Betibeglogene autotemcel

{{Short description|Gene therapy}} {{Use dmy dates|date=June 2023}} {{cs1 config |name-list-style=vanc |display-authors=6}} {{Infobox drug | image = | width = | alt = | caption =

| pronounce = | tradename = Zynteglo | Drugs.com = {{drugs.com|monograph|betibeglogene-autotemcel}} | MedlinePlus = a622065 | licence_CA =  | licence_EU = yes | DailyMedID = Betibeglogene autotemcel | licence_US =  | pregnancy_AU =  | pregnancy_AU_comment = | pregnancy_category= Contraindicated<ref name="Zynteglo SmPC" /><ref name="Zynteglo EPAR" /> | routes_of_administration = Intravenous<ref name="Zynteglo FDA label" /> | class = | ATCvet = | ATC_prefix = B06 | ATC_suffix = AX02 | ATC_supplemental =

| legal_AU =  | legal_AU_comment = | legal_BR =  | legal_BR_comment = | legal_CA =  | legal_CA_comment = | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK = POM | legal_UK_comment = <ref name="Zynteglo SmPC">{{cite web | title=Zynteglo dispersion for infusion - Summary of Product Characteristics (SmPC) | website=(emc) | date=12 May 2020 | url=https://www.medicines.org.uk/emc/product/10893 | access-date=3 January 2021 }}{{Dead link|date=August 2022 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> | legal_US = Rx-only | legal_US_comment = <ref name="Zynteglo FDA label">{{cite web | title=Zynteglo- betibeglogene autotemcel suspension | website=DailyMed | date=26 August 2022 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=86931613-c262-47f5-8202-bc31fa69ad3d | access-date=19 November 2022 | archive-date=19 November 2022 | archive-url=https://web.archive.org/web/20221119055415/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=86931613-c262-47f5-8202-bc31fa69ad3d | url-status=live }}</ref><ref>{{cite web | title=Zynteglo | website=U.S. Food and Drug Administration | date=17 August 2022 | url=https://www.fda.gov/vaccines-blood-biologics/zynteglo | access-date=26 August 2022 | archive-date=26 August 2022 | archive-url=https://web.archive.org/web/20220826182752/https://www.fda.gov/vaccines-blood-biologics/zynteglo }}</ref><ref name="FDA PR 20220817">{{cite press release | title=FDA Approves First Cell-Based Gene Therapy to Treat Adult and Pediatric Patients with Beta-thalassemia Who Require Regular Blood Transfusions | website=U.S. Food and Drug Administration (FDA) | date=17 August 2022 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-treat-adult-and-pediatric-patients-beta-thalassemia-who | access-date=20 August 2022 | archive-date=21 August 2022 | archive-url=https://web.archive.org/web/20220821044703/https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-treat-adult-and-pediatric-patients-beta-thalassemia-who }} {{PD-notice}}</ref> | legal_EU = Rx-only | legal_EU_comment = <ref name="Zynteglo EPAR" /> | legal_UN =  | legal_UN_comment = | legal_status = Rx-only

| IUPAC_name = | chemical_formula = | C= | H= | Ag= | Al= | As= | Au= | B= | Bi= | Br= | Ca= | Cl= | Co= | F= | Fe= | Gd= | I= | K= | Li= | Mg= | Mn= | N= | Na= | O= | P= | Pt= | S= | Sb= | Se= | Sr= | Tc= | Zn= | charge= | molecular_weight = | SMILES = | StdInChI = | StdInChI_comment = | StdInChIKey = | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''Betibeglogene autotemcel''', sold under the brand name '''Zynteglo''', is a gene therapy for the treatment for beta thalassemia.<ref name="Zynteglo SmPC" /><ref name="FDA PR 20220817" /><ref name="Zynteglo EPAR" /> It was developed by Bluebird Bio and was given breakthrough therapy designation by the US Food and Drug Administration in February 2015.<ref>{{cite news|date=3 February 2015|title=Ten things you might have missed Monday from the world of business|url=https://www.bostonglobe.com/business/2015/02/03/ten-things-you-might-have-missed-monday-from-world-business/VlQl4rdNeHZMxWlXJJcxEK/story.html|newspaper=The Boston Globe|access-date=13 February 2015|archive-date=1 August 2020|archive-url=https://web.archive.org/web/20200801005421/https://www.bostonglobe.com/business/2015/02/03/ten-things-you-might-have-missed-monday-from-world-business/VlQl4rdNeHZMxWlXJJcxEK/story.html|url-status=live}}</ref><ref>{{cite web |url= https://www.geg-tech.com/lentiviral-vectors/vectors-crispr/ |title= Lentiviral vectors |date= 27 June 2019 |access-date= 8 July 2019 |archive-date= 21 August 2022 |archive-url= https://web.archive.org/web/20220821045521/https://www.geg-tech.com/lentiviral-vectors/vectors-crispr/ |url-status= live }}</ref>

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).<ref name="FDA PR 20220817" />

It was approved for medical use in the European Union in May 2019,<ref name="Zynteglo EPAR">{{cite web |title=Zynteglo EPAR |url=https://www.ema.europa.eu/en/medicines/human/EPAR/zynteglo |website=European Medicines Agency (EMA) |access-date=16 August 2019 |date=25 March 2019 |archive-date=16 August 2019 |archive-url=https://web.archive.org/web/20190816150354/https://www.ema.europa.eu/en/medicines/human/EPAR/zynteglo |url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> and in the United States in August 2022.<ref name="FDA PR 20220817" />

== 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.<ref name="Zynteglo EPAR" />

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.<ref name="Zynteglo EPAR" /> It is given as an autologous intravenous infusion and the dose depends on the recipient's body weight.<ref name="Zynteglo FDA label" /><ref name="Zynteglo EPAR" />

Before betibeglogene autotemcel is given, the recipient receives conditioning chemotherapy to clear their bone marrow of cells (myeloablation).<ref name="Zynteglo EPAR" />

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.<ref name="Zynteglo EPAR" /> 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.<ref name="Zynteglo EPAR" /> The effects of betibeglogene autotemcel are expected to last for the recipient's lifetime.<ref name="Zynteglo EPAR" />

==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.<ref>{{cite journal | vauthors = Cao A, Galanello R | title = Beta-thalassemia | journal = Genetics in Medicine | volume = 12 | issue = 2 | pages = 61–76 | date = February 2010 | pmid = 20098328 | doi = 10.1097/GIM.0b013e3181cd68ed | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Negre O, Bartholomae C, Beuzard Y, Cavazzana M, Christiansen L, Courne C, Deichmann A, Denaro M, de Dreuzy E, Finer M, Fronza R, Gillet-Legrand B, Joubert C, Kutner R, Leboulch P, Maouche L, Paulard A, Pierciey FJ, Rothe M, Ryu B, Schmidt M, von Kalle C, Payen E, Veres G | title = Preclinical evaluation of efficacy and safety of an improved lentiviral vector for the treatment of β-thalassemia and sickle cell disease | journal = Current Gene Therapy | volume = 15 | issue = 1 | pages = 64–81 | year = 2015 | pmid = 25429463 | pmc = 4440358 | doi = 10.2174/1566523214666141127095336 | url = https://dash.harvard.edu/bitstream/handle/1/16121099/4440358.pdf?sequence=1 | access-date = 19 June 2018 | url-status = live | archive-url = https://web.archive.org/web/20180719061935/https://dash.harvard.edu/bitstream/handle/1/16121099/4440358.pdf?sequence=1 | archive-date = 19 July 2018 }}</ref><ref>{{cite journal |vauthors = Thompson AA, Rasko JE, Hongeng S, Kwiatkowski JL, Schiller G, von Kalle C, Cavazzana M, Leboulch P, Petrusich A, Soni S, Walters MC |title=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) |journal=Blood |volume=124 |issue=21 |page=549 |year=2014 |url=http://www.bloodjournal.org/content/124/21/549 |doi=10.1182/blood.V124.21.549.549 |doi-access= |access-date=13 February 2015 |archive-date=18 October 2019 |archive-url=https://web.archive.org/web/20191018035453/https://ashpublications.org/blood/article/124/21/549/92213/Initial-Results-from-the-Northstar-Study-HGB-204-A |url-status=live |url-access=subscription }}</ref>

== 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.<ref>{{cite journal | vauthors = Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F, Down J, Denaro M, Brady T, Westerman K, Cavallesco R, Gillet-Legrand B, Caccavelli L, Sgarra R, Maouche-Chrétien L, Bernaudin F, Girot R, Dorazio R, Mulder GJ, Polack A, Bank A, Soulier J, Larghero J, Kabbara N, Dalle B, Gourmel B, Socie G, Chrétien S, Cartier N, Aubourg P, Fischer A, Cornetta K, Galacteros F, Beuzard Y, Gluckman E, Bushman F, Hacein-Bey-Abina S, Leboulch P | title = Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia | journal = Nature | volume = 467 | issue = 7313 | pages = 318–322 | date = September 2010 | pmid = 20844535 | pmc = 3355472 | doi = 10.1038/nature09328 | bibcode = 2010Natur.467..318C }}</ref><ref>{{cite news| vauthors = Winslow R |date=8 December 2015|title=New Gene Therapy Shows Promise for Lethal Blood Disease|url=https://www.wsj.com/articles/new-gene-therapy-shows-promise-for-lethal-blood-disease-1418080608|newspaper=The Wall Street Journal|access-date=13 February 2015|url-access=subscription|archive-date=2 March 2020|archive-url=https://web.archive.org/web/20200302025751/https://www.wsj.com/articles/new-gene-therapy-shows-promise-for-lethal-blood-disease-1418080608|url-status=live}}</ref><ref>(8 December 2014) [https://finance.yahoo.com/news/bluebird-bio-announces-data-demonstrating-224500318.html bluebird bio Announces Data Demonstrating First Four Patients with β-Thalassemia Major Treated with LentiGlobin are Transfusion-Free] {{Webarchive|url=https://web.archive.org/web/20150926034345/https://finance.yahoo.com/news/bluebird-bio-announces-data-demonstrating-224500318.html |date=26 September 2015 }} Yahoo News, Retrieved 17 May 2015</ref> 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.<ref>{{cite journal | vauthors = Thompson AA, Walters MC, Kwiatkowski J, Rasko JE, 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, Pondarré C, Beuzard Y, Chrétien 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 | title = Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia | journal = The New England Journal of Medicine | volume = 378 | issue = 16 | pages = 1479–1493 | date = April 2018 | pmid = 29669226 | doi = 10.1056/NEJMoa1705342 | doi-access = free }}</ref><ref>{{cite news| vauthors = Stein R |date=18 April 2018|title=Gene Therapy For Inherited Blood Disorder Reduced Transfusions|url=https://www.npr.org/sections/health-shots/2018/04/18/602914728/gene-therapy-for-inherited-blood-disorder-reduced-transfusions|work=NPR|access-date=4 March 2019|archive-date=21 August 2022|archive-url=https://web.archive.org/web/20220821045451/https://www.npr.org/sections/health-shots/2018/04/18/602914728/gene-therapy-for-inherited-blood-disorder-reduced-transfusions|url-status=live}}</ref>

In February 2021, a clinical trial<ref name=":0">{{ClinicalTrialsGov|NCT02140554|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}}</ref> of betibeglogene autotemcel in sickle cell anemia was suspended following an unexpected instance of acute myeloid leukemia.<ref>{{cite web|title=Bluebird bio Halts Sickle Cell Trials After Leukemia Diagnosis|url=https://www.biospace.com/article/-bluebird-bio-shares-plunge-34-percent-after-halting-sickle-cell-trials/|access-date=27 June 2021|website=BioSpace|date=16 February 2021 |archive-date=27 June 2021|archive-url=https://web.archive.org/web/20210627221911/https://www.biospace.com/article/-bluebird-bio-shares-plunge-34-percent-after-halting-sickle-cell-trials/|url-status=live}}</ref> The HGB-206 Phase 1/2 study is expected to conclude in March 2023.<ref name=":0" />

It was designated an orphan drug by the European Medicines Agency (EMA) and by the US Food and Drug Administration (FDA) in 2013.<ref name="Zynteglo EPAR" /><ref>{{cite web | title=Autologous CD34+ hematopoietic stem cells transduced with LentiGlobin BB305 lentiviral vector encoding the human BA-T87Q-globin gene Orphan Drug Designations and Approvals | website=U.S. Food and Drug Administration (FDA) | date=18 March 2013 | url=https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=390513 | access-date=8 June 2020 | archive-date=9 June 2020 | archive-url=https://web.archive.org/web/20200609060858/https://www.accessdata.fda.gov/scripts/opdlisting/oopd/detailedIndex.cfm?cfgridkey=390513 }}</ref> The Food and Drug Administration has also declared betibeglogene autotemcel a Regenerative Medicine Advanced Therapy.<ref>{{cite press release|title=bluebird bio Announces Temporary Suspension on Phase 1/2 and Phase 3 Studies of LentiGlobin Gene Therapy for Sickle Cell Disease (bb1111)|url=https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-temporary-suspension-phase-12-and-phase-3|date=16 February 2021|access-date=27 June 2021|website=Bluebird Bio|archive-date=27 June 2021|archive-url=https://web.archive.org/web/20210627222040/https://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-temporary-suspension-phase-12-and-phase-3|url-status=live}}</ref>

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.<ref name="FDA PR 20220817" /> 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.<ref name="FDA PR 20220817" />

== Society and culture == === Legal status === It was approved for medical use in the European Union in May 2019,<ref name="Zynteglo EPAR" /> and in the United States in August 2022.<ref name="FDA PR 20220817" /> 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.<ref>Zynteglo: Withdrawal of the marketing authorisation in the European Union 30 March 2022 [https://www.ema.europa.eu/documents/public-statement/public-statement-zynteglo-withdrawal-marketing-authorisation-european-union_en.pdf EMA/192892/2022] {{Webarchive|url=https://web.archive.org/web/20240726165138/https://www.ema.europa.eu/documents/public-statement/public-statement-zynteglo-withdrawal-marketing-authorisation-european-union_en.pdf |date=26 July 2024 }}</ref>

=== Economics === Bluebird bio charges $2.8 million in the United States for a treatment of Zynteglo.<ref>{{cite web |last=Kansteiner |first=Fraiser |date=17 August 2022 |title=UPDATED: Bluebird bio's $2.8M gene therapy Zynteglo wins FDA backing. Will its US launch take flight? |url=https://www.fiercepharma.com/pharma/bluebirds-28m-gene-therapy-zynteglo-gets-fda-backing-beta-thalassemia |access-date=25 January 2023 |website=Fierce Pharma |archive-date=25 January 2023 |archive-url=https://web.archive.org/web/20230125024536/https://www.fiercepharma.com/pharma/bluebirds-28m-gene-therapy-zynteglo-gets-fda-backing-beta-thalassemia |url-status=live }}</ref><ref>{{cite journal |last1=Carvalho |first1=Thiago |title=Discontinued CRISPR gene therapy for sickle-cell disease improves symptoms |journal=Nature Medicine |date=2 October 2023 |volume=29 |issue=11 |pages=2669–2670 |doi=10.1038/d41591-023-00088-6|pmid=37783810 |s2cid=263607753 }}</ref>

=== Names === The international nonproprietary name (INN) is betibeglogene autotemcel.<ref>{{cite journal | year=2020 | title=International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 83 | journal=WHO Drug Information | volume=34 | issue=1 | page=34 | url=https://www.who.int/medicines/publications/druginformation/issues/DrugInformation2019_Vol34-1/en/ | archive-url=https://web.archive.org/web/20200715194522/https://www.who.int/medicines/publications/druginformation/issues/DrugInformation2019_Vol34-1/en/ | archive-date=15 July 2020 }}</ref>

== References == {{Reflist}}

{{DEFAULTSORT:Betibeglogene Autotemcel}} Category:Biotechnology Category:Disorders of globin and globulin proteins Category:Gene delivery Category:Approved gene therapies Category:Hereditary hemolytic anemias Category:Orphan drugs