Delving into the Latest Updates on Betibeglogene autotemcel with Synapse

Overview

Basic Info

Drug Type

Gene therapy, Hematopoietic stem cell therapy

Synonyms

2009 EGT-produced vector, Autologous CD34+ cell enriched population that contains hematopoietic stem cells transduced with lentiglobin BB305 lentiviral vector encoding the beta-A-T87Q-globin gene, Autologous CD34+ cells encoding βA-T87Q-globin gene

+ [12]

Target

β-globin

Mechanism

β-globin stimulants(Hemoglobin beta chain stimulants), Gene transference

Therapeutic Areas

Congenital DisordersHemic and Lymphatic DiseasesOther Diseases

Active Indication

ThalassemiaBeta-ThalassemiaAnemia, Sickle Cell

Inactive Indication

Transfusion-dependent Beta ThalassemiaTransfusion-dependent Thalassemia

Originator Organization

bluebird bio, Inc.

Active Organization

bluebird bio, Inc.

Inactive Organization-

Drug Highest PhaseApproved

First Approval Date

EU (29 May 2019),

Transfusion-dependent Beta Thalassemia

RegulationPriority Review (US), Fast Track (US), Rare Pediatric Disease (US), Orphan Drug (EU), PRIME (EU), Regenerative Medicine Advanced Therapy (US), Accelerated assessment (EU), Breakthrough Therapy (US), Orphan Drug (US)

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This is a single-arm, multi-site, single-dose, Phase 3 study in approximately 18 participants less than or equal to (<=) 50 years of age with transfusion-dependent β-thalassemia (TDT), who have a β0/β0, β0/IVS-I-110, or IVS-I-110/IVS-I-110 genotype. The study will evaluate the efficacy and safety of autologous hematopoietic stem cell transplantation (HSCT) using LentiGlobin BB305 Drug Product.

Start Date08 Jun 2017

Sponsor / Collaborator

bluebird bio, Inc.

100 Clinical Results associated with Betibeglogene autotemcel

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100 Translational Medicine associated with Betibeglogene autotemcel

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100 Patents (Medical) associated with Betibeglogene autotemcel

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36

Literatures (Medical) associated with Betibeglogene autotemcel

01 Nov 2024·LANCET

Betibeglogene autotemcel gene therapy in patients with transfusion-dependent, severe genotype β-thalassaemia (HGB-212): a non-randomised, multicentre, single-arm, open-label, single-dose, phase 3 trial

Article

Author: Tao, Ge ; Thuret, Isabelle ; Sauer, Martin G ; Kwiatkowski, Janet L ; Colvin, Richard A ; Hongeng, Suradej ; Kunz, Joachim B ; Yannaki, Evangelia ; Walters, Mark C ; Kulozik, Andreas E ; Thompson, Alexis A ; Locatelli, Franco ; Lodaya, Ankit ; Ali, Shamshad ; Thrasher, Adrian J ; Lal, Ashutosh ; Elliot, Heidi ; Lee, Ji ; Thakar, Himal L

BACKGROUND:

Transfusion-dependent β-thalassaemia (TDT) is a severe disease, resulting in lifelong blood transfusions, iron overload, and associated complications. Betibeglogene autotemcel (beti-cel) gene therapy uses autologous haematopoietic stem and progenitor cells (HSPCs) transduced with BB305 lentiviral vector to enable transfusion independence.

METHODS:

HGB-212 was a non-randomised, multicentre, single-arm, open-label, phase 3 study of beti-cel in patients with TDT conducted at eight centres in France, Germany, Greece, Italy, the UK, and the USA. Patients with β⁰/β⁰, β⁰/β^+IVS-I-110, or β^+IVS-I-110/β^+IVS-I-110 genotypes, clinically stable TDT, and a transfusion history of at least 100 mL/kg per year of packed red blood cells (pRBCs) or at least eight transfusions of pRBCs per year in the 2 years before enrolment were eligible for participation. After undergoing HSPC mobilisation and busulfan-based, pharmacokinetic-adjusted myeloablative conditioning, patients were infused with beti-cel and followed up for 24 months. The primary efficacy outcome was transfusion independence, defined as weighted average haemoglobin level of 9 g/dL or above without pRBC transfusions for 12 or more months. The primary outcome was measured in all patients who received an infusion of beti-cel (transplant population); safety was evaluated in all patients who initiated study treatment (intention-to-treat population). Patients were eligible to enrol in the ongoing 13-year long-term follow-up study (for a total of 15 years), LTF-303 (registered at ClinicalTrials.gov, NCT02633943). This trial, HGB-212, was registered at ClinicalTrials.gov (NCT03207009), and is complete.

FINDINGS:

From June 8, 2017, to March 12, 2020, 20 patients were screened for eligibility. One patient was ineligible and one withdrew consent before HSPC mobilisation and myeloablative conditioning. Of the 18 patients who received beti-cel, ten (56%) were male and eight (44%) were female; 13 (72%) were younger than 18 years at the time of informed consent, and five (28%) were older than 18 years. 12 (67%) patients had β⁰/β⁰ genotypes, three (17%) had β⁰/ β^+IVS-I-110, and three (17%) had β^+IVS-I-110/β^+IVS-I-110. As of Jan 30, 2023, all patients enrolled in the long-term follow-up study and the median follow-up was 47·9 months (range 23·8-59·0). All 18 patients were evaluable for transfusion independence, with 16 (89%) of 18 reaching and maintaining transfusion independence to last follow=up (estimated effect size 89·9% [95% CI 65·3-98·6]). All patients had at least one adverse event after beti-cel infusion. There were no serious adverse events considered to be related to beti-cel, and no deaths.

INTERPRETATION:

These data demonstrate that beti-cel can allow patients with genotypes that cause severe β-thalassaemia (β⁰/β⁰, β⁰/β^+IVS-I-110, or β^+IVS-I-110/β^+IVS-I-110) to reach transfusion independence. Beti-cel offers the potential to attain near-normal haemoglobin levels for those with severe forms of TDT, and a potentially curative option without the risks and limitations of allogeneic HSPC transplantation. Patients are being followed up for a total of 15 years to assess the durability of transfusion independence and long-term safety profile of beti-cel.

FUNDING:

Bluebird Bio, Somerville, MA, USA.

01 Apr 2024·International immunopharmacology

Biomimetic nanoparticles for effective Celastrol delivery to targeted treatment of rheumatoid arthritis through the ROS-NF-κB inflammasome axis

Article

Author: Hou, Ruixing ; Shen, Jiquan ; Wang, Bo ; Wang, Xinggao

Previous study has indicated that Celastrol (Cel) has various physiological and pharmacological effects, including antibacterial, antioxidant, pro-apoptotic, anticancer and anti-rheumatoid arthritis (RA) effects. However, low water solubility, low oral bioavailability, narrow treatment window, and high incidence of systemic adverse reactions still limit the further clinical application of Cel. Here, aiming at effectively overcome those shortcomings of Cel to boost its beneficial effects for treating RA, we developed the leukosome (LEUKO) coated biomimetic nanoparticles (NPs) for the targeted delivery of Cel to arthritis injury area in RA. LEUKO were synthesized using membrane proteins purified from activated J774 macrophage. LEUKO and Cel-loaded LEUKO (Cel@LEUKO) were characterized using dynamic light scattering and transmission electron microscopy. Our results demonstrated that Cel@LEUKO can inhibit the inflammatory response of lipopolysaccharide (LPS) induced mouse monocyte macrophage leukemia cells (RAW264.7 cells) and human rheumatoid arthritis synovial fibroblasts (MH7A) cells through the inhibition of reactive oxygen species (ROS)-NF-κB pathway. In addition, research has shown that LEUKO effectively targets and transports Cel to the inflammatory site of RA, increased drug concentration in affected areas, reduced systemic toxicity of Cel, and reduced clinical symptoms, inflammatory infiltration, bone erosion, and serum inflammatory factors in collagen-induced arthritis (CIA) rats.

01 Dec 2023·Molecular therapy. Methods & clinical development

Drug product attributes predict clinical efficacy in betibeglogene autotemcel gene therapy for β-thalassemia

Article

Author: Kral, Kelly ; Whitney, Dustin ; d'Anjou, Marc ; Pierciey, Francis J ; Gayron, Marisa ; Colvin, Richard A ; Fincker, Maeva ; Shestopalov, Ilya

Ex vivo autologous hematopoietic stem cell lentiviral-based gene therapy with betibeglogene autotemcel has been studied in patients with transfusion-dependent β-thalassemia in Phase III clinical trials (HGB-207 and HGB-212), with 90% of patients reaching transfusion independence (TI). Here, we explore manufacturing parameters, drug product quality attributes, and limited patient characteristics that had an impact on clinical efficacy in HGB-207 and HGB-212. Retrospective analysis revealed that the peripheral blood vector copy number (VCN) was related to TI, with a strong correlation between peripheral blood VCN at 6 months and gene therapy-derived therapeutic protein (HbA^T87Q) expression at 6 months (correlation coefficient, 0.8681; p < 0.0001; R² = 0.7536). A peripheral blood VCN threshold of ≥0.75 copies per diploid genome at 6 months post betibeglogene autotemcel infusion provided a stringent surrogate biomarker for TI and was used as the outcome variable for multivariate analysis using a random forest classifier. The top predictive feature of clinical efficacy was found to be the percentage of lentiviral vector-positive cells in the drug product. This retrospective analysis is critical to understanding the key product quality attributes that can predict clinical efficacy in lentiviral vector gene therapy within this clinical trial population.

201

News (Medical) associated with Betibeglogene autotemcel

15 Nov 2024

·www.biopharmadive.com

Halozyme bids for Evotec; BeiGene gets a new name

Today, a brief rundown of news involving Evotec, Bluebird bio and the company formerly known as BeiGene, as well as updates from Leerink Partners and Abeona Therapeutics that you may have missed.Halozyme Therapeutics has made an unsolicited bid to buydrug discovery specialist Evotec for 11 euros per share in cash, an offer worth some 2 billion euros in total. In a press release, Halozyme said the combined company could offer increased scale and become a highly attractive strategic partner to the drug industry. Evotec, in its own statement, said it would carefully analyze this expression of interest. Ned PagliaruloBluebird bio has recorded its first revenue from sales of Lyfgenia, the companys gene therapy for sickle cell disease that won U.S. approval late last year. The process to prepare and receive Lyfgenia is lengthy, so only recently did the first patient actually get an infusion, at which point Bluebird books revenue for the $3.1 million therapy.Another 16 patients have started the process to receive treatment. The company is counting on climbing demand for Lyfgenia and its two other gene therapies, Zynteglo and Skysona, as it works to break even. Currently, it has enough cash to fund operations into the first quarter. Ned PagliaruloCancer drugmaker BeiGene will now operate under the name BeOne Medicines, a change that it says reflects its commitment to oncology research. The name also distances the company from its roots in China, a connection that may be less helpful as lawmakers in the U.S. increasingly view such ties as a national security risk. BeOne, which trades on the Hong Kong and Shanghai stock exchanges as well as the Nasdaq, is headquartered in California and in Switzerland. Ned PagliaruloAdaptimmune will lay off a third of its workforce in a bid to save about $300 million and break even financially in 2027, the company said Wednesday. Adaptimmune in August won U.S. clearance for its first product, a cell therapy called Tecelra for a type of soft tissue cancer. Going forward, the company will focus resources on that launch and another program in development for similar cancers, while partnering off two unrelated projects in preclinical testing. Its also shutting down a Phase 2 study in ovarian tumors.Ben FidlerLeerink Partnershas named two senior managing directors, Grant Curry and Jason Truman, to join its biopharma M&A team. Truman previously worked in a similar role at Guggenheim Securities, while Curry was a managing director at Gordon Dyal & Co. Leerink, which reemerged via a management buy-out after the collapse of SVB Financial Group,hopes to grow its M&A business. Outside of the big banks, Centerview Partners, Lazard and PJT Partners currently win the most deal business from drugmakers, according to BioPharma Dive data. Ned PagliaruloBy the end of next April, Abeona Therapeutics should know whether the Food and Drug Administration will approve its gene therapy pz-cel for a rare wound healing condition known as recessive dystrophic epidermolysis bullosa. The agency rejected pz-cel this past April, asking Abeona for more information on how its produced.The company then resubmitted its application with new information and, on Thursday, secured a target decision date of April 29, 2025 from the agency. Ned Pagliarulo '

Gene TherapyAcquisitionExecutive ChangeDrug ApprovalPhase 2

14 Nov 2024

·endpts.com

As bluebird projects more commercial demand, the biotech continues to seek cash

Bluebird reported that 17 people with sickle cell disease have started the process of receiving its gene therapy Lyfgenia. Bluebird said in its third-quarter earnings Thursday that it recognized revenue from Lyfgenia, though it did not specify how much. In total, the gene therapy biotech reported $10.6 million in revenue, but it said it expects at least double that — $25 million — next quarter. The company dosed its first sickle cell patient with Lyfgenia, the New York Times reported in September. Vertex Pharmaceuticals, which markets the gene-edited sickle cell and thalassemia therapy Casgevy, reported that it dosed its first patient in the third quarter and recorded $2 million in revenue. That patient was a 13-year-old thalassemia patient from Saudi Arabia , Vertex confirmed to Endpoints News via email. On Thursday, bluebird also said that 35 people have started the process of receiving Zynteglo, a similar therapy for thalassemia. It reported five patient starts for Skysona, a gene therapy for cerebral adrenoleukodystrophy. The biotech added it has 17 additional starts across its gene therapy portfolio scheduled for the rest of the year, along with 30 scheduled in 2025. “Patient starts more than doubled from our second to third quarter update, providing clear evidence that our commercial launches continued to accelerate,” bluebird CEO Andrew Obenshain said in a press statement. “We remain focused on securing additional cash resources to extend our runway, which we believe would enable us to achieve this vision and reach cash flow break-even in the second half of 2025.” Bluebird announced in September that it was laying off 25% of its workforce and cutting expenses by 20%. Earlier in the year, the biotech had to rework the terms of a loan with Hercules capital, and it currently has cash to fund operations into the first quarter of 2025. When asked in an analyst call about how the company was going to get more cash, CFO James Sterling said the “strategy to extend the runway includes renegotiating key contracts and other cost initiatives, and our partnership with Hercules is key in helping move those forward.” Bluebird is also at risk of being delisted from Nasdaq and is trying to implement a reverse stock split to avoid that. It’s convening a stockholder meeting on Dec. 4 to vote on the reverse stock split.

Gene Therapy

14 Nov 2024

·firstwordpharma.com

Bluebird bio needs cash injection to fund operations beyond Q1 next year

Bluebird bio revealed in its third-quarter report Thursday that it remains in a tight financial position and needs to secure more funds in order to avoid running out of cash by early 2025 — casting a shadow over otherwise encouraging signs of commercial progress for its gene therapy portfolio.The announcement puts pressure on the company to garner additional financing within the next few months to bridge the gap to its projected cash flow break-even in the second half of next year."Based on our current forecasts, which assumes continued cost saving initiatives, successfully renegotiating key contracts and continued collaborative engagement from Hercules, we expect our existing cash and cash equivalents will enable us to fund our operations into the first quarter of 2025," stated Chief Financial Officer James Sterling during the company's earnings call.This past March, bluebird inked a $175-million, five-year term loan facility with Hercules Capital, securing funding that the company said was expected to extend its cash runway for 24 months. Bluebird later announced it would let go of about a quarter of its staff in an effort to scale back operating expenses by 20% as its trio of gene therapies struggled to get off the ground.The company ended September with $118.7 million in cash and cash equivalents, including $48 million in restricted cash — a stark contrast to its 2018 position when it held $1.6 billion (see – Vital Signs: The last flight of the bluebird).Seventeen starts for LyfgeniaThe update comes amid a backdrop of third-quarter momentum. Bluebird reported 57 patient starts completed to date in 2024 across its three approved gene therapies: 35 for Zynteglo in beta-thalassemia, 17 for sickle cell disease treatment Lyfgenia (compared to only four in Q2), and 5 for Skysona in cerebral adrenoleukodystrophy. An additional 17 starts are scheduled through year-end.Tom Klima, chief commercial and operating officer, highlighted strong early indicators for 2025, noting "30 patient starts already scheduled in 2025," with the "vast majority" of those in the first quarter. He also pointed to a near-perfect conversion rate from scheduled to treated patients. "So far, it's very high… Essentially, 100% are converting to a start. The only variable is just the time."He added, "We have plans to double capacity for Lyfgenia in 2026 based on anticipated demand."Meanwhile, the company's network of qualified treatment centres (QTCs) has more than 70 locations in the US, with approximately 30 having initiated for one of its therapies. "I think the most exciting part of that is we have about 40 QTCs that are looking to start their first patients. So, I think it's a nice indicator of growth ahead," Klima said.

Gene Therapy

100 Deals associated with Betibeglogene autotemcel

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External Link

KEGG	Wiki	ATC	Drug Bank
-	Betibeglogene autotemcel	B06AX	-

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Thalassemia	US	bluebird bio, Inc.	17 Aug 2022
Transfusion-dependent Beta Thalassemia	EU	bluebird bio, Inc.	29 May 2019
Transfusion-dependent Beta Thalassemia	IS	bluebird bio, Inc.	29 May 2019
Transfusion-dependent Beta Thalassemia	LI	bluebird bio, Inc.	29 May 2019
Transfusion-dependent Beta Thalassemia	NO	bluebird bio, Inc.	29 May 2019
Beta-Thalassemia	GB	bluebird bio, Inc.	-

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Anemia, Sickle Cell	NDA/BLA	US	bluebird bio, Inc.	25 Apr 2023
Transfusion-dependent Thalassemia	Phase 3	US	bluebird bio, Inc.	08 Aug 2016
Transfusion-dependent Thalassemia	Phase 3	FR	bluebird bio, Inc.	08 Aug 2016
Transfusion-dependent Thalassemia	Phase 3	DE	bluebird bio, Inc.	08 Aug 2016
Transfusion-dependent Thalassemia	Phase 3	IT	bluebird bio, Inc.	08 Aug 2016
Transfusion-dependent Thalassemia	Phase 3	TH	bluebird bio, Inc.	08 Aug 2016
Transfusion-dependent Thalassemia	Phase 3	GB	bluebird bio, Inc.	08 Aug 2016

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


ASH2024	Not Applicable	Transfusion-dependent Thalassemia	-	Beti-cel gene therapy	ydjawzoutm(htvylesvcx) = No insertional oncogenesis reported pzgfibuncw (qvhaptddxu ) View more	-	07 Dec 2024
NCT03207009 (HGB-212, Literature) Manual	Phase 3	Transfusion-dependent Beta Thalassemia	18	Betibeglogene autotemcel	uaunwzjeao(sqrpqrobcr) = rtoryoyflx vggybtymcm (rcpokghhml ) View more	Positive	08 Nov 2024
Tandem Meetings ASTCT and CIBMTR2024	Not Applicable	Transfusion-dependent Thalassemia	-	G-CSF and plerixafor	jvqsmhufqv(ajhdkezijl) = Most patients (51/66 [77.3%]) had ≥1 adverse event (AE) attributed to mobilization and apheresis. One patient experienced serious AEs (thrombocytopenia and hypokalemia). gyxqsidygc (dkidiocfat ) View more	-	01 Feb 2024
Tandem Meetings ASTCT and CIBMTR2024	Not Applicable	Transfusion-dependent Thalassemia	-	Beti-cel gene therapy		-	01 Feb 2024
HGB-210 (BusinessWire) Manual	Not Applicable	Anemia, Sickle Cell	47	LYFGENIA	xnfxzauptf(irktjrlrkz) = mcxxirgfzf ahhikbhvqz (bqgygqulez ) View more	Positive	09 Dec 2023
FDA Manual	Phase 1/2	Anemia, Sickle Cell	45	LYFGENIA	comcssjdby(fkqlhpjxfe) = odqffxjhxz jvampqxpuh (yhktbekoze, 71 - 97) View more	Positive	08 Dec 2023
Tandem Meetings ASTCT and CIBMTR2022	Not Applicable	Transfusion-dependent Beta Thalassemia	-	Beti-cel gene therapy	ebmxyzivbu(vinntxfspe) = Seven pts experienced DP-related adverse events (AEs) occurring between infusion and engraftment (abdominal pain [n=5], dyspnea [n=1], hot flush [n=1], non-cardiac chest pain [n=1], and tachycardia [n=1]), and 4 pts experienced DP-related AEs occurring between engraftment and 2 y post-infusion (thrombocytopenia [n=3], erythroid dysplasia [n=1], extremity pain[n=1], leukopenia [n=1], and neutropenia [n=1]). No DP-related AEs occurred >2 y post-infusion. dcqmnnqlfg (khxyzdyxmm ) View more	-	01 Mar 2022
HGB-206 \| bb1111 (Tandem Meetings ASTCT and CIBMTR2022)	Phase 1/2	Anemia, Sickle Cell	35	LentiGlobin for SCD (bb1111) gene therapy	swbpquoige(nlqkzkyedd) = cjutdtnxgi mwhkgtytbf (pzrhwxzgxo )	Positive	01 Mar 2022
HGB-206 (Tandem Meetings ASTCT and CIBMTR2022)	Phase 1/2	BB305 lentiviral vector (LVV)	-	Lentiglobin (Group A)	jrjlucucrm(ckyxznlnih) = The most common SAEs in Groups A and C are shown in Table 2. Two AML events were reported in Group A, and none in Group C. iebxlckcau (vaefjvuxbs )	Positive	01 Mar 2022
HGB-206 (Tandem Meetings ASTCT and CIBMTR2022)	Phase 1/2	BB305 lentiviral vector (LVV)	-	Lentiglobin (Group C)		Positive	01 Mar 2022
NCT03207009 \| NCT02906202 (Tandem Meetings ASTCT and CIBMTR2022)	Phase 3	Transfusion-dependent Thalassemia	37	Beti-cel gene therapy	eyspgwlzio(njkfhjqyey) = bsiuydjufu bqzzcuxgxf (moncpcxiso )	Positive	01 Mar 2022
Tandem Meetings ASTCT and CIBMTR2022	Not Applicable	Transfusion-dependent Beta Thalassemia HbA T87Q	2	Beti-cel gene therapy	fhrnfnntdx(fpykybhekz) = Post-infusion AEs for pt 1 included febrile neutropenia, elevated C-reactive protein, pruritus, gingivitis, mild mucositis, and vertigo. wgbjfiefpn (nfkjrpkztk ) View more	Positive	01 Mar 2022