Lyfgenia (lovotibeglogene autotemcel) / bluebird bio - LARVOL DELTA

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

Non-genotoxic conditioning to increase donor chimerism levels in a mismatched murine transplant model for sickle cell disease (ASH 2025) - "The recently FDA-approved gene therapies Lyfgenia and Casgevy also employ MAC...We first investigated theefficiency of CD45- and CD117-sap as conditioning agents compared to classical total body irradiation(TBI) and busulfan. Our base conditioning regimen also included post-transplant cyclophosphamide (PT-Cy) and sirolimus...HPLC analysis at 20 weeks post-HCT showed that recipients conditioned with CD117-sapexhibited donor-derived Hb, while recipients conditioned with 200cGy TBI showed mixed donor/recipientHb. Furthermore, BM analysis at 24 weeks post-HCT also showed a significant increase in the frequenciesof donor-derived short- (52.50±5.67% vs 4.80±2.40%, p=0.0010) and long-term (43.28±5.79% vs0.79±0.79%, p=0.0016) hematopoietic stem cells in CD117-sap conditioned recipients, which furtherconfirms the successful long-term engraftment of CD117-sap conditioned recipients.In summary, CD117-sap, in combination with anti-thy1.2, PT-Cy, and sirolimus, is..."

Preclinical • Anemia • Gene Therapies • Genetic Disorders • Hematological Malignancies • Sickle Cell Disease • Transplantation • KIT • PTPRC • THY1

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

Provider practices and preparedness for gene therapy in pediatric sickle cell disease: A national survey of pediatric hematologists (ASH 2025) - "In 2023, the FDA approvedtwo autologous gene therapies for patients ≥12 years old with recurrent vaso-occlusive crises (VOCs):lovotibeglogene autotemcel (Bluebird Bio) and exagamglogene autotemcel (Vertex/CRISPR Therapeutics).Despite their promise, integration into routine care remains challenging due to strict trial criteria andlimited implementation guidance. This national survey highlights substantial variability in gene therapy referral practices forpediatric sickle cell disease, particularly in cases involving neurologic complications and across differentprovider types. While hematologists with a SCD-focused practice reported greater comfort with GTcounseling, they were less likely to recommend GT in certain high-risk scenarios. These findingsemphasize the urgent need for standardized, evidence-based guidelines and targeted provider educationto ensure equitable access and appropriate integration of GT into pediatric SCD care."

Clinical • Gene therapy • Bone Marrow Transplantation • Cardiovascular • Gene Therapies • Genetic Disorders • Pediatrics • Sickle Cell Disease

Engineered extracellular vesicles for In Vivo gene therapy in sickle cell disease (ASH 2025) - "In2023, the FDA approved two gene therapies for SCD: Casgevy and Lyfgenia. Our innovative approach has the potential to serve as a foundationaltechnology for a safer, more accessible, and non-viral gene therapy applicable to a broad range ofgenetic disorders. The successful completion of this project will generate critical proof-of-concept dataand enable us to pursue further translational development for in vivo gene therapy for SCD."

Gene therapy • Preclinical • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • CD63

Differing Definitions of Vaso-Occlusion in Clinical Studies of Sickle Cell Disease Can Result in Differing Outcomes (ASH 2023) - " We reviewed completed and ongoing clinical trials and published articles using endpoints assessing the reduction or elimination of vaso-occlusive crisis/events, including trials of (i) exagamglogene autotemcel (exa-cel, CRISPR/Cas-9 based genome editing treatment), (ii) lovotibeglogene autotemcel (lovo-cel, gene addition therapy), (iii) L-glutamine, (iv) voxelotor, (v) hydroxyurea (HU) and (vi) crizanlizumab. Requirements for health care facility visits in the definitions of severe VOC (exa-cel), VOC, and SCPC were more broadly inclusive and include events that would not be counted in the definitions of severe VOE (lovo-cel) or painful crisis. Clinically, support for this observation comes from our analysis of exa-cel SCD pivotal clinical trial data using these different definitions, which showed the number of patients free from vaso-occlusive episodes changed depending on the definition of vaso-occlusion employed. These results show differences in vaso-occlusion..."

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

Efficacy, Safety, and Health-Related Quality of Life (HRQOL) in Patients with Sickle Cell Disease (SCD) Who Have Received Lovotibeglogene Autotemcel (Lovo-cel) Gene Therapy: Up to 60 Months of Follow-up (ASH 2023) - P, P1/2, P3 | "Patients with SCD and recurrent severe vaso-occlusive events (VOEs) or history of overt stroke underwent plerixafor mobilization and apheresis followed by myeloablative busulfan conditioning and lovo-cel infusion. One-time treatment with lovo-cel resulted in sustained HbAT87Q production and near-complete resolution of VOEs and severe VOEs up to 18 months post treatment; the safety profile was consistent with underlying SCD and myeloablative conditioning. Patients reported sustained improvements in pain intensity, pain interference, and fatigue. Ongoing long-term follow-up will continue to provide important information on efficacy, safety, and patient experience post lovo-cel treatment."

Clinical • Gene therapy • HEOR • Cardiovascular • Dental Disorders • Fatigue • Gene Therapies • Genetic Disorders • Hematological Disorders • Hematological Malignancies • Hepatology • Mood Disorders • Myelodysplastic Syndrome • Neuralgia • Oncology • Pain • Pediatrics • Psychiatry • Sickle Cell Disease • Stomatitis • Thrombocytopenia

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

Transformative Therapies for Sickle Cell Disease: A Global Stakeholder Perception Study on Advanced Cell Therapies (ASH 2024) - "Exagamglogene autotemcel(EA) was the preferred gene therapy (20%), followed by lovotibeglogene autotemcel(L) (16.7%), 63.3%had no preference. It highlights fertility preservation, access to QTC, risk of secondary malignancy and cost barriers critical factors in patient selection. Future research should focus on expanding the donor pool for HSCT, gathering long-term data on GT's safety and efficacy, and developing strategies to alleviate the financial burden associated with these TT."

Clinical • Metastases • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Graft versus Host Disease • Hematological Disorders • Immunology • Pediatrics • Sickle Cell Disease

Maximizing Safety and Efficacy in Hematopoietic Stem Cell Gene Therapy (ASH 2024) - "Hematopoietic stem cell (HSC) gene therapy has been recently successfully employed for certain rare blood disorders including hemoglobinopathies, which resulted even in marketing authorizations such as Lyfgenia™ and Casgevy™. Based on these results, we propose a combined strategy of transduction enhancers on the automated platform to achieve significantly higher transduction efficiency. Ongoing experiments investigate the mechanisms involved in better performance of lentiviral transduction on the automated platform with molecular analysis via Next Generation Sequencing (NGS) and respective bioinformatics analysis."

Clinical • Gene therapy • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • CD34

Multi-Disciplinary Care Model for Transition and Re-Transition after Gene Therapy in Sickle Cell Disease (ASH 2024) - "This led to the Food and Drug Administration (FDA) approval of the lentiviral-based gene addition product (lovotibeglogene autotemcel) and CRISPR-Cas9 based gene editing product (exagamglogene autotemcel) for patients with SCD above 12 years of age. Our team's collaborative approach to SCD care with sickle cell specialists, transplant team and other care providers and CBO continues into the long term follow up period, including ongoing supportive services for both patients and their families. Conclusion : As newer therapies are developed and approved for transformative SCD care, development of a transitional model with early engagement of an interdisciplinary team is critical for empowering sickle cell warriors and for their successful transition back into the community."

Gene therapy • Bone Marrow Transplantation • Fatigue • Gene Therapies • Genetic Disorders • Hematological Disorders • Mood Disorders • Psychiatry • Sickle Cell Disease

Participants with a History of Stroke in Lovotibeglogene Autotemcel (Lovo-cel) Clinical Trials (ASH 2024) - P, P1/2, P3 | "Longer follow-up will be required to understand the impact on neurovasculature and risk of stroke recurrence. These data will help inform real-world lovo-cel treatment recommendations and decisions for those with SCD and their care providers."

Clinical • Cardiovascular • Genetic Disorders • Hematological Disorders • Ischemic stroke • Sickle Cell Disease • Vascular Neurology

An Update on Lovotibeglogene Autotemcel (Lovo-cel) Clinical Trials for Sickle Cell Disease (SCD) and Analysis of Early Predictors of Response to Lovo-Cel (ASH 2024) - P, P1/2, P3 | "Conclusions : One-time lovo-cel treatment results in sustained HbAT87Q production and eliminated VOEs and sVOEs in a majority of participants. Models developed in this post hoc analysis enable prediction of the likelihood of VOE-CR and sVOE-CR using measurements as early as 6 mo post treatment."

Clinical • Genetic Disorders • Hematological Disorders • Pediatrics • Sickle Cell Disease

Ernest Beutler Lecture and Prize (ASH 2024) - "In the last year, both globin gene addition (lovo-cel) and CRISPR gene editing (exa-cel) therapies received FDA approval. Dr. John Tisdale will summarize recent advances in ex vivo modification of hematopoietic stem cells for both lentiviral gene and CRISPR gene editing therapies for the hemoglobin disorders, concentrating on clinical parameters and prospects for improving preconditioning and moving toward strategies that would allow application without the need for hospitalization and intensive supportive care."

Beta-Thalassemia • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • BCL11A

Maximizing safety and efficacy in hematopoietic stem cell gene therapy (ESGCT 2024) - "Hematopoietic stem cell (HSC) gene therapy has been recently successfully employed for certain rare blood disorders including hemoglobinopathies, which resulted even in marketing authorizations such as Lyfgenia™ and Casgevy™. Based on these results, we propose a combined strategy of transduction enhancers on the automated platform to achieve significantly higher transduction efficiency. Ongoing experiments investigate the mechanisms involved in better performance of lentiviral transduction on the automated platform with molecular analysis via Next Generation Sequencing (NGS) and respective bioinformatics analysis."

Clinical • Gene therapy • Gene Therapies • Hematological Disorders • Sickle Cell Disease • CD34

Sickle Cell Disease and Gene Therapy Among African Americans: A Dilemma and Challenge. (PubMed, J Racial Ethn Health Disparities) - "Although the US Food and Drug Administration's recently approved groundbreaking base editing gene therapies of Casgevy and Lyfgenia have been declared promising in treating SCD, uptake for the therapies has been low. Though the treatment of SCD through gene therapy has sparked some excitement in the African American community, it is also causing a dilemma and challenges. This paper documents the dilemma and challenges associated with gene therapy among the African American SCD community and what can be done to address them."

Journal • Review • Cardiovascular • Gene Therapies • Genetic Disorders • Heart Failure • Hematological Disorders • Pain • Sickle Cell Disease

Advances in Sickle Cell Disease Treatment: A Comparative Review of Hematopoietic Stem Cell Transplantation and Gene Therapy (Casgevy and Lyfgenia). (PubMed, Stem Cells Dev) - "This milestone marks a crucial moment in the history of both SCD and gene therapies and thus warrants exploring the considerations revolving around their implementation. Although these therapies seem to offer hope for patients ineligible for HSCT, their long-term outcomes remain unassessed-further studies with extended follow-up are needed to confirm their safety and durability."

Journal • Review • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Hematological Disorders • Oncology • Sickle Cell Disease • Transplantation

Updated Review of Current Therapeutic Approaches for the Management of Sickle Cell Disease. (PubMed, Cardiovasc Hematol Disord Drug Targets) - "There are six Food and Drug Administration (FDA)-approved drugs, hydroxyurea, L-glutamine, crizanlizumab- TMCA, voxelotor, Casgevy, and Lyfgenia, that are used for the prophylaxis and treatment of serious complications of sickle cell disease. Ongoing research seeks to enhance treatment options and develop potential cures for SCD. This review attempts to present a comprehensive overview of the current therapeutic approaches and newly developed innovative medicines to combat and potentially eradicate SCD with an emphasis on their mechanisms, efficacy, and clinical implications."

Journal • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Hematological Disorders • Infectious Disease • Pain • 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

Implementing the Generalized Risk-Adjusted Cost-Effectiveness (GRACE) Model for Sickle Cell Disease (SCD) - A Case Study. (PubMed, Value Health) - "The GRACE method offers a more comprehensive and precise estimation of societal value, leading to more efficient and equitable resource allocation. This study not only highlights the limitations of traditional CEA in capturing the total societal value of treatments for severe diseases, but also provides a roadmap for incorporating GRACE model elements into HTAs, thereby facilitating broader acceptance of innovative therapies that significantly enhance patient QoL."

HEOR • Journal • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

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

Cost-Effectiveness of Gene Therapy for Sickle Cell Disease in Uganda: Tailoring High-Income Evidence to Uganda's Context (ASGCT 2025) - "To estimate lifetime SoC costs in Uganda, we employed a Markov model designed to simulate the progression of patients across three health states: (1) standard of care (SoC) without hydroxyurea, (2) SoC with fixed dose hydroxyurea, and (3) death...Application of lovo-cel (bluebird bio) or exa-cel (Vertex Therapeutics) gene therapy for SCD was targeted to the same patient populations for authorized use in the U.S. and Europe: eligible individuals with SCD aged 12 years and older who meet specific trial inclusion criteria...2023) is lower than the scaled cost of a SCD gene therapy product in this model, suggesting a profit margin is possible for a locally manufactured gene therapy product for the treatment of SCD in Uganda. Disease Focus of Abstract:Sickle Cell"

Cost effectiveness • Gene therapy • HEOR • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease • SCD

Payment Models for Sickle-Cell Disease Gene Therapies in Colorado Medicaid: Real-World Data Analysis (ISPOR 2025) - "The introduction of exagamglogene autotemcel (exa-cel) and lovotibeglogene autotemcel (lovo-cel) required a comprehensive evaluation of potential payment strategies. The significance of real-world data was emphasized in identifying eligible patient populations and determining the actual costs of SoC. Furthermore, the analysis pointed out that the duration of contracts has a significant impact on financial outcomes."

Clinical • Gene therapy • Medicaid • Real-world • Real-world evidence • Reimbursement • US reimbursement • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Advances in Gene Therapy for Sickle Cell Disease: From Preclinical Innovations to Clinical Implementation and Access Challenges. (PubMed, CRISPR J) - "In this review, we discuss recent preclinical studies and clinical trials of gene and cell therapies, focusing on the progress of FDA-approved treatments like Lyfgenia and Casgevy. We also examine the many challenges, including accessibility, safety, and long-term efficacy, which continue to shape the future of SCD gene therapy."

Journal • Preclinical • Review • Bone Marrow Transplantation • Cardiovascular • Gene Therapies • Genetic Disorders • Hematological Disorders • Infectious Disease • Pain • Sickle Cell Disease • Transplantation • SCD