Zynteglo (betibeglogene autotemcel) / bluebird bio - LARVOL DELTA

Early post-marketing safety signals of CRISPR-edited exagamglogene autotemcel (Casgevy) versus lentiviral betibeglogene autotemcel (Zynteglo): A faers disproportionality study, 2014–2025 (ASH 2025) - "This first FAERS-based safety analysis of CRISPR-edited therapy suggests Casgevy may be associated with early post-infusion gastrointestinal/mucosal and bleeding events, while Zynteglo shows a broader haematologic and vascular signal profile, with isolated liver and immune AEs. These disproportionate reporting signals, although preliminary, support enhanced clinical vigilance, especially for mucosal toxicity and bleeding. Limitations include small case counts, underreporting biases in FAERS, absent exposure denominators, and potential misclassification from manual PT grouping."

Clinical • P4 data • Beta-Thalassemia • Gene Therapies • Genetic Disorders • Hematological Disorders • Infectious Disease • Sickle Cell Disease

An automated platform for lentiviral transduction for HSC gene therapy promotes fitness of hematopoietic stem cells combined with higher transduction efficiency (ASH 2025) - "Although therapies for HSC gene therapy have been recently approved (Zynteglo™, Lyfgenia™ and Casgevy®), still certain challenges remain associated with high costs, scalability and safety related to leukemic events. Notably, low-density lipoprotein receptor (LDL-R), the cellular receptor that serves for the recognition by the VSV glycoprotein, was accordingly upregulated in cells processed on the CliniMACS Prodigy. These results suggest that the CliniMACS Prodigy promotes higher stemness or better fitness of HSCs while simultaneously allowing for higher transduction efficiencies due to downregulation of immune related pathways and upregulation of cholesterol and sterol binding."

Gene therapy • IO biomarker • Dyslipidemia • Gene Therapies • Immunology • Infectious Disease • CD34 • TLR8

Accelerating access to gene therapy: Lessons from commercial implementation in sickle cell disease and transfusion-dependent thalassemia (ASH 2025) - "With >700 patient-years of follow-up in clinical trials, Zynteglo (approved Aug 2022 for thalassemia) and Lyfgenia (approvedDec 2023 for sickle cell disease) are now in real-world use in the United States. This real-world analysis is the first to characterize commercial gene therapy implementation,demonstrating scalable delivery and accelerated access over time. Cross-program learning andcentralized support enabled faster treatment across a national network. With published payer coveragefor >250M lives – without a single ultimate denial – these findings offer a functioning model for genetherapy implementation."

Gene therapy • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Rapid immune reconstitution in patients with transfusion-dependent thalassemia following betibeglogene autotemcel: A real-world experience (ASH 2025) - "These therapies use single-agent busulfanmyeloablative conditioning (Bu-MAC) and CD34+ selected autologous gene-modified hematopoietic stemcells (GM-HSCs) depleted of T cells. These findings suggest that patients with TDT treated with beti-cel are functionallylymphocyte replete 3 months after Bu-MAC and infusion of CD34+ selected GM-HSCs and remain sothereafter. Three months after infusion, patients possessed sufficient lymphocyte subset counts andPHA-induced T cell proliferation responses suggesting that patients may not require further monitoringor prophylaxis for viral reactivation. Patients also had B and T cell subsets associated with generatingprotective vaccine responses signaling potential vaccine-readiness at this time."

Clinical • Real-world • Real-world evidence • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Infectious Disease • Tetanus • CD27 • CD8 • CXCR5

Improvement in Iron Burden in Patients with Transfusion-Dependent β-Thalassemia (TDT) Treated with Betibeglogene Autotemcel (Beti-cel) Gene Therapy: Up to 9 Years of Follow-up (ASH 2023) - P, P1/2, P3 | "Safety of beti-cel treatment largely reflected the known side effects of hematopoietic stem cell collection and the busulfan conditioning regimen. In this analysis with up to 9 years of follow up, patients treated with beti-cel who achieved TI also demonstrated sustained improvements in iron burden, and the majority of patients were able to stop chelation. Collectively, these results demonstrate the long-term durability and stability of response after beti-cel gene therapy in patients with TDT."

Clinical • Gene therapy • Beta-Thalassemia • Gene Therapies • Genetic Disorders • Hematological Disorders • Pediatrics

Sustained Efficacy, Safety, and Improved Quality of Life in Adult and Pediatric Patients with Transfusion-Dependent β-Thalassemia up to 9 Years Post Treatment with Betibeglogene Autotemcel (Beti-cel) (ASH 2023) - P, P1/2, P3 | "Five patients experienced serious veno-occlusive liver disease; all 5 received defibrotide and recovered. Beti-cel is a potentially curative gene therapy for patients with TDT across ages and genotypes through achievement of TI and normal or near-normal Hb. These data will inform real-world beti-cel treatment decisions for patients with TDT and providers."

Clinical • HEOR • Beta-Thalassemia • Gene Therapies • Genetic Disorders • Hematological Disorders • Hepatology • Pediatrics • Thrombocytopenia • CD34

Gene Therapies for Hemoglobinopathies: Efficacy, Cell Collection & Transfusion Support. (PubMed, Transfus Med Rev) - "The U.S. Food and Drug Administration (FDA) has approved GTs for both SCD and TDT: lovotibeglogene autotemcel (Lyfgenia) and exagamglogene autotemcel (Casgevy) in 2023 for SCD and betibeglogene autotemcel (Zynteglo) in 2022 and exagamglogene autotemcel (Casgevy) in 2024 for TDT. This article appraises the studies the FDA approvals were based upon, with comments on transfusion and stem collection regimens. The latter aspects highlighting variability in practice and the need for additional studies to optimize pretransfusion regimens and the collection process for successful GT."

Journal • Beta-Thalassemia • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Graft versus Host Disease • Hematological Disorders • Immunology • Sickle Cell Disease • Transplantation

Betibeglogene Autotemcel (beti-cel) Gene Addition Therapy Results in Durable Hemoglobin a Production with up to 10 Years of Follow-up with Transfusion-Dependent β-Thalassemia (ASH 2024) - P, P1/2, P3 | "Conclusion : These data provide evidence of the sustained favorable benefit-risk profile of gene addition therapy with beti-cel in participants with TDT and will inform real-world treatment decisions. Beti-cel is a potentially curative gene addition therapy for patients with TDT across genotypes and ages through achievement of durable TI, normal or near-normal Hb, and a favorable long-term safety profile with up to 10 years of follow-up."

Beta-Thalassemia • Gene Therapies • Genetic Disorders • Hematological Disorders • Pediatrics

Curative Therapies for Hemophilias and Hemoglobinopathies in Adults: Immune, Gene, and Stem Cell Approaches in a Global Context. (PubMed, Biomedicines) - "Recent advances in immune-based therapeutics (e.g., emicizumab, concizumab, crizanlizumab), viral vector-mediated gene addition (e.g., Roctavian, Hemgenix), and gene-modified autologous stem cell therapies (e.g., Zynteglo, Casgevy) have ushered in a new era of disease-modifying and potentially curative interventions. Equitable access, particularly in regions bearing the highest disease burden, will require collaborative funding strategies, regional capacity building, and inclusive regulatory frameworks. This review summarizes the current landscape of curative therapy, outlines implementation barriers, and calls for coordinated international action to ensure that transformative care reaches all affected individuals worldwide."

Journal • Review • Beta-Thalassemia • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Hematological Disorders • Hemophilia • Hemophilia A • Rare Diseases • Sickle Cell Disease • Transplantation

MAXIMIZING SAFETY AND EFFICACY IN HEMATOPOIETIC STEM CELLS GENE THERAPY (EHA 2025) - "Background: Although therapies for HSC gene therapy have been recently approved (Zynteglo™, Lyfgenia™ and Casgevy®), still certain challenges remain associated with high costs, scalability and safety related to leukemic events. Based on these results, we propose a combined strategy of transduction enhancers and the use of Baboon envelope pseudotyped LV on the automated CliniMACS Prodigy platform to achieve significantly higher transduction efficiencies and enhanced engraftment."

Clinical • Gene therapy • Gene Therapies • CD34 • FLT3

A Targeted Literature Review of Value-Based Agreements (VBAs) for Cell and Gene Therapies in the United States (ISPOR 2025) - "The therapies with VBAs in place included: Beqvez, Casgevy, Hemgenix, Kymriah, Luxturna, Lyfgenia, Roctavian, Vyjuvek, Zolgensma, and Zynteglo... In this review, multiple VBAs for CGTs were identified across multiple disease areas. Most payers did not publicly disclose which outcomes measures the VBAs were assessing. Of those that did, outcomes assessed could be sourced from routine patient visits and/or adjudicated claims, placing no additional burden on providers to collect data for the sole purpose of the VBA."

Gene therapy • Review • Gene Therapies

Maximizing Safety and Efficacy in Hematopoietic Stem Cell Gene Therapy (ASGCT 2025) - "Although new treatments for hematopoietic stem cell (HSC) gene therapy have been recently approved for several diseases such as beta-thalassemia (Zynteglo), sickle cell disease (Lyfgenia and Casgevy), and adrenoleukodystrophy (Skysona), a certain number of challenges still remain such as the high costs and scalability associated with these therapies, as well as the increased safety concerns regarding the related leukemic events. Experiments to investigate the mechanisms involved in better performance of LV transduction on the automated platform, including detailed molecular analysis of gene expression pathways by Next Generation Sequencing (NGS), are ongoing. Disease Focus of Abstract:Other Other: Rare diseases of the blood such as (but not limited to) hemoglobinopathies"

Clinical • Gene therapy • Beta-Thalassemia • Gene Therapies • Genetic Disorders • Hematological Disorders • Rare Diseases • Sickle Cell Disease • CD34 • FLT3

Post-Approval, Real-World Experience with Betibeglogene Autotemcel for Transfusion-Dependent Beta Thalassemia (TCT-ASTCT-CIBMTR 2025) - "Patients received beti-cel after conditioning with single-agent PK-adjusted busulfan over four days...He received eculizumab due to elevated sc5b-9 without other thrombotic microangiopathy criteria, eventually engrafting platelets with romiplostim support after 82 days... Our experience demonstrates consistent achievement of RBC transfusion independence in patients with TDT receiving commercial beti-cel. Patients experienced prolonged platelet engraftment time and high platelet transfusion requirements, which were associated with severe bleeding in patients with VOD or HLA Class I alloimmunization. Further studies will seek to mitigate bleeding complications by reducing VOD rates and to explore the impact of HLA Class I alloimmunization in patients receiving beti-cel for TDT."

Clinical • Real-world • Real-world evidence • Beta-Thalassemia • Genetic Disorders • Hepatology • Subarachnoid Hemorrhage • Thrombocytopenia • CD34

Streamlining the Coordination of Advanced Cellular and Gene Therapies: A Checklist Approach for Transplant Coordinators (TCT-ASTCT-CIBMTR 2025) - "Methods, Intervention, & Analysis Adapted from the design of a pre-existing coordination checklist for autologous/allogeneic stem cell transplant, 3 additional checklists were developed for Omisirge cord transplant, Zynteglo and Lyfgenia gene therapies. This tool can allow for standardization to prevent any oversight in the coordination process. The checklist can be revised as processes and additional therapies are initiated to assist with coordination and developing the plan of care."

Gene therapy • Metastases • Bone Marrow Transplantation • Gene Therapies • Transplantation

Betibeglogene Autotemcel (Beti-cel) Gene Addition Therapy Results in Durable Hemoglobin A (HbA) Production with up to 10 Years of Follow-up in Participants with Transfusion-Dependent β-Thalassemia (TCT-ASTCT-CIBMTR 2025) - P, P1/2, P3 | "Beti-cel is a potentially curative therapy for patients with TDT across genotypes and ages through achievement of durable TI and a favorable safety profile up to 10 y. These data will inform real-world treatment decisions."

Beta-Thalassemia • Genetic Disorders • Oncology • Pediatrics

Long-Term Follow-Up Data Continue to Support Beti-Cel as a Potentially Curative Gene Therapy for β-Thalassemia Patients Who Require Regular Transfusions Through Achievement of Durable Transfusion Independence and Normal or Near-Normal Adult Hb Levels (Businesswire) - P1/2 | N=7 | NCT02151526 | P3 | N=24 | NCT02906202 | P3 | N=19 | NCT03207009 | Sponsor: bluebird bio | "Two participants had 10 years of follow-up, and 51 (81.0%) participants had 5 or more years of follow-up...Of 63 patients, 52 (90.2% in Phase 3 studies and 68.2% in Phase 1/2 studies) achieved TI. All except one patient maintained TI through last follow-up. The median weighted average hemoglobin during TI was 10.2 mg/dL for Phase 1/2 studies and 11.2 mg/dL for Phase 3 studies. Achievement and maintenance of TI and median weighted average hemoglobin were similar across ages and genotypes...Among participants who achieved TI, improvements in serum ferritin and liver iron concentration were sustained through month 60. 28/37 (75.7%) study participants who achieved TI in Phase 3 studies are no longer undergoing iron chelation therapy...None of the study participants had a fatal event."

P1/2 data • P3 data • Beta-Thalassemia • Hematological Disorders

Evaluation of Safety and Efficacy of Novel FDAApproved CRISPRCas9 Therapies Exagamglogene Autotemcel and Betibeglogene Autotemcel for Beta Thalassemia A Literature Review (ASHP 2024) - No abstract available

Clinical • Review • Beta-Thalassemia • Genetic Disorders

Finding a Way for Patients to Access Gene Therapies (ISPOR-EU 2024) - "Out of 9 funded single-administration GTx (eladocagene exuparvovec, etranacogene dezaparvovec, betibeglogene autotemcel, valoctocogene roxaparvovec, voretigene neparvovec, exagamglogene autotemcel, lovotibeglogene autotemcel, atidarsagene autotemcel, onasemnogene abeparvovec), RSAs were identified in the US (n=7), UK (n=5), Canada (n=3), and Australia (n=2)... To manage uncertainties around long-term benefits and financial impact, local decision-makers implement RSAs. Canada and UK mainly use financial-based schemes built on simple price discounts. Australia and the US aim at implementing schemes whereby treatment cost payers incur corresponds to expected health outcome for a particular patient."

Clinical • Gene therapy • Gene Therapies • Rare Diseases

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. (PubMed, Lancet) - P, P3 | "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."

Gene therapy • Journal • P3 data • Beta-Thalassemia • Gene Therapies • Hematological Disorders • Transplantation

bluebird bio to Present Additional Long-Term Follow-up Data from Gene Therapy Programs in Sickle Cell Disease and Beta-Thalassemia at the 66th American Society of Hematology (ASH) Annual Meeting and Exposition (Businesswire) - "bluebird bio will present updated follow-up data and analysis of early predictors and response to lovotibeglogene autotemcel (lovo-cel) in patients from HGB-206 and HGB-210 studies, demonstrating consistent clinical outcomes as early as six months post infusion and continued durability of clinical benefit of lovo-cel...The company will also present updated long-term analyses of efficacy, safety, and health related quality of life data of betibeglogene autotemcel (beti-cel) in patients with transfusion-dependent beta-thalassemia (TDT)."

P1/2 data • P3 data • Beta-Thalassemia • Sickle Cell Disease

Gene Therapy: A Revolutionary Step in Treating Thalassemia. (PubMed, Hematol Rep) - "FDA-approved ZYNTEGLO is a potentially one-time curative treatment for β-Thalassemia. Although cutting-edge, its use is limited because of the high cost-a price of USD 2.8 million per patient."

Gene therapy • Journal • Review • Beta-Thalassemia • Gene Therapies • Genetic Disorders • Hematological Disorders

NAVIGATING HAPTOGLOBIN ALLERGY CONCERNS IN PREPARATION FOR GENE THERAPY FOR BETA THALASSEMIA (ACAAI 2024) - "A promising gene therapy, betibeglogene autotemcel, was approved in 2022...With »6-18 mg/mL of albumin in the gene therapy after wash steps, we deemed it safe to proceed. This case is an example of how to challenge a patient to haptoglobin using a commercially available product (albumin) given limitations in testing for haptoglobin hypersensitivity and in isolating haptoglobin for direct challenge."

Gene therapy • Allergy • Beta-Thalassemia • Gene Therapies • Genetic Disorders • Immunology • HP

Gene Therapy in Transfusion-Dependent Non-β0/β0 Genotype β-Thalassemia: First Real-World Experience of Beti-cel. (PubMed, Blood Adv) - "We report the first real-world application of betibeglogene autotemcel (beti-cel; ZYNTEGLO™) during its period of active license in Europe from January 2020 to March 2022 for patients aged ≥ 12 years without a β0/β0 genotype and without a human leukocyte antigen (HLA)-matched sibling donor, before beti-cel marketing authorization was withdrawn by its holder due to non-safety reasons...Eight patients received beti-cel post busulfan myeloablative conditioning, all achieving transfusion independence within 8 to 59 days with posttreatment hemoglobin levels ranging from 11.3 to 19.3 g/dL...Additionally, we observed unexpected posttreatment sequelae: 1 patient developed polycythemia that could not be explained by known genetic or acquired mechanisms, 1 patient developed posttreatment depression and anxiety prohibiting her from returning to work, and 1 patient developed fatigue severely compromising both quality of life and work capacity. This real-world experience corroborates..."

Gene therapy • Journal • Real-world • Real-world evidence • Beta-Thalassemia • CNS Disorders • Depression • Endocrine Disorders • Fatigue • Gene Therapies • Genetic Disorders • Mood Disorders • Psychiatry

Betibeglogene autotemcel (Zynteglo) for beta thalassemia. (PubMed, Med Lett Drugs Ther) - No abstract available

Journal • Beta-Thalassemia • Genetic Disorders

In brief: Casgevy for beta thalassemia. (PubMed, Med Lett Drugs Ther) - No abstract available

Journal • Beta-Thalassemia • Genetic Disorders • Hematological Disorders • Sickle Cell Disease