Written and Reviewed by Team Pharmacally
Introduction
Casgevy (exagamglogene autotemcel) is a breakthrough in gene therapy and precision medicine. It was developed utilizing the CRISPR-Cas9 technology and aims to treat specific genetic disorders like Beta-Thalassemia by targeting and editing faulty DNA sequences. This article examines the production and pharmacological profile along with future prospects of Casgevy.
Production Using CRISPR Technology
Casgevy (exagamglogene autotemcel) is a novel gene therapy for sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT). It works by applying CRISPR/Cas9 gene editing to a patient’s own hematopoietic stem cells, boosting the production of fetal haemoglobin (HbF), thus reducing the manifestations of the disease.
Manufacturing Process:
1. Stem Cell Collection: It starts with the collection of hematopoietic stem cells of a patient, responsible for the generation of blood cells.
2. Gene Editing: These collected cells are then genetically modified using CRISPR/Cas9 technology. The gene editing targets the BCL11A gene, which is one of the critical regulators of HbF production, to enhance its expression in erythroid lineage cells.
3. Cell Expansion and Quality Control: In the laboratory, the edited cells are expanded in sufficient quantities to be transplanted. Severe quality control measures are used to ensure the safety and effectiveness of the altered cells.
4. Conditioning Regimen: Before the reinfusion, patients will undergo a conditioning regimen, possibly chemotherapy, which will prepare their bone marrow to accept the new stem cells.
5. Reinfusion: The modified stem cells are then reinfused into the patient where they engraft and begin producing healthy red blood cells with high levels of HbF.
Manufacturing Facilities:
In September 2024, Lonza entered into a long-term commercial supply agreement with Vertex Pharmaceuticals for the manufacturing of Casgevy. The manufacturing of Casgevy is done at Lonza’s Geleen facility in the Netherlands, which received FDA, EMA, and MHRA approval for the commercial production of Casgevy.
Indications
Casgevy is indicated for the treatment of rare monogenic disorders, including:
Sickle Cell Disease (SCD): a group of genetic disorders that involve an abnormal form of haemoglobin, called haemoglobin S. This results in red blood cells becoming sickle-shaped, or crescent- shaped. These sickle cells are less flexible and adhere to one another, causing an obstruction in small blood vessels, which leads to various complications.
Transfusion-Dependent Beta Thalassemia: The severest form of beta-thalassemia is a congenital blood condition that causes deficiencies in the output of haemoglobin. Since haemoglobin is responsible for carrying oxygen from the lungs, TDT produces chronic anaemia and other squeal due to a marked decline or absence of functional beta-globin chains in haemoglobin.
Mechanism of Action
Casgevy, exagamglogene autotemcel is a single course gene therapy, intended for use in patient suffering from sickle cell disease and transfusion-dependent beta thalassemia, thus curing the basic pathogenic mutations in these conditions
Acquisition of Patient’s Stem Cells Collection of the patient’s own HSCs that are responsible for the production of blood cells forms the starting process.
Gene editing by CRISPR/Cas9. HSCs edited using the power of CRISPR/Cas9 to disrupt or knockdown BCL11A. This transcription factor keeps the fetal form of haemoglobin, or HbF, repressed postnatal. Editing BCL11A into these cells to suppress it decreases its effect to let more HbF get produced.
Reinfusion into the Patient: The modified HSCs are then reinfused into the patient. Once in the bone marrow, these cells engraft and differentiate into red blood cells that produce higher levels of HbF.
Therapeutic Effect: Elevated HbF levels prevent the sickling of red blood cells in SCD and reduce the need for transfusions in TDT by compensating for the defective haemoglobin. This approach addresses the root cause of these diseases, offering a potential functional cure.
Safety Profile
Its safety profile has been assessed in clinical trials, and findings are generally consistent with those expected from busulfan myeloablative conditioning and hematopoietic stem cell transplantation.
Common Side Effects:
Low Platelet Levels: This can cause impaired blood clotting and bleeding.
Low White Blood Cell Levels: This increases susceptibility to infections.
Abdominal Pain, Musculoskeletal Pain, Headache, Pruritus are some of other common and non serious types of adverse reactions. All these side effects are usually short-term and reversible once the patient’s body recuperates after therapy.
Serious Adverse Reactions:
Serious adverse reactions attributed to Casgevy occurred in 2 (3.7%) patients with TDT:
Febrile Neutropenia: Fever with reduced neutrophils, making infection more likely to occur
Mucositis: Inflammation of the mucous membranes.
These reactions were generally consistent with those expected from busulfan myeloablative conditioning and hematopoietic stem cell transplantation.
Monitoring and Management:
Neutrophil Engraftment: Monitoring is essential to ensure proper neutrophil recovery.
Platelet Levels: Regular assessments to detect and manage thrombocytopenia.
Infection Vigilance: Close observation for signs of infection, especially during periods of low white blood cell counts.
It’s crucial for healthcare providers to monitor these parameters closely and manage any adverse effects promptly to ensure patient safety during and after treatment with Casgevy.
Clinical Trial Results
Casgevy (exagamglogene autotemcel) is a first-in-class gene-editing therapy designed to treat sickle cell disease (SCD) and transfusion-dependent beta-thalassemia (TDT). Clinical trials have shown its efficacy and safety, and it has been approved in several countries.
Clinical Trial Results for Sickle Cell Disease:
In a landmark study of 44 adult and adolescent patients with severe SCD, all participants were successfully engrafted without graft failure or rejection. Among the 31 patients who have had adequate follow-up, 29 (93.5%) remained free of severe VOCs for at least 12 consecutive months.
These results were published in the New England Journal of Medicine in April 2024, indicating Casgevy as a promising therapy for the transformation of SCD.
Clinical Trial Results for Transfusion-Dependent Beta-Thalassemia:
In another clinical trial, 42 patients with TDT were administered Casgevy. Of them, 39 (92.9%) stopped receiving blood transfusions for at least a year after the treatment.
These results appeared in the New England Journal of Medicine in April 2024, confirming Casgevy’s efficacy for the treatment of TDT.
Regulatory Status
Casgevy (exagamglogene autotemcel) is a gene-editing therapy developed for the treatment of transfusion-dependent beta-thalassemia (TDT) and severe sickle cell disease (SCD). Its regulatory status varies across different regions:
United States:
In January 2024, the U.S. Food and Drug Administration approved Casgevy for treating patients aged 12 years and older with transfusion-dependent beta-thalassemia. This approval was based on a favourable benefit-risk assessment, as 91.4% of subjects achieved transfusion independence and maintained a haemoglobin level of ≥9 g/dL for at least 12 consecutive months during the study.
European Union:
In the European Union, the EMA has recommended approval of Casgevy in the month of December 2023. Conditional marketing authorization has been issued by the European Commission for the treatment of transfusion-dependent beta-thalassemia and sickle cell disease in the patients who are aged 12 years and above in February 2024. It was the first authorization of a CRISPR/Cas9-based gene therapy approved in Europe.
United Kingdom:
In November 2023, the UK Medicines and Healthcare products Regulatory Agency authorized Casgevy for the treatment of sickle cell disease and beta-thalassemia. From 1 August 2024, the National Health Service in England has provided access to Casgevy with a list price of £1.7 million per course of treatment.
Overall, Casgevy has received the required regulatory approvals in the United States, the European Union, and the United Kingdom for use in the treatment of transfusion-dependent beta-thalassemia and severe sickle cell disease.
Future Prospects
Market Challenges and Future Prospects
Despite its clinical success, Casgevy faces challenges:
High Treatment Costs: Priced at approximately $2 million per patient, the therapy’s affordability remains a concern.
Manufacturing Complexity: The whole process of gene editing and reinfusion of cells is highly complex.
In the future, CRISPR Therapeutics has also presented strategic goals for 2025, such as updates on Casgevy’s launch and progress in other gene-editing therapies.
The company looks forward to increasing treatment facilities and building manufacturing capacity to cater for international demand.
In summary, Casgevy represents a significant step forward in gene therapy, which can potentially cure severe blood disorders. Challenges notwithstanding, research is ongoing and strategic initiatives are likely to improve access and affordability, thus expanding the reach of the therapy in the coming years.
References:
- Adashi, Eli Y. et al., CRISPR Therapy of Sickle Cell Disease: The Dawning of the Gene Editing Era, The American Journal of Medicine, Volume 137, Issue 5, 390 – 392
- Li T, Yang Y, Qi H, et al, CRISPR/Cas9 therapeutics: progress and prospects. Sig Transduct Target Ther 8, 36 (2023). Available from https://doi.org/10.1038/s41392-023-01309-7
- Singh A, Irfan H, Fatima E, Nazir Z, Verma A, Akilimali A. Revolutionary breakthrough: FDA approves CASGEVY, the first CRISPR/Cas9 gene therapy for sickle cell disease. Ann Med Surg (Lond). 2024 May 15;86(8):4555-4559. doi: 10.1097/MS9.0000000000002146, PMID: 39118728; PMCID: PMC11305803
- Park SH, Bao G. CRISPR/Cas9 gene editing for curing sickle cell disease. Transfus Apher Sci. 2021 Feb;60(1):103060. doi: 10.1016/j.transci.2021.103060. Epub 2021 Jan 10. PMID: 33455878; PMCID: PMC8049447
- Lonza and Vertex Sign a Long-Term Commercial Supply Agreement for CASGEVY® (exagamglogene autotemcel)
- Highlights of prescribing information, CASGEVY (exagamglogene autotemcel), suspension for intravenous infusion, available from https://pi.vrtx.com/files/uspi_exagamglogene_autotemcel.pdf
- CASGEVY® is a CRISPR/Cas9-modified autologous CD34+ cellular gene therapy, Casgevy (exagamglogene autotemcel) Mechanism of Action, available from https://www.casgevyhcp.com/sickle-cell-disease/mechanism-of-action
- Casgevy, Drugs.com, available from https://www.drugs.com/casgevy.html
- CRISPR Clinical Trials: A 2024 Updates, Hope Henderson, Innovative Genomic Institute, 24 March 2024, News Release, Lonza
- The clinical study was designed to determine the possible benefits and risks of CASGEVY, available from https://www.casgevy.com/sickle-cell-disease/study-information
- H. Frangoul, F. Locatelli, A. Sharma, Exagamglogene Autotemcel for Severe Sickle Cell Disease, N Engl J Med 2024;390:1649-62. DOI: 10.1056/NEJMoa2309676
- Ranco Locatelli, Peter Lang, Donna Wall, et al, Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia, N Engl J Med 2024;390:1663-1676, DOI: 10.1056/NEJMoa2309673
- Parums DV. Editorial: First Regulatory Approvals for CRISPR-Cas9 Therapeutic Gene Editing for Sickle Cell Disease and Transfusion-Dependent β-Thalassemia. Med Sci Monit. 2024 Mar 1;30:e944204. Doi: 10.12659/MSM.944204. PMID: 38425279; PMCID: PMC10913280.
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