NAV

Betibeglogene autotemcel

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
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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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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Treatment ofΒ thalassemia•••••••••••••••••• •••••••••••••••• ••••••• ••• ••••• •••• ••••••••••••••••••••••
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Pharmacodynamics

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

TargetActionsOrganism
AAlpha globin
binder
Humans
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

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.
DrugInteraction
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interactions in your software
CefiderocolThe risk or severity of adverse effects can be increased when Cefiderocol is combined with Betibeglogene autotemcel.
Chromium picolinateThe risk or severity of adverse effects can be increased when Chromium picolinate is combined with Betibeglogene autotemcel.
ElvitegravirThe therapeutic efficacy of Betibeglogene autotemcel can be decreased when used in combination with Elvitegravir.
FostemsavirThe therapeutic efficacy of Betibeglogene autotemcel can be decreased when used in combination with Fostemsavir.
HydroxyureaThe therapeutic efficacy of Betibeglogene autotemcel can be decreased when used in combination with Hydroxyurea.
Food Interactions
Not Available

Products

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International/Other Brands
Zynteglo (bluebird bio, Inc.)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ZyntegloSuspension20000000 1/1Intravenousbluebird bio, Inc.2022-08-17Not applicableUS flag
Zynteglo10600000 cells/mLIntravenousBluebird Bio (Netherlands) B.V.2021-01-122022-11-30EU flag

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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. FDA Approved Drug Products: ZYNTEGLO (betibeglogene autotemcel) suspension for intravenous infusion [Link]
  6. 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]
RxNav
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Wikipedia
Betibeglogene_autotemcel

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2CompletedTreatmentBeta-Thalassemia Major / Sickle Cell Disease (SCD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
SuspensionIntravenous20000000 1/1
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
Not Available

Targets

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Details1. Alpha globin
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
  1. 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