FDA Approves First CRISPR-Based Gene-Editing Therapy for Sickle Cell Disease

In December 2023, the U.S. Food and Drug Administration (FDA) approved Casgevy (exagamglogene autotemcel), marking the first authorization of a CRISPR-based gene-editing therapy in the United States. Developed collaboratively by Vertex Pharmaceuticals and CRISPR Therapeutics, Casgevy is designed to treat sickle cell disease (SCD) in patients aged 12 and older who experience recurrent vaso-occlusive crises (VOCs).

Sickle cell disease is a hereditary blood disorder affecting approximately 100,000 individuals in the U.S., predominantly Black Americans. The disease is characterized by the production of abnormal hemoglobin, leading to the deformation of red blood cells into a sickle shape. These misshapen cells can obstruct blood flow, causing severe pain episodes known as VOCs, organ damage, and increased risk of stroke.

Casgevy employs CRISPR/Cas9 gene-editing technology to modify the patient's own hematopoietic stem cells. The therapy targets the BCL11A gene, reducing its expression in red blood cell precursors. This reduction leads to increased production of fetal hemoglobin (HbF), a form of hemoglobin present during fetal development that has a higher affinity for oxygen. Elevated HbF levels can prevent the sickling of red blood cells, thereby mitigating the symptoms of SCD.

Clinical trials have demonstrated promising results for Casgevy. In studies involving patients with severe SCD, 96.7% of participants experienced no severe VOCs for at least one year following treatment. Additionally, 100% of participants remained hospitalization-free for the same duration. These outcomes suggest that Casgevy offers a durable and potentially curative solution for individuals suffering from this debilitating condition.

The FDA's approval of Casgevy in December 2023 was a landmark event, representing the first authorization of a CRISPR-based therapy in the U.S. Prior to this, in November 2023, the United Kingdom's Medicines and Healthcare products Regulatory Agency (MHRA) granted conditional marketing authorization for Casgevy, making it the first regulatory body worldwide to approve a CRISPR-based gene-editing therapy. Subsequently, in February 2024, the European Commission approved Casgevy for the treatment of SCD and transfusion-dependent beta thalassemia (TDT) in patients aged 12 and older.

Vertex Pharmaceuticals, headquartered in Boston, Massachusetts, is a global biotechnology company specializing in developing therapies for serious diseases. CRISPR Therapeutics, based in Zug, Switzerland, focuses on translating CRISPR/Cas9 gene-editing technology into transformative medicines. The collaboration between these two companies has been pivotal in bringing Casgevy to market, combining Vertex's expertise in drug development with CRISPR Therapeutics' pioneering work in gene editing.

Reshma Kewalramani, M.D., Chief Executive Officer and President of Vertex Pharmaceuticals, emphasized the significance of the FDA's approval:

"CASGEVY’s approval by the FDA is momentous: it is the first CRISPR-based gene-editing therapy to be approved in the U.S. As importantly, CASGEVY is a first-in-class treatment that offers the potential of a one-time transformative therapy for eligible patients with sickle cell disease."

Samarth Kulkarni, Ph.D., Chairman and Chief Executive Officer of CRISPR Therapeutics, reflected on the achievement:

"When our company was founded, we had a vision to translate CRISPR technology into multiple breakthrough therapies. So, this U.S. approval of the first-ever medicine using CRISPR gene editing is breathtaking, and a truly humbling moment for me personally and for the whole organization."

The approval of Casgevy has profound implications for the treatment of SCD, particularly within the Black community, which is disproportionately affected by the disease. The availability of a potentially curative, one-time therapy addresses a significant unmet medical need and offers hope for improved quality of life. Moreover, this milestone paves the way for the application of CRISPR-based therapies to other genetic disorders, potentially revolutionizing the field of medicine.

While Casgevy represents a significant advancement in treatment, its cost is substantial. In England, the National Health Service (NHS) approved the therapy at a price of £1.7 million per patient. However, a confidential agreement ensures the treatment is provided at a discount. The high cost underscores the need for discussions on healthcare funding and accessibility to ensure that patients who could benefit from such therapies have equitable access.

In summary, the FDA's approval of Casgevy marks a significant milestone in gene therapy, offering a potential one-time treatment for SCD patients. This development not only provides hope for those affected by sickle cell disease but also sets a precedent for future CRISPR-based treatments targeting various genetic disorders.