdun, MD, director of the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research. “Gene therapy holds the promise of delivering more targeted and effective treatments, especially for individuals with rare diseases where the current treatment options are limited.” 

The first FDA-approved CRISPR-based gene therapy

Casgevy, a cell-based gene therapy, is approved for the treatment of SCD in patients 12 years of age and older with recurrent vaso-occlusive crises. Casgevy is the first FDA-approved therapy utilizing CRISPR/Cas9 gene-editing technology. Patients’ hematopoietic stem cells are modified using this technology. 

CRISPR/Cas9 can be directed to cut DNA in targeted areas, enabling the ability to accurately edit DNA where it was cut. The modified blood stem cells are transplanted back into the patient where they engraft within the bone marrow and increase the production of fetal hemoglobin (HbF), a type of hemoglobin that facilitates oxygen delivery. In patients with SCD, increased levels of HbF prevent the sickling of red blood cells.

How does Lyfgenia work?

Lyfgenia is a cell-based gene therapy. Lyfgenia uses a lentiviral vector for gene editing and is approved for the treatment of patients 12 years of age and older with SCD and a history of vaso-occlusive events. With Lyfgenia, the patient’s blood stem cells are genetically modified to produce HbAT87Q, a gene-therapy-derived hemoglobin that functions similarly to hemoglobin A, which is the normal adult hemoglobin produced in persons not affected by SCD. Red blood cells containing HbAT87Q have a lower risk of sickling and occluding blood flow. These modified stem cells are then delivered to the patient. 

Both products are made from patients’ own blood stem cells, which are modified and delivered back as a one-time, single-dose infusion as part of a hematopoietic (blood) stem cell transplant. Prior to treatment, once a patient’s stem cells are collected, they must undergo myeloablative conditioning, a process that removes cells from the bone marrow so they can be replaced with the modified cells in Casgevy and Lyfgenia. Patients who received Casgevy or Lyfgenia will be followed in a long-term study to evaluate each product’s safety and effectiveness. 

“These approvals represent an important medical advance with the use of innovative cell-based gene therapies to target potentially devastating diseases and improve public health,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research. “Today’s actions follow rigorous evaluations of the scientific and clinical data needed to support approval, reflecting the FDA’s commitment to facilitating the development of safe and effective treatments for conditions with severe impacts on human health.”

Data supporting Casgevy’s efficacy

The safety and effectiveness of Casgevy were evaluated in an ongoing single-arm, multicenter trial in adult and adolescent patients with SCD. Patients had a history of at least two protocol-defined severe VOCs during each of the two years before screening. The primary efficacy outcome was freedom from severe VOC episodes for at least 12 consecutive months during the 24-month follow-up period. 

A total of 44 patients were treated with Casgevy. Of the 31 patients with sufficient follow-up time to be evaluable, 29 (93.5 percent) achieved this outcome. All treated patients achieved successful engraftment with no patients experiencing graft failure or graft rejection. 

The most common side effects 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. 

Data supporting Lyfgenia’s efficacy

The safety and effectiveness of Lyfgenia are based on the analysis of data from a single-arm, 24-month, multicenter study in patients with SCD and history of VOEs between the ages of 12- and 50-years-old. Effectiveness was evaluated based on the complete resolution of VOEs (VOE-CR) between six and 18 months after infusion with Lyfgenia. About 28 of 32 patients (88 percent) achieved VOE-CR during this period. 

The most common side effects included stomatitis (mouth sores of the lips, mouth, and throat), low levels of platelets, white and red blood cells, and febrile neutropenia, consistent with chemotherapy and underlying disease. 

Hematologic malignancy has occurred in patients treated with Lyfgenia. 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. 

Both the Casgevy and Lyfgenia applications received Priority Review, Orphan Drug, Fast Track and Regenerative Medicine Advanced Therapy designations. 

- This press release was originally published on the U.S. Food and Drug Administration website