Sickle Cell Breakthrough: FDA Greenlights First Gene Therapies
The U.S. Food and Drug Administration (FDA) has ushered in a new era of medical innovation with the recent approval of two groundbreaking cell-based gene therapies, Casgevy and Lyfgenia.
These therapies represent a significant milestone as the first cell-based gene treatments for sickle cell disease (SCD) approved for patients aged 12 and older.
Notably, Casgevy stands out as the inaugural FDA-approved therapy utilizing CRISPR/Cas9, a revolutionary genome editing technology, marking a leap forward in gene therapy.
Sickle cell disease, a group of inherited blood disorders, afflicts approximately 100,000 individuals in the United States, with a higher prevalence among African Americans and, to a lesser extent, Hispanic Americans.
The primary pathology in SCD is attributed to a mutation in hemoglobin, a protein found in red blood cells responsible for delivering oxygen to the body’s tissues. This mutation induces a characteristic crescent or “sickle” shape in red blood cells, restricting blood flow in vessels and impairing oxygen delivery to tissues.
The consequence is severe pain and organ damage, referred to as vaso-occlusive events (VOEs) or vaso-occlusive crises (VOCs). The recurrence of these crises can lead to life-threatening disabilities and premature death.
Director of the Office of Therapeutic Products within the FDA’s Center for Biologics Evaluation and Research, Dr. Nicole Verdun, emphasized the gravity of sickle cell disease, stating, “Sickle cell disease is a rare, debilitating and life-threatening blood disorder with significant unmet need.” The approval of Casgevy and Lyfgenia is a testament to the FDA’s commitment to advancing medical solutions for individuals whose lives have been severely impacted by this disease.
Casgevy, a cell-based gene therapy, has been approved for treating sickle cell disease in patients aged 12 and older experiencing recurrent vaso-occlusive crises. What sets Casgevy apart is its utilization of CRISPR/Cas9 technology, enabling precise genome editing.
The process involves modifying patients’ hematopoietic stem cells through CRISPR/Cas9, a system that cuts DNA in targeted areas, allowing for accurate editing – removal, addition, or replacement of DNA. Modified stem cells are then transplanted back into the patient, where they engraft within the bone marrow, boosting the production of fetal hemoglobin (HbF). Increased levels of HbF effectively prevent the sickling of red blood cells, offering a potential breakthrough in the management of sickle cell disease.
Lyfgenia, the second approved gene therapy, employs a lentiviral vector for genetic modification and is indicated for the treatment of patients aged 12 and older with sickle cell disease and a history of vaso-occlusive events.
This therapy differs from Casgevy in its mechanism, as it produces HbAT87Q, a gene-therapy-derived hemoglobin that mimics the function of normal adult hemoglobin, reducing the risk of sickling and blood flow occlusion. Like Casgevy, Lyfgenia involves modifying patients’ blood stem cells, which are then reintroduced through a one-time, single-dose infusion.
Both Casgevy and Lyfgenia herald a new era in personalized medicine, as these therapies are crafted from the patient’s blood stem cells. However, the treatment journey is complex, involving myeloablative conditioning (high-dose chemotherapy) to prepare the bone marrow for the introduction of modified cells.
The success of these therapies is further underscored by the rigorous evaluation of scientific and clinical data, culminating in designations such as Priority Review, Orphan Drug, Fast Track, and Regenerative Medicine Advanced Therapy.
The FDA’s Director of the Center for Biologics Evaluation and Research, Dr. Peter Marks, expressed the significance of these 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.” The agency is dedicated to facilitating the development of safe and effective treatments, especially for conditions with severe impacts on human health.
While the approvals mark a significant leap forward, concerns have been raised about the accessibility of these therapies. The intricate and time-consuming procedures, potential risks such as infertility, and the associated costs present challenges to widespread adoption.
Vertex Pharmaceuticals and Bluebird Bio, the companies behind Casgevy and Lyfgenia, estimate eligibility for approximately 16,000 to 20,000 patients. Despite the enthusiasm from payers, patients, and physicians, the lengthy treatment process and associated costs may limit the adoption of these groundbreaking therapies.
Vertex CEO Dr. Reshma Kewalramani addressed concerns about the cost, stating, “We believe the price of medicine to reflect the value that it brings, and the value that this brings is a one-time therapy for potentially a lifetime of cure.” The company plans to charge $2.2 million per patient for Casgevy, while Bluebird Bio intends to charge $3.1 million per patient for Lyfgenia.
The FDA, mindful of potential side effects, has included a black box warning for Lyfgenia due to rare cases of hematologic malignancy observed in patients. The warning underscores the need for lifelong monitoring of individuals receiving this therapy. Dr. Marks emphasized that the FDA wants patients to be aware of all potential side effects of the entire treatment process, considering the totality of the therapy given.
Vertex and Bluebird Bio are committed to long-term monitoring through a 15-year post-approval study for patients receiving these gene therapies. This extensive monitoring period aims to provide comprehensive insights into the safety and effectiveness of Casgevy and Lyfgenia.
The FDA’s approval of Casgevy and Lyfgenia represents a groundbreaking development in the treatment landscape for sickle cell disease. These innovative cell-based gene therapies offer hope for individuals with limited treatment options and the potential for a lifetime cure.
While the road ahead may pose challenges in terms of accessibility and cost, the FDA’s commitment to ensuring the safety and efficacy of these therapies underscores the transformative impact they could have on public health. The ongoing monitoring and post-approval studies will further contribute to our understanding of the long-term benefits and potential risks associated with these pioneering treatments.