Exagamglogene autotemcel

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Exagamglogene autotemcel
Clinical data
Trade names Casgevy
Other namesCTX001, exa-cel
AHFS/Drugs.com Casgevy
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administration 		Intravenous
ATC code
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Legal status
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UNII
KEGG

Exagamglogene autotemcel, sold under the brand name Casgevy, is a gene therapy used for the treatment of sickle cell disease [1] [3] and transfusion-dependent beta thalassemia. [1] It was developed by Vertex Pharmaceuticals and CRISPR Therapeutics. [6]

Contents

The most common side effects include low levels of platelets and white blood cells, mouth sores, nausea, musculoskeletal pain, abdominal pain, vomiting, febrile neutropenia (fever and low white blood cell count), headache, and itching. [7]

The treatment was approved in the United Kingdom for the treatment of sickle cell disease and transfusion-dependent beta thalassemia in November 2023. [8] [9] [10] It was approved in the United States for the treatment of sickle cell disease in December 2023 and for the treatment of transfusion-dependent beta thalassemia in January 2024. [7] [11] [12]

Exagamglogene autotemcel is the first cell-based gene therapy treatment utilizing CRISPR/Cas9 gene editing technology to be approved by the US Food and Drug Administration (FDA). [7]

Medical uses

In the UK, exagamglogene autotemcel is indicated for the treatment of transfusion-dependent beta thalassemia and sickle cell disease in patients aged 12 years and older who should be treated with hematopoietic stem cell transplantation but for whom a suitable stem cell donor is not available. [1]

In the US, exagamglogene autotemcel is indicated for the treatment of sickle cell disease in people aged 12 years and older with recurrent vaso-occlusive crises, [4] and for the treatment of people with transfusion-dependent beta-thalassemia. [4] [13]

The gene therapy is made from the recipient's own blood stem cells, which are modified, and are given back as a one-time, single-dose infusion as part of a hematopoietic (blood) stem cell transplant. [7] Prior to treatment, the recipient's own stem cells are collected, and then the recipient must undergo myeloablative conditioning (high-dose chemotherapy), a process that removes cells from the bone marrow so they can be replaced with the modified cells in exagamglogene autotemcel. [7] The modified blood stem cells are transplanted back into the recipient where they engraft (attach and multiply) within the bone marrow and increase the production of fetal hemoglobin (HbF), a type of hemoglobin that facilitates oxygen delivery. [7]

Side effects

The most common side effects observed in clinical studies included low levels of platelets and white blood cells, mouth sores, nausea, musculoskeletal pain, abdominal pain, vomiting, febrile neutropenia (fever and low white blood cell count), headache and itching. [7]

History

The safety and effectiveness of exagamglogene autotemcel were evaluated in an ongoing single-arm, multi-center trial in adult and adolescent participants with sickle cell disease. [7] Participants had a history of at least two protocol-defined severe vaso-occlusive crises during each of the two years prior to screening. [7] The primary efficacy outcome was freedom from severe vaso-occlusive crisis episodes for at least twelve consecutive months during the 24-month follow-up period. [7] A total of 44 participants were treated with exagamglogene autotemcel. [7] Of the 31 participants with sufficient follow-up time to be evaluable, 29 (93.5%) achieved this outcome. [7] All treated participants achieved successful engraftment with no participants experiencing graft failure or graft rejection. [7]

The US Food and Drug Administration (FDA) granted the application for exagamglogene autotemcel priority review, orphan drug, fast track, and regenerative medicine advanced therapy designations. [7] The FDA granted approval of Casgevy to Vertex Pharmaceuticals. [7]

Society and culture

In December 2023, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Casgevy, intended for the treatment of transfusion‑dependent β‑thalassemia and sickle cell disease. [14] [15] As Casgevy is an advanced therapy medicinal product, the CHMP positive opinion is based on an assessment by the Committee for Advanced Therapies. [14] The applicant for this medicinal product is Vertex Pharmaceuticals (Ireland) Limited. [14]

Economics

The therapy has a US list price of US$2.2 million. [16] The cost effectiveness threshold of the therapy in the US is estimated to be between $1.35 million and $2.05 million [17] depending on perspective (healthcare vs limited societal) and assuming the willingness to pay for 1 quality-adjusted life year (QALY) at $100,000–$150,000. [18]

The UK price is estimated to be £1 million. [19] [20]

Related Research Articles

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Gene therapy is a medical technology that aims to produce a therapeutic effect through the manipulation of gene expression or through altering the biological properties of living cells.

<span class="mw-page-title-main">Thalassemia</span> Family of inherited blood disorders

Thalassemias are inherited blood disorders that result in abnormal hemoglobin. Symptoms depend on the type of thalassemia and can vary from none to severe. Often there is mild to severe anemia as thalassemia can affect the production of red blood cells and also affect how long the red blood cells live. Symptoms of anemia include feeling tired and having pale skin. Other symptoms of thalassemia include bone problems, an enlarged spleen, yellowish skin, pulmonary hypertension, and dark urine. Slow growth may occur in children. Symptoms and presentations of thalassemia can change over time. Older terms included Cooley's anemia and Mediterranean anemia for beta-thalassemia. These have been superseded by the terms Transfusion-Dependent Thalassemia (TDT) and non-Transfusion-Dependent Thalassemia (NTDT). Patients with TDT require regular transfusions, typically every two to five weeks. TDTs include Beta-thalassemia major, nondeletional HbH disease, survived Hb Bart's disease, and severe HbE/beta-thalassemia.

<span class="mw-page-title-main">Vertex Pharmaceuticals</span> American pharmaceutical company

Vertex Pharmaceuticals Incorporated is an American biopharmaceutical company based in Boston, Massachusetts. It was one of the first biotech firms to use an explicit strategy of rational drug design rather than combinatorial chemistry. It maintains headquarters in South Boston, Massachusetts, and three research facilities, in San Diego, California, and Milton Park, Oxfordshire, England.

<span class="mw-page-title-main">Alpha-thalassemia</span> Thalassemia involving the genes HBA1and HBA2 hemoglobin genes

Alpha-thalassemia is a form of thalassemia involving the genes HBA1 and HBA2. Thalassemias are a group of inherited blood conditions which result in the impaired production of hemoglobin, the molecule that carries oxygen in the blood. Normal hemoglobin consists of two alpha chains and two beta chains; in alpha-thalassemia, there is a quantitative decrease in the amount of alpha chains, resulting in fewer normal hemoglobin molecules. Furthermore, alpha-thalassemia leads to the production of unstable beta globin molecules which cause increased red blood cell destruction. The degree of impairment is based on which clinical phenotype is present.

<span class="mw-page-title-main">Beta thalassemia</span> Blood disorder

Beta thalassemias are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to clinically asymptomatic individuals. Global annual incidence is estimated at one in 100,000. Beta thalassemias occur due to malfunctions in the hemoglobin subunit beta or HBB. The severity of the disease depends on the nature of the mutation.

<span class="mw-page-title-main">Sickle cell disease</span> Group of genetic blood disorders

Sickle cell disease (SCD), also simply called sickle cell, is a group of hemoglobin-related blood disorders typically inherited. The most common type is known as sickle cell anemia. It results in an abnormality in the oxygen-carrying protein haemoglobin found in red blood cells. This leads to a rigid, sickle-like shape under certain circumstances. Problems in sickle cell disease typically begin around 5 to 6 months of age. A number of health problems may develop, such as attacks of pain in joints, anemia, swelling in the hands and feet, bacterial infections, dizziness and stroke. Long-term pain may develop as people get older. The average life expectancy in the developed world is 40 to 60 years. It often gets worse with age. All the major organs are affected by sickle cell disease. The liver, heart, kidneys, gallbladder, eyes, bones, and joints also can suffer damage from the abnormal functions of the sickle cells, and their inability to flow through the small blood vessels correctly.

Treatment of the inherited blood disorder thalassemia depends upon the level of severity. For mild forms of the condition, advice and counseling are often all that are necessary. For more severe forms, treatment may consist in blood transfusion; chelation therapy to reverse iron overload, using drugs such as deferoxamine, deferiprone, or deferasirox; medication with the antioxidant indicaxanthin to prevent the breakdown of hemoglobin; or a bone marrow transplant using material from a compatible donor, or from the patient's mother. Removal of the spleen (splenectomy) could theoretically help to reduce the need for blood transfusions in people with thalassaemia major or intermedia but there is currently no reliable evidence from clinical trials about its effects. Population screening has had some success as a preventive measure.

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<span class="mw-page-title-main">Transfusion-dependent anemia</span>

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References

  1. 1 2 3 4 "Summary of Product Characteristics". Medicines and Healthcare products Regulatory Agency (MHRA). 15 November 2023. Archived from the original (PDF) on 8 December 2023. Retrieved 9 December 2023.
  2. ↑ "Casgevy 4–13 x 10Exp6 cells/mL dispersion for infusion". Electronic Medicines Compendium. 24 November 2023. Archived from the original on 9 December 2023. Retrieved 9 December 2023.
  3. 1 2 "Casgevy- exagamglogene autotemcel injection, suspension". DailyMed. 22 January 2024. Retrieved 3 March 2024.
  4. 1 2 3 "Casgevy". U.S. Food and Drug Administration (FDA). 8 December 2023. Archived from the original on 19 December 2023. Retrieved 8 December 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain.
  5. ↑ "Casgevy product information". Union Register of medicinal products. 12 February 2024. Retrieved 19 February 2024.
  6. ↑ Stein R (31 October 2023). "FDA advisers see no roadblocks for gene-editing treatment for sickle cell disease". NPR. Archived from the original on 4 December 2023. Retrieved 4 December 2023.
  7. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 "FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease". U.S. Food and Drug Administration (FDA). 8 December 2023. Archived from the original on 8 December 2023. Retrieved 8 December 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  8. ↑ "MHRA authorises world-first gene therapy that aims to cure sickle-cell disease and transfusion-dependent β-thalassemia". Medicines and Healthcare products Regulatory Agency (MHRA) (Press release). 16 November 2023. Archived from the original on 25 November 2023. Retrieved 8 December 2023.
  9. ↑ Sheridan C (November 2023). "The world's first CRISPR therapy is approved: who will receive it?". Nature Biotechnology. 42 (1): 3–4. doi:10.1038/d41587-023-00016-6. PMID   37989785. S2CID   265350318. Archived from the original on 4 December 2023. Retrieved 4 December 2023.
  10. ↑ "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" (Press release). Vertex Pharmaceuticals. 16 November 2023. Archived from the original on 22 November 2023. Retrieved 9 December 2023– via Business Wire.
  11. ↑ "Vertex and CRISPR Therapeutics Announce US FDA Approval of Casgevy (exagamglogene autotemcel) for the Treatment of Sickle Cell Disease" (Press release). Vertex Pharmaceuticals. 8 December 2023. Archived from the original on 9 December 2023. Retrieved 9 December 2023– via Business Wire.
  12. ↑ Commissioner, Office of the (16 January 2024). "FDA Roundup: January 16, 2024". FDA. Retrieved 19 January 2024.
  13. ↑ "FDA Roundup: January 16, 2024". U.S. Food and Drug Administration (FDA) (Press release). 16 January 2024. Archived from the original on 17 January 2024. Retrieved 17 January 2024.
  14. 1 2 3 "Casgevy EPAR". European Medicines Agency (EMA). 14 December 2023. Archived from the original on 19 December 2023. Retrieved 16 December 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  15. ↑ "First gene editing therapy to treat beta thalassemia and severe sickle cell disease". European Medicines Agency (EMA) (Press release). 15 December 2023. Archived from the original on 16 December 2023. Retrieved 16 December 2023.
  16. ↑ Feuerstein A (8 December 2023). "In historic decision, FDA approves a CRISPR-based medicine for treatment of sickle cell disease". STAT. Archived from the original on 9 December 2023. Retrieved 10 December 2023.
  17. ↑ "ICER Publishes Final Evidence Report on Gene Therapies for Sickle Cell Disease". Institute for Clinical and Economic Review . Archived from the original on 4 December 2023. Retrieved 4 December 2023.
  18. ↑ "Value Assessment Framework". Institute for Clinical and Economic Review . Archived from the original on 14 November 2023. Retrieved 10 December 2023.
  19. ↑ Pinkstone J, Searles M (16 November 2023). "Life-changing blood disease treatment approved at £1m cost per patient". The Telegraph. Archived from the original on 10 December 2023. Retrieved 10 December 2023.
  20. ↑ Wong C (November 2023). "UK first to approve CRISPR treatment for diseases: what you need to know". Nature. 623 (7988): 676–677. Bibcode:2023Natur.623..676W. doi: 10.1038/d41586-023-03590-6 . PMID   37974039.

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