Following approval in the United Kingdom and the United States, the European Medicines Agency (EMA) has recommended approval of CRISPR gene therapy for the treatment of beta thalassemia and sickle cell anemia in December 2023. Finally on February 12, 2024 the European Commission has given its authorization.
The treatment, called Casgevy, edits the patient’s blood cells using CRISPR/Cas9 technology. The EMA considers that the benefits of this gene therapy outweigh the possible risks for patients.
Sickle cell anemia and beta thalassemia are two rare inherited diseases caused by genetic mutations that affect the production or function of hemoglobin, the protein found in red blood cells that carries oxygen throughout the body.
Sickle cell anemia can cause severe pain, organ damage, and a shortened life due to deformed or “sickle” blood cells. People with sickle cell anemia produce unusually shaped red blood cells that can cause problems because they do not live as long as healthy blood cells and can block blood vessels, causing pain and life-threatening infections. This disease mostly affects people of African or Caribbean origin.
Beta thalassemia affects red blood cells and can cause anemia of varying severity. People with beta thalassemia do not produce enough hemoglobin, which is used by red blood cells to carry oxygen. Beta thalassemia mainly affects people of Mediterranean, South Asian, Southeast Asian, and Middle Eastern origin.
To date, the only permanent treatment option for both blood conditions is a bone marrow transplant from a compatible donor.
Casgevy is designed to edit the defective gene in the patient’s bone marrow stem cells so that it produces functional hemoglobin. Clinical evidence shows that the new treatment can effectively achieve normal hemoglobin production in patients and alleviate the symptoms of the disease.
The treatment consists of extracting stem cells from the patient’s bone marrow, which are genetically modified using CRISPR/Cas9 gene editing technology, consisting of the application of “molecular scissors” capable of cutting a strand of DNA at a specific site, essentially deactivating the defective gene. The edited cells are then infused back into the patient, allowing them to synthesize functional hemoglobin and correct the underlying disease.
This new therapy may free patients from frequent transfusions and vaso-occlusive crises that occur when sickle red blood cells block small blood vessels.
The EMA has based its recommendation on two trials with patients between 12 and 35 years old. In the first, 42 patients with transfusion-dependent beta thalassemia who received a single dose were included. Of these 42 patients, 39 were transfusion-free for at least one year. In the second trial, 29 patients with sickle cell anemia were included. Of these 29 patients, 28 were free of episodes of vaso-occlusive crises for at least 12 consecutive months.
In its overall assessment of the available data, the EMA’s Committee for Advanced Therapies (CAT) concluded that the benefits of Casgevy outweighed the possible risks in patients with beta thalassemia and sickle cell anemia. The EMA’s Human Medicines Committee (CHMP) agreed with the CAT’s positive assessment and also recommended the approval of this medicine.
The opinion adopted by the CHMP is an intermediate step on Casgevy’s path towards patient access. The opinion will now be sent to the European Commission for a decision on an EU-wide marketing authorisation. Once marketing authorization has been granted, decisions on pricing will be taken at the level of each Member State.
In the United Kingdom the price of Casgevy is estimated to be around £1 million and in the United States $2.2 million per patient.
As we already mentioned in our Observatory, the American Victoria Gray was the first patient with sickle cell anemia to be cured using this experimental therapy, as she herself explained at a Congress held in London in March 2023.
The clinical application of gene editing to correct certain pathologies represents a hopeful advance for the approach of diseases for which, until now, no curative treatments were available.
Advances in this field are slow, due to the need to ensure that the side effects of these techniques do not outweigh the expected benefits.
Since 2018, the Spanish Agency for Medicines and Health Products (AEMPS) has already authorized four clinical trials in Spain with cells subjected to these promising genomic editing techniques, three of them with CRISPR/Cas (the technology used in Casgevy) and one with the TALEN (transcription activator-like effector nuclease) system.
The complexity of the human genome, the interaction between the different genes that make it up and the still imperfect CRISPR editing technique, are factors that limit the effectiveness of these techniques and can cause the appearance of unwanted effects, due to the unwanted affectation of certain genes caused by the editing technique itself or by the interaction of the edited genes with other regions of the genome, the consequences of which are difficult to predict.
In the current case, the positive benefit-risk balance of previous clinical trials has promoted its approval as a genetic therapy to treat patients affected by the pathologies described.
In other cases the results raise doubts, such as the recent case of a genetic editing clinical trial aimed at reducing LDL cholesterol levels, in which one of the ten recruited volunteers died after participating in the trial. The volunteers received an injection of VERVE-101 to deactivate the gene responsible for the disease and saw their LDL cholesterol level reduced by up to 55% after 28 days. Before the experiment, their plasma level was twice as high as usual. One of the patients died of a heart attack five weeks later, although a direct relationship between the treatment and the patient’s death could not be confirmed.
The application of prudent criteria in gene editing therapies constitutes an unavoidable requirement to ensure their effectiveness and safety in the short and long term, limiting their application to adult cells and tissues. Never on embryos in which the possible unwanted effects can affect all the cells of the individual and their offspring.
Finally, the astronomical costs of these therapies – $2.2 million in the US – make them currently unaffordable for the vast majority of affected patients, and difficult to afford by public and private health systems.
It is desirable that advances in research into gene-editing therapies not only increase their efficacy and safety rates, but also bring about a significant reduction in their costs that allow them to be offered to those affected in a realistic manner.
Julio Tudela and Ester Bosch
Bioethics Observatory – Institute of Life Sciences
Catholic University of Valencia