In December 2023, the U.S. Food and Drug Administration (FDA) approved two groundbreaking gene therapies for sickle cell disease (SCD): Casgevy and Lyfgenia. These approvals mark a significant advancement in the treatment of SCD, offering new hope to the approximately 100,000 individuals in the United States affected by this debilitating condition.

Casgevy, developed by CRISPR Therapeutics and Vertex Pharmaceuticals, is notable for being the first CRISPR-based gene-editing therapy approved in the United States. Lyfgenia, developed by bluebird bio, utilizes a lentiviral vector for genetic modification. Both therapies are designed for patients aged 12 and older with severe SCD characterized by recurrent vaso-occlusive crises. These treatments involve modifying a patient's own hematopoietic stem cells to produce healthy red blood cells, offering the potential for a functional cure.

Sickle cell disease is a hereditary blood disorder predominantly affecting individuals of African descent. It is characterized by the production of abnormal hemoglobin, leading to the formation of rigid, sickle-shaped red blood cells. These misshapen cells can obstruct blood flow, causing severe pain episodes known as vaso-occlusive crises, organ damage, and increased risk of stroke. Approximately 100,000 people in the United States live with SCD, with the majority being African American.

The safety and efficacy of Casgevy were evaluated in an ongoing single-arm, multi-center trial involving 44 patients. Of the 31 patients with sufficient follow-up time, 29 (93.5%) were free from severe vaso-occlusive crises for at least 12 consecutive months during the 24-month follow-up period. No patients experienced graft failure or rejection. Common side effects included low levels of platelets and white blood cells, mouth sores, nausea, musculoskeletal pain, abdominal pain, vomiting, febrile neutropenia, headache, and itching.

For Lyfgenia, safety and effectiveness were based on data from a single-arm, 24-month multicenter study involving 32 patients. Twenty-eight (88%) achieved complete resolution of vaso-occlusive events during the follow-up period. Common side effects included stomatitis (mouth sores), low levels of platelets, white blood cells, and red blood cells, and febrile neutropenia. Notably, the FDA added a boxed warning for Lyfgenia due to the potential risk of blood cancers, as two patients in clinical trials developed acute myeloid leukemia post-treatment.

The therapies come with significant costs: Casgevy is priced at $2.2 million per patient, while Lyfgenia is priced at $3.1 million. These high costs raise concerns about accessibility, especially for patients in low-income regions. Efforts are underway to negotiate better pricing and develop payment models to make these treatments more accessible. For instance, the Centers for Medicare and Medicaid Services (CMS) has developed the voluntary Cell and Gene Therapy Access Model to help states pay for these therapies for Medicaid-covered individuals.

The Sickle Cell Disease Association of America (SCDAA) welcomed the FDA's approval of these therapies, stating:

"We at the Sickle Cell Disease Association of America Inc. celebrate that two gene therapies are approved for sickle cell disease by the FDA today, Dec. 8. This double milestone was a long time coming, and sickle cell disease now joins the ranks of other genetic diseases with gene therapy treatments."

The approval of Casgevy and Lyfgenia represents a significant advancement in the treatment of SCD, offering potential cures for a disease that has long had limited therapeutic options. However, challenges remain in terms of cost, accessibility, and long-term safety monitoring. Ongoing research and policy efforts are essential to address these issues and ensure that patients worldwide can benefit from these groundbreaking therapies.