Betibeglogene autotemcel

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Betibeglogene autotemcel
Clinical data
Trade names Zynteglo
Other namesLentiGlobin BB305, autologous CD34+ cells encoding βA-T87Q-globin gene
AHFS/Drugs.com Monograph
MedlinePlus a622065
License data
Pregnancy
category
Routes of
administration 		Intravenous [3]
ATC code
Legal status
Legal status
Identifiers
DrugBank
UNII
KEGG

Betibeglogene autotemcel, sold under the brand name Zynteglo, is a gene therapy for the treatment for beta thalassemia. [1] [5] [2] It was developed by Bluebird Bio and was given breakthrough therapy designation by the US Food and Drug Administration in February 2015. [6] [7]

Contents

The most common adverse reactions include reduced platelet and other blood cell levels, as well as mucositis, febrile neutropenia, vomiting, pyrexia (fever), alopecia (hair loss), epistaxis (nosebleed), abdominal pain, musculoskeletal pain, cough, headache, diarrhea, rash, constipation, nausea, decreased appetite, pigmentation disorder and pruritus (itch). [5]

It was approved for medical use in the European Union in May 2019, [2] and in the United States in August 2022. [5]

Medical uses

Betibeglogene autotemcel is indicated for the treatment of people twelve years and older with transfusion-dependent beta thalassemia who do not have a β0/β0 genotype, for whom hematopoietic stem cell (HSC) transplantation is appropriate but a human leukocyte antigen (HLA)-matched related HSC donor is not available. [2]

Betibeglogene autotemcel is made individually for each recipient out of stem cells collected from their blood, and must only be given to the recipient for whom it is made. [2] It is given as an autologous intravenous infusion and the dose depends on the recipient's body weight. [3] [2]

Before betibeglogene autotemcel is given, the recipient receives conditioning chemotherapy to clear their bone marrow of cells (myeloablation). [2]

To make betibeglogene autotemcel, the stem cells taken from the recipient's blood are modified by a virus that carries working copies of the beta globin gene into the cells. [2] When these modified cells are given back to the recipient, they are transported in the bloodstream to the bone marrow where they start to make healthy red blood cells that produce beta globin. [2] The effects of betibeglogene autotemcel are expected to last for the recipient's lifetime. [2]

Mechanism of action

Beta thalassemia is caused by mutations to or deletions of the HBB gene leading to reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to clinically asymptomatic individuals. [8] LentiGlobin BB305 is a lentiviral vector which inserts a functioning version of the HBB gene into a recipient's blood-producing hematopoietic stem cells (HSC) ex vivo. The resulting engineered HSCs are then reintroduced to the recipient. [9] [10]

History

In early clinical trials several participants with beta thalassemia, who usually require frequent blood transfusions to treat their disease, were able to forgo blood transfusions for extended periods of time. [11] [12] [13] In 2018, results from phase 1-2 trials suggested that of 22 participants receiving Lentiglobin gene therapy, 15 were able to stop or reduce regular blood transfusions. [14] [15]

In February 2021, a clinical trial [16] of betibeglogene autotemcel in sickle cell anemia was suspended following an unexpected instance of acute myeloid leukemia. [17] The HGB-206 Phase 1/2 study is expected to conclude in March 2023. [16]

It was designated an orphan drug by the European Medicines Agency (EMA) and by the US Food and Drug Administration (FDA) in 2013. [2] [18] The Food and Drug Administration has also declared betibeglogene autotemcel a Regenerative Medicine Advanced Therapy. [19]

The safety and effectiveness of betibeglogene autotemcel were established in two multicenter clinical studies that included adult and pediatric participants with beta-thalassemia requiring regular transfusions. [5] Effectiveness was established based on achievement of transfusion independence, which is attained when the participant maintains a predetermined level of hemoglobin without needing any red blood cell transfusions for at least 12 months. Of 41 participants receiving betibeglogene autotemcel, 89% achieved transfusion independence. [5]

Society and culture

It was approved for medical use in the European Union in May 2019, [2] and in the United States in August 2022. [5] On 24 March 2022, the European Commission withdrew the marketing authorisation for Zynteglo at the request of bluebird bio (Netherlands) B.V, for commercial reasons. [20]

Economics

Bluebird bio charges $2.8 million in the United States for a treatment of Zynteglo. [21] [22]

Names

The international nonproprietary name (INN) is betibeglogene autotemcel. [23]

Related Research Articles

<span class="mw-page-title-main">Gene therapy</span> Medical field

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">Hemoglobinopathy</span> Any of various genetic disorders of blood

Hemoglobinopathy is the medical term for a group of inherited blood disorders and diseases that primarily affect red blood cells. They are single-gene disorders and, in most cases, they are inherited as autosomal co-dominant traits.

<span class="mw-page-title-main">Thalassemia</span> Medical condition

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.

<span class="mw-page-title-main">Hematopoietic stem cell transplantation</span> Medical procedure to replace blood or immune stem cells

Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produce additional normal blood cells. It may be autologous, allogeneic or syngeneic.

<span class="mw-page-title-main">Hemoglobin A</span> 4f CC w I/ pop m onf

Hemoglobin A (HbA), also known as adult hemoglobin, hemoglobin A1 or α2β2, is the most common human hemoglobin tetramer, accounting for over 97% of the total red blood cell hemoglobin. Hemoglobin is an oxygen-binding protein, found in erythrocytes, which transports oxygen from the lungs to the tissues. Hemoglobin A is the most common adult form of hemoglobin and exists as a tetramer containing two alpha subunits and two beta subunits (α2β2). Hemoglobin A2 (HbA2) is a less common adult form of hemoglobin and is composed of two alpha and two delta-globin subunits. This hemoglobin makes up 1-3% of hemoglobin in adults.

<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> Thalassemia characterized by the reduced or absent synthesis of the beta globin chains of hemoglobin

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.

Luspatercept, sold under the brand name Reblozyl, is a medication used for the treatment of anemia in beta thalassemia and myelodysplastic syndromes.

<span class="mw-page-title-main">Sangamo Therapeutics</span> American cell and gene therapy company

Sangamo Therapeutics, Inc. is an American biotechnology company based in Brisbane, California. It applies cell and gene therapy to combat haemophilia and other genetic diseases.

Pierre Charneau is a French virologist, inventor, and head of the Molecular Virology and Vaccinology Unit (VMV) at the Pasteur Institute and an acknowledged specialist in HIV, lentiviral gene transfer vectors, and their medical applications. His discovery of the central DNA-flap structure in the HIV genome, and its role in viral entry into the nucleus of the infected cell, grounded the optimization of lentiviral vectors and allowed for more than 20 years of development in gene therapy and vaccines based on this gene delivery technology. Charneau has published more than 100 research articles and holds 25 patents in the field of HIV and lentiviral vectors.

<span class="mw-page-title-main">Marina Cavazzana</span> Italian physician and cellular biologist

Marina Cavazzana is a professor of Paediatric Immunology at the Necker-Enfants Malades Hospital and the Imagine Institute, as well as an academic at Paris Descartes University. She was awarded the Irène Joliot-Curie Prize in 2012 and elected to the National Academy of Medicine in 2019.

bluebird bio, Inc., based in Somerville, Massachusetts, is a biotechnology company that develops gene therapies for severe genetic disorders.

<span class="mw-page-title-main">Michel Sadelain</span>

Michel Sadelain is an genetic engineer and cell therapist at Memorial Sloan Kettering Cancer Center, New York, New York, where he holds the Steve and Barbara Friedman Chair. He is the founding director of the Center for Cell Engineering and the head of the Gene Transfer and Gene Expression Laboratory. He is a member of the department of medicine at Memorial Hospital and of the immunology program at the Sloan Kettering Institute. He is best known for his major contributions to T cell engineering and chimeric antigen receptor (CAR) therapy, an immunotherapy based on the genetic engineering of a patient's own T cells to treat cancer.

<span class="mw-page-title-main">CRISPR Therapeutics</span> Swiss-American biotechnology company

CRISPR Therapeutics AG is a Swiss–American biotechnology company headquartered in Zug, Switzerland. It was one of the first companies formed to utilize the CRISPR gene editing platform to develop medicines for the treatment of various rare and common diseases. The company has approximately 500 employees and has offices in Zug, Switzerland, Boston, Massachusetts, San Francisco, California and London, United Kingdom. Its manufacturing facility in Framingham, Massachusetts won the Facilities of the Year Award (FOYA) award in 2022. The company’s lead program, exagamglogene autotemcel, or exa-cel, was granted regulatory approval in December 2023.

Elivaldogene autotemcel, sold under the brand name Skysona, is a gene therapy used to treat cerebral adrenoleukodystrophy (CALD). It was developed by Bluebird bio and was given breakthrough therapy designation by the U.S. Food and Drug Administration in May 2018.

Regenerative Medicine Advanced Therapy (RMAT) is a designation given by the Food and Drug Administration to drug candidates intended to treat serious or life-threatening conditions under the 21st Century Cures Act. A RMAT designation allows for accelerated approval based surrogate or intermediate endpoints.

OTL-103 (GSK-2696275) is a gene therapy for Wiskott–Aldrich syndrome, a rare primary immunodeficiency caused by mutations in the gene that codes for Wiskott–Aldrich syndrome protein (WASp). It was developed by Orchard Therapeutics in conjunction with GlaxoSmithKline. It is currently undergoing Phase I/II of clinical trials that are expected to conclude in October 2025.

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

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References

  1. 1 2 3 "Zynteglo dispersion for infusion - Summary of Product Characteristics (SmPC)". (emc). 12 May 2020. Retrieved 3 January 2021.[ permanent dead link ]
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 "Zynteglo EPAR". European Medicines Agency (EMA). 25 March 2019. Archived from the original on 16 August 2019. Retrieved 16 August 2019. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  3. 1 2 3 "Zynteglo- betibeglogene autotemcel suspension". DailyMed. 26 August 2022. Retrieved 19 November 2022.
  4. ↑ "Zynteglo". U.S. Food and Drug Administration. 17 August 2022. Archived from the original on 26 August 2022. Retrieved 26 August 2022.
  5. 1 2 3 4 5 6 7 "FDA Approves First Cell-Based Gene Therapy to Treat Adult and Pediatric Patients with Beta-thalassemia Who Require Regular Blood Transfusions". U.S. Food and Drug Administration (FDA) (Press release). 17 August 2022. Archived from the original on 21 August 2022. Retrieved 20 August 2022.PD-icon.svg This article incorporates text from this source, which is in the public domain.
  6. ↑ "Ten things you might have missed Monday from the world of business". The Boston Globe . 3 February 2015. Archived from the original on 1 August 2020. Retrieved 13 February 2015.
  7. ↑ "Lentiviral vectors". 27 June 2019. Archived from the original on 21 August 2022. Retrieved 8 July 2019.
  8. ↑ Cao A, Galanello R (February 2010). "Beta-thalassemia". Genetics in Medicine. 12 (2): 61–76. doi: 10.1097/GIM.0b013e3181cd68ed . PMID   20098328.
  9. ↑ Negre O, Bartholomae C, Beuzard Y, Cavazzana M, Christiansen L, Courne C, et al. (2015). "Preclinical evaluation of efficacy and safety of an improved lentiviral vector for the treatment of β-thalassemia and sickle cell disease" (PDF). Current Gene Therapy. 15 (1): 64–81. doi:10.2174/1566523214666141127095336. PMC   4440358 . PMID   25429463. Archived (PDF) from the original on 19 July 2018. Retrieved 19 June 2018.
  10. ↑ Thompson AA, Rasko JE, Hongeng S, Kwiatkowski JL, Schiller G, von Kalle C, et al. (2014). "Initial Results from the Northstar Study (HGB-204): A Phase 1/2 Study of Gene Therapy for β-Thalassemia Major Via Transplantation of Autologous Hematopoietic Stem Cells Transduced Ex Vivo with a Lentiviral βΑ-T87Q -Globin Vector (LentiGlobin BB305 Drug Product)". Blood. 124 (21): 549. doi:10.1182/blood.V124.21.549.549. Archived from the original on 18 October 2019. Retrieved 13 February 2015.
  11. ↑ Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F, et al. (September 2010). "Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia". Nature. 467 (7313): 318–322. Bibcode:2010Natur.467..318C. doi:10.1038/nature09328. PMC   3355472 . PMID   20844535.
  12. ↑ Winslow R (8 December 2015). "New Gene Therapy Shows Promise for Lethal Blood Disease" . The Wall Street Journal . Archived from the original on 2 March 2020. Retrieved 13 February 2015.
  13. ↑ (8 December 2014) bluebird bio Announces Data Demonstrating First Four Patients with β-Thalassemia Major Treated with LentiGlobin are Transfusion-Free Archived 26 September 2015 at the Wayback Machine Yahoo News, Retrieved 17 May 2015
  14. ↑ Thompson AA, Walters MC, Kwiatkowski J, Rasko JE, Ribeil JA, Hongeng S, et al. (April 2018). "Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia". The New England Journal of Medicine. 378 (16): 1479–1493. doi: 10.1056/NEJMoa1705342 . PMID   29669226.
  15. ↑ Stein R (18 April 2018). "Gene Therapy For Inherited Blood Disorder Reduced Transfusions". NPR . Archived from the original on 21 August 2022. Retrieved 4 March 2019.
  16. 1 2 Clinical trial number NCT02140554 for "A Phase 1/2 Study Evaluating Gene Therapy by Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo With the LentiGlobin BB305 Lentiviral Vector in Subjects With Severe Sickle Cell Disease" at ClinicalTrials.gov
  17. ↑ "Bluebird bio Halts Sickle Cell Trials After Leukemia Diagnosis". BioSpace. Archived from the original on 27 June 2021. Retrieved 27 June 2021.
  18. ↑ "Autologous CD34+ hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector encoding the human BA-T87Q-globin gene Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 18 March 2013. Archived from the original on 9 June 2020. Retrieved 8 June 2020.
  19. ↑ "bluebird bio Announces Temporary Suspension on Phase 1/2 and Phase 3 Studies of LentiGlobin Gene Therapy for Sickle Cell Disease (bb1111)". Bluebird Bio (Press release). 16 February 2021. Archived from the original on 27 June 2021. Retrieved 27 June 2021.
  20. ↑ Zynteglo: Withdrawal of the marketing authorisation in the European Union 30 March 2022 EMA/192892/2022
  21. ↑ Kansteiner F (17 August 2022). "UPDATED: Bluebird bio's $2.8M gene therapy Zynteglo wins FDA backing. Will its US launch take flight?". Fierce Pharma. Retrieved 25 January 2023.
  22. ↑ Carvalho T (2 October 2023). "Discontinued CRISPR gene therapy for sickle-cell disease improves symptoms". Nature Medicine. 29 (11): 2669–2670. doi:10.1038/d41591-023-00088-6. PMID   37783810. S2CID   263607753.
  23. ↑ World Health Organization (2020). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 83". WHO Drug Information. 34 (1): 34. Archived from the original on 15 July 2020.
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