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Central Research
First CRISPR therapy for a genetic disease approved
The UK drug regulatory agency has approved the first CRISPR genome-editing therapy for a genetic disease. It is Casgevy, a treatment for sickle cell disease and beta-thalassemia, developed by Vertex Pharmaceuticals and CRISPR Therapeutics.
The approval, just 11 years after the publication of the first article outlining the potential of CRISPR tools for genome editing, reflects the revolution this technique has brought about and the significant progress made in recent years.
“This is a world first and a significant moment for researchers, doctors, and above all, for people with sickle cell anemia and beta-thalassemia,” noted Josu de la Fuente, a professor and researcher at Imperial College London who participated in the clinical trials evaluating Casgevy. “These are hereditary blood disorders that have a profound impact on people’s lives. This approval provides a new option for patients who meet the necessary requirements and are awaiting innovative therapies.”
“Both sickle cell anemia and beta-thalassemia are lifelong, painful diseases that, in some cases, can be fatal,” emphasized Julian Beach, Interim Executive Director of Quality and Access to Healthcare at the UK Medicines and Healthcare products Regulatory Agency. “I am pleased to announce that we have authorized an innovative and pioneering gene-editing treatment called Casgevy, which, according to trials, restores the production of healthy hemoglobin in the majority of patients with sickle cell anemia and transfusion-dependent β-thalassemia, thus alleviating the symptoms of the disease.”
A therapy aimed at treating two diseases caused by alterations in the same gene
Casgevy, the commercial name for exagamglogene autotemcel or exa-cel, is indicated for the treatment of patients with sickle cell anemia or beta-thalassemia who meet certain established criteria.
Both diseases are blood disorders caused by mutations in the HBB gene that compromise the production of hemoglobin. In the case of sickle cell anemia, the resulting defective hemoglobin causes red blood cells to take on an incorrect shape, leading to two main consequences. Firstly, these red blood cells die prematurely, which can result in anemia. Secondly, they can obstruct small blood vessels, causing issues in the distribution of blood to organs and episodes of pain.
In the case of beta-thalassemia, the production of hemoglobin is significantly reduced, leading to anemia and other associated complications.
Additionally, patients have a higher risk of developing abnormal blood clots. In severe cases, the disease requires regular transfusions, which come with their risks, such as increased iron in the blood, which can be harmful to certain organs and bodily functions.
What is Casgevy, the first CRISPR therapy?
Casgevy is an ex vivo cell therapy with modified cells to produce functional hemoglobin. The treatment involves obtaining hematopoietic stem cells (those that generate different types of blood cells) from patients, modifying them using CRISPR tools, amplifying them in the laboratory, and then reintroducing them back into the patients.
The genetic modification strategy leverages a highly relevant feature in both diseases: the responsible mutations affect the HBB gene, which encodes beta-globin, an essential component in adult hemoglobin. The key is that patients have another potential source of beta-globin intact: the gene that produces fetal beta-globin. The expression of this gene is automatically silenced shortly after birth, replaced by adult beta-globin. However, researchers have found a way to maintain its expression in patients who do not produce adult beta-globin.
Regulation of the first CRISPR therapy and other open questions
Gasgevy, approved in the United Kingdom, is also under review by other regulatory agencies such as the European Medicines Agency, the United States Food and Drug Administration (FDA), and the Saudi Food and Drug Authority. In the U.S., the review for transfusion-dependent thalassemia is scheduled for March 30, 2024.
An open question remains regarding the price of the therapy. To establish the treatment’s cost, the responsible companies will take into account the research, development, and production costs of the drug, which must be prepared on a personalized basis for each patient. Currently, there is no official figure, although the Institute for Clinical and Economic Review estimates that the necessary price for the treatment to be cost-effective should range between 1.35 and 2 million dollars. Zynteglo, a similar therapy targeting beta-thalassemia without genetic editing, is priced at 2.8 million dollars in the U.S. In Europe, the initially set price was 1.8 million dollars. However, due to various production issues, the responsible company, Bluebird, decided to focus solely on the U.S. market.
In comparison to the potential cost of the therapy, the healthcare expenses for patients with sickle cell anemia or beta-thalassemia are high. For instance, it has been estimated that, up to the age of 64, the attributable medical expenditure for each patient with sickle cell anemia amounts to 1.7 million dollars (for insured patients). It remains to be seen whether the final price of the therapy enables all individuals who could benefit from it to receive the treatment. Ultimately, the question is whether the therapy, in addition to being effective, will be accessible.
The debut of CRISPR
Gasgevy’s approval marks a milestone for gene therapies. It is the first CRISPR-based therapy approved for the treatment of a genetic disease. The recent development of CRISPR and derived genome editing systems represents a highly promising opportunity for numerous genetic diseases. Evidence of this is seen in the numerous clinical trials utilizing these technologies to correct genetic errors responsible for various diseases.
Vertex Pharmaceuticals and CRISPR Therapeutics, the latter co-founded by Emmanuelle Charpentier, jointly awarded the Nobel Prize in Chemistry in 2020 with Jennifer Doudna for the development of CRISPR as a method of genetic editing, have been involved in the development of Gasgevy. Currently, both companies have various therapies under investigation for diseases such as diabetes, Duchenne muscular dystrophy, or cardiovascular disease.
Amparo Tolosa, PhD
Scientific Director of Genotipia
Sources
Vertex and CRISPR Therapeutics Announce Authorization of the First CRISPR/Cas9 Gene-Edited Therapy, CASGEVY™ (exagamglogene autotemcel), by the United Kingdom MHRA for the Treatment of Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia. Retrieved from: https://ir.crisprtx.com/news-releases/news-release-details/ vertex-and-crispr-therapeutics-announce-authorization-first
UK approves world-first gene-editing treatment for blood disorders. Retrieved from: https://www.imperial.ac.uk/news/249536/uk-approves-world-first-gene-editingtreatment-blood/
MHRA authorises world-first gene therapy that aims to cure sickle-cell disease and transfusion-dependent β-thalassemia. Retrieved from: https://www.gov.uk/government/ news/mhra-authorises-world-first-gene-therapy-that-aims-to-cure-sickle-cell-disease-and-transfusion-dependent-thalassemia
