The European Medicines Agency (EMA) has recommended granting conditional marketing authorization for Casgevy (exagamglogene autotemcel) for the treatment of transfusion-dependent beta-thalassemia and severe sickle cell disease in patients 12 years or older who are appropriate candidates for hematopoietic stem cell transplantation but a suitable donor is not available. The treatment was approved earlier this month by the US Food and Drug Administration.
Beta-thalassemia and sickle cell disease are inherited blood disorders. Hemoglobin production is reduced in patients with beta-thalassemia, resulting in low red blood cell count and symptoms like fatigue, shortness of breath, and irregular heartbeats. In patients with sickle cell disease, the body produces defective hemoglobin that can clump together and clog blood vessels, reducing the oxygen supply to tissues and leading to a very painful condition called vaso-occlusive crisis.
Until recently, the only effective treatment for both conditions was stem cell or bone marrow transplantation, but it is challenging to find suitable donors and well-equipped care facilities for this procedure.
Ex Vivo Stem Cell Editing
Casgevy is relatively new and has the potential to reduce the burden of frequent transfusions and improve the quality of life in patients with blood disorders. It is a cellular therapy that uses CRISPR/Cas9 technology and contains exagamglogene autotemcel, a hematologic agent, as its active substance. The stem cells from the patient's blood are mobilized and edited ex vivo by CRISPR/Cas9 technology at the erythroid-specific enhancer region of the BCL11A gene. The patient undergoes conditioning treatment to prepare the bone marrow before the modified cells are infused back. The treated cells then take residence in the bone marrow where they are meant to provide functioning hemoglobin by increasing fetal hemoglobin production.
Casgevy is intended for one-time administration and its effects are thought to last a lifetime.
Trials Are Ongoing
The EMA has recommended Casgevy for beta-thalassemia on the basis of initial, positive results from an ongoing single-arm trial. The primary efficacy set included 42 patients with transfusion-dependent beta -thalassemia who received a single Casgevy dose, of which 39 (~93%) patients remained transfusion-free for 1 year or longer.
The trial that dictated EMA's recommendation of Casgevy for sickle cell disease is also ongoing. It included 29 patients with severe sickle cell disease, of whom 28 (97%) were free of vaso-occlusive crises for at least 12 consecutive months.
The safety results were based on data of 97 adolescent and adult patients with either disease condition who received Casgevy from the two above-mentioned trials and another long-term follow-up study. No significant safety concerns were identified.
The most common side effects are low white blood cell counts, including febrile neutropenia, low platelet levels, liver disease, nausea, vomiting, headache, and mouth sores. The medications needed for the modified blood cells to engraft and replace the unmodified stem cells are behind these adverse events.
More Research Needed
Even though more data will be required to pen a clearer picture about the efficacy and safety profile of Casgevy, EMA's expert committee for cell- and gene-based medicines has found that the benefits of Casgevy outweigh the possible risks.
Casgevy has been supported through the EMA's priority medicines (PRIME) scheme. The scheme targets medical conditions with an unmet need, for which there is no available therapy or a new therapy could provide significant benefit s compared with existing treatments. For new therapies to be accepted for PRIME, they should demonstrate substantial potential for improving clinical outcomes, such as preventing the onset and duration of a condition or improving the morbidity or mortality of a disease.
Vertex Pharmaceuticals (Ireland) Limited has until August 2026 to submit the complete data from the trials that are currently underway, along with the results of the ongoing long-term follow-up study and any additional research that might be carried out. To track the long-term effectiveness and safety of this gene therapy, patients treated with Casgevy need to be followed up for 15 years. The company is also required to perform and submit findings from research based on data from a patient registry to provide more insights into the treatment's long-term safety and efficacy.
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