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Identification
- Summary
Betibeglogene autotemcel is a hematopoietic stem cell-based gene therapy used in the treatment of β-thalassemia in adult and pediatric patients who require regular red blood cell transfusions.
- Brand Names
- Zynteglo
- Generic Name
- Betibeglogene autotemcel
- DrugBank Accession Number
- DB16900
- Background
Betibeglogene autotemcel is an autologous gene therapy that adds functional copies of the β-globin gene (βA-T87Q-globin) to hematopoietic stem cells in order to treat β-thalassemia.5 β-thalassemia is a condition caused by mutations in the β-globin gene (HBB) that leads to a significant decrease in the production of β-globin. This affects hemoglobin levels, and in patients with severe forms of this disease, long-term red cell transfusions are required for survival and the prevention of serious complications.1 Allogeneic hematopoietic-cell transplantation would be a therapeutic option in patients with β-thalassemia; however, this process is reserved for young children with an HLA-identical sibling donor due to the risks of graft rejection, graft-versus-host disease, and other treatment-related toxic effects.1
Patients treated with betibeglogene autotemcel are given an infusion of their own hematopoietic stem cells, previously enriched for CD34+ and transduced ex vivo with BB305 LVV, a self-inactivating lentiviral vector (LVV).5 BB305 LVV encodes βA-T87Q-globin, compensating for the lack of β-globin in these patients. The use of betibeglogene autotemcel is more effective in patients with β-thalassemia with residual β-globin synthesis (non-β0/β0 genotype) compared to those with no detectable β-globin production (β0/β0).1,4 Betibeglogene autotemcel was approved by the FDA in August 2022 and is the first ex-vivo lentiviral vector gene therapy available in the U.S. for the treatment of people with β-thalassemia.6
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Cell transplant therapies
Autologous cell transplant - Synonyms
- Autologous CD34+ cells encoding βA-T87Q-Globin gene
- Beti-cel
- LentiGlobin BB305
Pharmacology
- Indication
Betibeglogene autotemcel is indicated for the treatment of adult and pediatric patients with β-thalassemia who require regular red blood cell (RBC) transfusions.5
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Β thalassemia •••••••••••• •••••• ••••••••• ••••••• ••••••• ••• ••••• •••• •••••••••••• •••••••••• - Contraindications & Blackbox Warnings
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Betibeglogene autotemcel produces a modified β-globin protein (βA-T87Q-globin) that combines with α-globin to form functional hemoglobin A (HbAT87Q). HbAT87Q was measured in patients to evaluate the pharmacodynamics of betibeglogene autotemcel. After betibeglogene autotemcel infusion, HbAT87Q levels increased steadily and stabilized after approximately 6 months. In phase 3 studies, patients (n=35) had a month 6 median HbAT87Q of 8.7 g/dL, and similar levels were recorded at month 24 (n=30, 8.8 g/dL).5 Measurements done at month 36, where HbAT87Q levels continued to remain durable suggest that the βA-T87Q-globin gene is integrated into long-term hematopoietic stem cells.5
The use of betibeglogene autotemcel has been associated with delayed platelet engraftment as well as a higher risk of neutrophil engraftment failure and insertional oncogenesis. Allergic reactions to betibeglogene autotemcel may occur.5 Also, due to the presence of BB305 LVV proviral DNA, patients treated with betibeglogene autotemcel may test positive in HIV polymerase chain reaction (PCR) assays.5
- Mechanism of action
Betibeglogene autotemcel is an autologous gene therapy that adds functional copies of the β-globin (HBB) gene to hematopoietic stem cells to treat β-thalassemia.5 β-thalassemia is a hereditary disease caused by more than 200 mutations in HBB, a gene responsible for encoding the β-subunit of hemoglobin A.1,2 In patients with β-thalassemia, β-globin production is abolished (β0) or reduced (β+), leading to intracellular hemichrome precipitation, ineffective erythropoiesis, chronic hemolysis, and profound anemia. Long-term red cell transfusions are needed for survival and the prevention of serious complications in patients with the most severe form of this disease.1
Betibeglogene autotemcel is a gene therapy consisting of autologous CD34+ cells. A patient’s hematopoietic stem cells are collected and enriched for CD34+ cells and transduced ex vivo with BB305 LVV, a self-inactivating lentiviral vector (LVV).5 BB305 LVV has a functional copy of HBB with an amino acid substitution of threonine (T) to glutamine (Q) at position 87 (βA-T87Q-globin).3,5 After betibeglogene autotemcel is infused into a patient, CD34+ hematopoietic stem cells engraft in the bone marrow and differentiate to produce βA-T87Q-globin that will combine with α-globin to form functional hemoglobin A. The expression of βA-T87Q-globin corrects the imbalance between α- and β-globin in patients with β-thalassemia, and may lead to normal hemoglobin levels. The use of betibeglogene autotemcel has the potential to eliminate the need for red blood cell transfusions.5
Target Actions Organism AAlpha globin binderHumans - Absorption
The nature of betibeglogene autotemcel is such that conventional pharmacokinetic studies on absorption are not applicable.5
- Volume of distribution
The nature of betibeglogene autotemcel is such that conventional pharmacokinetic studies on distribution are not applicable.5
- Protein binding
Not applicable.
- Metabolism
The nature of betibeglogene autotemcel is such that conventional pharmacokinetic studies on metabolism are not applicable.5
- Route of elimination
The nature of betibeglogene autotemcel is such that conventional pharmacokinetic studies on elimination are not applicable.5
- Half-life
Not Available
- Clearance
Not Available
- Adverse Effects
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Toxicity information regarding betibeglogene autotemcel is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as delayed platelet engraftment, neutrophil engraftment failure and insertional oncogenesis.5 Symptomatic and supportive measures are recommended. No carcinogenicity studies have been performed with betibeglogene autotemcel, and its effects on fertility have not been evaluated. In a mouse model of β-thalassemia, the intravenous administration of betibeglogene autotemcel did not show evidence of toxicity, genotoxicity, or oncogenesis.5
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareCefiderocol The risk or severity of adverse effects can be increased when Cefiderocol is combined with Betibeglogene autotemcel. Chromium picolinate The risk or severity of adverse effects can be increased when Chromium picolinate is combined with Betibeglogene autotemcel. Elvitegravir The therapeutic efficacy of Betibeglogene autotemcel can be decreased when used in combination with Elvitegravir. Fostemsavir The therapeutic efficacy of Betibeglogene autotemcel can be decreased when used in combination with Fostemsavir. Hydroxyurea The therapeutic efficacy of Betibeglogene autotemcel can be decreased when used in combination with Hydroxyurea. - Food Interactions
- Not Available
Products
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- Zynteglo (bluebird bio, Inc.)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Zynteglo Suspension 20000000 1/1 Intravenous bluebird bio, Inc. 2022-08-17 Not applicable US 
Zynteglo 10600000 cells/mL Intravenous Bluebird Bio (Netherlands) B.V. 2021-01-12 2019-03-28 EU 
Categories
- ATC Codes
- B06AX02 — Betibeglogene autotemcel
- Drug Categories
- Classification
- Not classified
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- MEE8487RTP
- CAS number
- Not Available
References
- Synthesis Reference
Bonner, M., et al. (2019). Vcn enhancer compositions and methods of using the same (U.S. Patent No. US 2019/0284533 A1). U.S. Patent and Trademark Office. https://patentimages.storage.googleapis.com/e2/ab/ac/4afae7ad9e148f/US20190284533A1.pdf
- General References
- Thompson AA, Walters MC, Kwiatkowski J, Rasko JEJ, Ribeil JA, Hongeng S, Magrin E, Schiller GJ, Payen E, Semeraro M, Moshous D, Lefrere F, Puy H, Bourget P, Magnani A, Caccavelli L, Diana JS, Suarez F, Monpoux F, Brousse V, Poirot C, Brouzes C, Meritet JF, Pondarre C, Beuzard Y, Chretien S, Lefebvre T, Teachey DT, Anurathapan U, Ho PJ, von Kalle C, Kletzel M, Vichinsky E, Soni S, Veres G, Negre O, Ross RW, Davidson D, Petrusich A, Sandler L, Asmal M, Hermine O, De Montalembert M, Hacein-Bey-Abina S, Blanche S, Leboulch P, Cavazzana M: Gene Therapy in Patients with Transfusion-Dependent beta-Thalassemia. N Engl J Med. 2018 Apr 19;378(16):1479-1493. doi: 10.1056/NEJMoa1705342. [Article]
- Sii-Felice K, Giorgi M, Leboulch P, Payen E: Hemoglobin disorders: lentiviral gene therapy in the starting blocks to enter clinical practice. Exp Hematol. 2018 Aug;64:12-32. doi: 10.1016/j.exphem.2018.05.004. Epub 2018 May 26. [Article]
- Locatelli F, Thompson AA, Kwiatkowski JL, Porter JB, Thrasher AJ, Hongeng S, Sauer MG, Thuret I, Lal A, Algeri M, Schneiderman J, Olson TS, Carpenter B, Amrolia PJ, Anurathapan U, Schambach A, Chabannon C, Schmidt M, Labik I, Elliot H, Guo R, Asmal M, Colvin RA, Walters MC: Betibeglogene Autotemcel Gene Therapy for Non-beta(0)/beta(0) Genotype beta-Thalassemia. N Engl J Med. 2022 Feb 3;386(5):415-427. doi: 10.1056/NEJMoa2113206. Epub 2021 Dec 11. [Article]
- Nualkaew T, Sii-Felice K, Giorgi M, McColl B, Gouzil J, Glaser A, Voon HPJ, Tee HY, Grigoriadis G, Svasti S, Fucharoen S, Hongeng S, Leboulch P, Payen E, Vadolas J: Coordinated beta-globin expression and alpha2-globin reduction in a multiplex lentiviral gene therapy vector for beta-thalassemia. Mol Ther. 2021 Sep 1;29(9):2841-2853. doi: 10.1016/j.ymthe.2021.04.037. Epub 2021 May 1. [Article]
- FDA Approved Drug Products: ZYNTEGLO (betibeglogene autotemcel) suspension for intravenous infusion [Link]
- Business Wire: bluebird bio Announces FDA Approval of ZYNTEGLO, the First Gene Therapy for People with Beta-Thalassemia Who Require Regular Red Blood Cell Transfusions [Link]
- External Links
- 2610349
- Wikipedia
- Betibeglogene_autotemcel
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data1, 2 Completed Treatment Beta-Thalassemia Major / Sickle Cell Disease (SCD) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Suspension Intravenous 20000000 1/1 - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Liquid
- Experimental Properties
- Not Available
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Binder
- Curator comments
- Betibeglogene autotemcel adds functional copies of a modified β-globin gene into patients’ hematopoietic stem cells (HSCs). The modified β-globin that is produced binds to α-globin to form functional hemoglobin A.
- General Function
- Not Available
- Specific Function
- Heme binding
- Gene Name
- Not Available
- Uniprot ID
- V9H1D9
- Uniprot Name
- Alpha globin
- Molecular Weight
- 13582.405 Da
References
- FDA Approved Drug Products: ZYNTEGLO (betibeglogene autotemcel) suspension for intravenous infusion [Link]
Drug created at August 22, 2022 18:10 / Updated at December 01, 2022 11:32