Betibeglogene autotemcel

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]

Betibeglogene autotemcel

Clinical data
Trade names	Zynteglo
Other names	LentiGlobin BB305, autologous CD34+ cells encoding βA-T87Q-globin gene
AHFS/Drugs.com	Monograph
MedlinePlus	a622065
License data	EU EMA: by INN US DailyMed: Betibeglogene autotemcel
Pregnancy category	Contraindicated[1][2]
Routes of administration	Intravenous[3]
ATC code	B06AX02 (WHO)
Legal status
Legal status	UK: POM (Prescription only)[1] US: ℞-only[3][4][5] EU: Rx-only[2] In general: ℞ (Prescription only)
Identifiers
DrugBank	DB16900
UNII	MEE8487RTP
KEGG	D11930

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

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] 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]

References

1. "Zynteglo dispersion for infusion - Summary of Product Characteristics (SmPC)". (emc). 12 May 2020. Retrieved 3 January 2021.^{[permanent dead link‍]}
2. "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 copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
3. "Zynteglo- betibeglogene autotemcel suspension". DailyMed. 26 August 2022. Archived from the original on 19 November 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. "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.
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. 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. 16 February 2021. 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 Archived 26 July 2024 at the Wayback Machine
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. Archived from the original on 25 January 2023. 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.