The European Medicines Agency (EMA) has recommended the granting of a conditional marketing authorization for Casgevy (Exagamglogene Autotemcel) to treat transfusion-dependent beta-thalassemia and severe sickle cell anemia in patients aged 12 and older who are eligible for hematopoietic stem cell transplantation but lack a suitable donor. The treatment was approved earlier this month by the U.S. Food and Drug Administration.
Beta-thalassemia and sickle cell anemia are inherited blood disorders. In patients with beta-thalassemia, hemoglobin production is reduced, leading to a low red blood cell count and symptoms such as fatigue, shortness of breath, and irregular heartbeat. In patients with sickle cell anemia, the body produces faulty hemoglobin that can clump and block blood vessels, reducing tissue oxygenation and causing a very painful condition known as a vaso-occlusive crisis.
Until recently, stem cell or bone marrow transplantation was the only effective treatment for both conditions. However, finding suitable donors and well-equipped care facilities for this procedure has been challenging.
Ex-vivo Stem Cell Processing
Casgevy is relatively new and has the potential to reduce the burden of frequent transfusions and improve the quality of life for patients with blood disorders. It is a cell therapy that utilizes CRISPR/Cas9 technology and contains Exagamglogene Autotemcel, a hematological agent. The patient’s blood stem cells are mobilized and edited ex vivo using 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 engraft in the bone marrow, where they are intended to increase fetal hemoglobin production for functional hemoglobin.
Casgevy is intended for a single administration and its effects are expected to last a lifetime.
The Processes at Play
The EMA recommended Casgevy based on the initial positive results from an ongoing single-arm study for beta-thalassemia treatment. The primary efficacy group included 42 patients with transfusion-dependent beta-thalassemia who received a single dose of Casgevy, of which 39 (~93%) patients remained transfusion-free for 1 year or longer.
The process for the EMA’s recommendation for Casgevy in sickle cell anemia is still ongoing. It included 29 patients with severe sickle cell anemia, of which 28 (97%) were free of vaso-occlusive crises for at least 12 consecutive months.
Safety outcomes were based on data from 97 adolescent and adult patients with both conditions who received Casgevy from the two aforementioned studies and another long-term follow-up study. No significant safety concerns were identified.
The most common side effects are low white blood cell count, including febrile neutropenia, low platelet count, liver disorders, nausea, vomiting, headaches, and mouth sores. These adverse events are attributed to the medications needed for the modified blood cells to proliferate and replace the unmodified stem cells.
Further Research Needed
While more data will be required to paint a clearer picture of Casgevy’s efficacy and safety profile, the EMA’s Committee for Advanced Therapies determined that the benefits of Casgevy outweigh the potential risks.
Casgevy was supported through the EMA’s Priority Medicines (PRIME) program. The program focuses on conditions with unmet needs for which there are no available treatments, or for which a new treatment could offer substantial benefits compared to existing options. To be accepted into PRIME, new therapies should have significant potential to improve clinical outcomes, such as preventing disease onset and duration or improving disease morbidity or mortality.
Vertex Pharmaceuticals (Ireland) Limited has until August 2026 to submit complete data from the ongoing studies and the results of the ongoing long-term follow-up study and any additional investigations. In order to monitor the long-term effectiveness and safety of this gene therapy, patients treated with Casgevy must be followed for 15 years. The company is also obliged to conduct and submit research findings based on data from a patient registry to gain further insights into the long-term safety and efficacy of the treatment.