Betibeglogene autotemcel
ベチベグロゲンアウトテムセル
2022/8/17, FDA APPROVED Zynteglo
Cellular therapy product
Treatment of betathalassemia
BB305 LVV, bb 1111
BB305 transduced SCD CD34+ HSCs bb1111
LentiGlobin BB305 LVV-transduced autologous SCD CD34+ HSCs bb1111
LentiGlobin drug product for SCD
LentiGlobin drug product for sickle cell disease
LentiGlobin for SCD bb1111
Betibeglogene autotemcel, sold under the brand name Zynteglo, is a medication for the treatment for beta thalassemia.[1][5][2] It was developed by Bluebird Bio and was given breakthrough therapy designation by the U.S. Food and Drug Administration in February 2015.[6][7]
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]
FDA Approves First Cell-Based Gene Therapy to Treat Adult and Pediatric Patients with Beta-thalassemia Who Require Regular Blood Transfusions
- For Immediate Release:
Today, the U.S. Food and Drug Administration approved Zynteglo (betibeglogene autotemcel), the first cell-based gene therapy for the treatment of adult and pediatric patients with beta-thalassemia who require regular red blood cell transfusions.
“Today’s approval is an important advance in the treatment of beta-thalassemia, particularly in individuals who require ongoing red blood cell transfusions,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research. “Given the potential health complications associated with this serious disease, this action highlights the FDA’s continued commitment to supporting development of innovative therapies for patients who have limited treatment options.”
Beta-thalassemia is a type of inherited blood disorder that causes a reduction of normal hemoglobin and red blood cells in the blood, through mutations in the beta-globin subunit, leading to insufficient delivery of oxygen in the body. The reduced levels of red blood cells can lead to a number of health issues including dizziness, weakness, fatigue, bone abnormalities and more serious complications. Transfusion-dependent beta-thalassemia, the most severe form of the condition, generally requires life-long red blood cell transfusions as the standard course of treatment. These regular transfusions can be associated with multiple health complications of their own, including problems in the heart, liver and other organs due to an excessive build-up of iron in the body.
Zynteglo is a one-time gene therapy product administered as a single dose. Each dose of Zynteglo is a customized treatment created using the patient’s own cells (bone marrow stem cells) that are genetically modified to produce functional beta-globin (a hemoglobin component).
The safety and effectiveness of Zynteglo were established in two multicenter clinical studies that included adult and pediatric patients with beta-thalassemia requiring regular transfusions. Effectiveness was established based on achievement of transfusion independence, which is attained when the patient maintains a pre-determined level of hemoglobin without needing any red blood cell transfusions for at least 12 months. Of 41 patients receiving Zynteglo, 89% achieved transfusion independence.
The most common adverse reactions associated with Zynteglo included 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).
There is a potential risk of blood cancer associated with this treatment; however, no cases have been seen in studies of Zynteglo. Patients who receive Zynteglo should have their blood monitored for at least 15 years for any evidence of cancer. Patients should also be monitored for hypersensitivity reactions during Zynteglo administration and should be monitored for thrombocytopenia and bleeding.
This application was granted a rare pediatric disease voucher, in addition to receiving Priority Review, Fast Track, Breakthrough Therapy, and Orphan designations.
The FDA granted approval of Zynteglo to bluebird bio, Inc.
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| Clinical data | |
|---|---|
| Trade names | Zynteglo |
| Other names | LentiGlobin BB305, autologous CD34+ cells encoding βA-T87Q-globin gene |
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| Routes of administration |
Intravenous[3] |
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Medical uses
Betibeglogene autotemcel is indicated for the treatment of people twelve years and older with transfusion-dependent beta thalassemia (TDT) 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 U.S. 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 particpiants with beta-thalassemia requiring regular transfusions.[5] Effectiveness was established based on achievement of transfusion independence, which is attained when the particpiant maintains a pre-determined level of hemoglobin without needing any red blood cell transfusions for at least 12 months. Of 41 particpiants receiving betibeglogene autotemcel, 89% achieved transfusion independence.[5]
Society and culture
Legal status
It was approved for medical use in the European Union in May 2019,[2] and in the United States in August 2022.[5]
Names
The international nonproprietary name (INN) is betibeglogene autotemcel.[20]
References
- ^ Jump up to:a b c “Zynteglo dispersion for infusion – Summary of Product Characteristics (SmPC)”. (emc). 12 May 2020. Retrieved 3 January 2021.[permanent dead link]
- ^ Jump up to:a b c d e f g h i j k l m “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.
- ^ Jump up to:a b c “Archived copy”. Archived from the original on 26 August 2022. Retrieved 26 August 2022.
- ^ “Zynteglo”. U.S. Food and Drug Administration. 17 August 2022. Archived from the original on 26 August 2022. Retrieved 26 August 2022.
- ^ Jump up to:a b c d e f g “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.
This article incorporates text from this source, which is in the public domain. - ^ “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.
- ^ “Lentiviral vectors”. 27 June 2019. Archived from the original on 21 August 2022. Retrieved 8 July 2019.
- ^ Cao A, Galanello R (February 2010). “Beta-thalassemia”. Genetics in Medicine. 12 (2): 61–76. doi:10.1097/GIM.0b013e3181cd68ed. PMID 20098328.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ (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
- ^ 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.
- ^ 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.
- ^ Jump up to:a b 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
- ^ “Bluebird bio Halts Sickle Cell Trials After Leukemia Diagnosis”. BioSpace. Archived from the original on 27 June 2021. Retrieved 27 June 2021.
- ^ “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.
- ^ “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.
- ^ 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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