In a significant milestone for medical innovation, the U.S. Food and Drug Administration (FDA) has granted approval to two groundbreaking cell-based gene therapies, Casgevy and Lyfgenia, for the treatment of sickle cell disease (SCD) in patients 12 years of age and older. This marks the first time that cell-based gene therapies have been approved for SCD, offering new hope for those affected by this inherited blood disorder.

Sickle cell disease affects approximately 100,000 people in the U.S., primarily African Americans and Hispanic Americans. It is characterized by a mutation in the hemoglobin protein, causing red blood cells to take on a sickle shape. These abnormal cells hinder blood flow, leading to excruciating pain and organ damage known as vaso-occlusive events (VOEs) or vaso-occlusive crises (VOCs). The recurrence of these crises can have life-threatening consequences.

Dr. Nicole Verdun, Director of the Office of Therapeutic Products within the FDA's Center for Biologics Evaluation and Research, expressed excitement about the approvals, stating, "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. 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."

Casgevy, one of the approved therapies, is a cell-based gene therapy that utilizes a type of genome editing technology called CRISPR/Cas9, marking a significant innovative advancement in the field of gene therapy. CRISPR/Cas9 allows for accurate editing of DNA, enabling the removal, addition, or replacement of specific genetic material. In the case of sickle cell disease patients treated with Casgevy, their hematopoietic stem cells undergo genome editing using CRISPR/Cas9 technology. The modified stem cells are then transplanted back into the patient's body, where they engraft within the bone marrow and increase the production of fetal hemoglobin (HbF). Increased levels of HbF prevent the sickling of red blood cells.

Lyfgenia, the second approved therapy, is a cell-based gene therapy that employs a lentiviral vector for genetic modification. This therapy is approved for patients 12 years of age and older with sickle cell disease and a history of vaso-occlusive events. Lyfgenia modifies the patient's own blood stem cells to produce HbAT87Q, a gene-therapy derived hemoglobin similar to the normal adult hemoglobin found in individuals not affected by sickle cell disease. Red blood cells containing HbAT87Q have a lower risk of sickling and obstructing blood flow.

Both Casgevy and Lyfgenia are administered as a one-time, single-dose infusion as part of a hematopoietic stem cell transplant. Prior to treatment, patients' own stem cells are collected, and a myeloablative conditioning (high-dose chemotherapy) is conducted to remove cells from the bone marrow before replacing them with the modified cells. Long-term studies will be conducted to evaluate the safety and effectiveness of these therapies on patients who have received Casgevy or Lyfgenia.

Dr. Peter Marks, Director of the FDA's Center for Biologics Evaluation and Research, emphasized the significance of the approvals, stating, "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." He further highlighted the FDA's commitment to facilitating the development of safe and effective treatments for conditions with severe impacts on human health.

The Casgevy therapy demonstrated promising results in an ongoing multi-center trial. Of the 31 patients evaluated, 93.5% achieved freedom from severe vaso-occlusive events for at least 12 consecutive months during the 24-month follow-up period. Successful engraftment was achieved in all treated patients with no incidents of graft failure or rejection. Common side effects included low levels of platelets and white blood cells, mouth sores, nausea, musculoskeletal pain, and abdominal pain.

The efficacy of Lyfgenia was evaluated based on data from a single-arm, 24-month multicenter study involving 32 patients. During the 6- to 18-month period following infusion with Lyfgenia, 88% of patients achieved complete resolution of vaso-occlusive events. Side effects included mouth sores, low levels of platelets, white blood cells, and red blood cells, and febrile neutropenia.

Both Casgevy and Lyfgenia have received Priority Review, Orphan Drug, Fast Track, and Regenerative Medicine Advanced Therapy designations. Casgevy was developed by Vertex Pharmaceuticals Inc., while Lyfgenia was developed by Bluebird Bio Inc.

The FDA's approval of these groundbreaking cell-based gene therapies signifies a major step forward in treating sickle cell disease. These advancements offer hope for patients living with the debilitating effects of this inherited blood disorder, and the ongoing long-term studies will provide valuable insights into the therapies' safety and effectiveness.