In a groundbreaking moment for medical science, the U.S. Food and Drug Administration (FDA) has approved two cutting-edge treatments, Casgevy and Lyfgenia, marking the first-ever cell-based gene therapies for sickle cell disease (SCD) in patients aged 12 and older. Notably, Casgevy stands out as the maiden FDA-approved therapy utilizing CRISPR/Cas9, a groundbreaking genome editing technology, signaling a paradigm shift in the landscape of gene therapy.
Sickle cell disease, a group of inherited blood disorders, disproportionately affects around 100,000 individuals in the U.S., with a higher incidence among African and Hispanic Americans. The condition arises from a mutation in hemoglobin, a crucial protein in red blood cells responsible for delivering oxygen to the body’s tissues. This mutation results in red blood cells adopting a crescent or “sickle” shape, impeding blood flow and causing vaso-occlusive events (VOEs) or crises that lead to severe pain and organ damage, often proving life-threatening.
The approval of Casgevy and Lyfgenia, as the first cell-based gene therapies, marks a monumental stride in the treatment of sickle cell disease. Dr. Nicole Verdun, Director of the Office of Therapeutic Products at the FDA’s Center for Biologics Evaluation and Research, expressed enthusiasm about the approval, stating, “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, utilizing CRISPR/Cas9 technology, involves modifying patients’ hematopoietic stem cells using precise genome editing. The edited cells are then reintroduced into the patient’s system, engrafting within the bone marrow and boosting the production of fetal hemoglobin (HbF). Elevated HbF levels prevent the sickling of red blood cells, offering a transformative treatment for those experiencing recurrent vaso-occlusive crises.
Lyfgenia, the second cell-based gene therapy, employs a lentiviral vector for genetic modification. This therapy is approved for patients with sickle cell disease and a history of vaso-occlusive events. Lyfgenia modifies the patient’s blood stem cells to produce HbAT87Q, a gene-therapy-derived hemoglobin that mimics the function of hemoglobin A, reducing the risk of sickling and blood flow obstruction. Both Casgevy and Lyfgenia are administered as one-time, single-dose infusions.
These therapies represent a significant leap forward in the treatment of sickle cell disease, offering hope to those affected. The safety and effectiveness of Casgevy were evaluated in an ongoing trial, with 93.5% of patients achieving freedom from severe VOC episodes. The most common side effects included low platelet and white blood cell levels, mouth sores, nausea, and musculoskeletal pain.
Lyfgenia’s safety and effectiveness were assessed based on a 24-month multicenter study, with 88% of patients achieving complete resolution of vaso-occlusive events between 6 and 18 months post-infusion. Common side effects included mouth sores, low blood cell levels, and febrile neutropenia.
Both Casgevy and Lyfgenia underwent rigorous evaluations, receiving Priority Review, Orphan Drug, Fast Track, and Regenerative Medicine Advanced Therapy designations. The FDA granted approval of Casgevy to Vertex Pharmaceuticals Inc. and approval of Lyfgenia to Bluebird Bio Inc.
As these revolutionary gene therapies pave the way for a new era in the treatment of sickle cell disease, they offer not only a lifeline for those affected but also a beacon of hope for the potential of gene therapy in addressing other rare diseases with limited treatment options. The FDA’s commitment to advancing safe and effective treatments for severe health conditions is evident in its rigorous evaluation process, ensuring a monumental impact on human health and medical progress.
While the FDA approval directly impacts SCD treatment in the U.S., its ripple effect is anticipated to reach African regions grappling with the burden of sickle cell disease. Sickle cell disease is prevalent in Africa, with a significant number of affected individuals, particularly in regions with higher rates of consanguinity. According to the World Health Organisation, Sickle cell prevalence is as high as 45% in parts of Uganda, and between 20-30% in Cameroon, Republic of Congo, Gabon, Ghana and Nigeria.
