Skysona (elivaldogene tavalentivec) / bluebird bio - LARVOL DELTA

Integrating Emerging Gene Therapies into CIBMTR Data Reporting Using Skysona As a Model (TCT-ASTCT-CIBMTR 2025) - "With proper preparation and collaboration among the data management team, our center was able to seamlessly report new Skysona data requirements to the CIBMTR. Over the following months, we will monitor new form completion as well as ask questions of clinical staff and submit tickets to CIBMTR as issues arise. NEXT STEPS: As a center, we plan to implement new learnings into our job aids and adapt the lessons learned to any upcoming gene therapy products."

Gene therapy • Gene Therapies • Infectious Disease • Metabolic Disorders • Oncology

Maximizing Safety and Efficacy in Hematopoietic Stem Cell Gene Therapy (TCT-ASTCT-CIBMTR 2025) - "Hematopoietic stem cell (HSC) gene therapy has been recently been aproved for beta-thalassemia, sicklce cell disease, and adrenal leukodystrophy, specifcially Lyfgenia ™ ,Casgevy ™ , Skysona TM, . Based on these results, we propose a combined strategy of transduction enhancers and the use of Baboon envelope pseudotyped LV on the automated platform to achieve significantly higher transduction efficiency. Ongoing experiments to investigate the mechanisms involved in better performance of LV transduction on the automated platform, validating BaEV pseudotyped LV on the automated platform, including detailed molecular analysis of gene expression pathways by Next Generation Sequencing (NGS), are underway."

Clinical • Gene therapy • Beta-Thalassemia • Gene Therapies • Hematological Disorders • Sickle Cell Disease • CD34

Elivaldogene autotemcel approved for treatment of cerebral adrenoleukodystrophy (CALD) in males: A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG). (PubMed, Genet Med Open) - No abstract available

Journal • Gene Therapies • Genetic Disorders

FDA Investigating Serious Risk of Hematologic Malignancy Following Skysona (elivaldogene autotemcel) (FDA) - "FDA is investigating the known risk of hematologic malignancies with serious outcomes, including those such as hospitalization, the requirement for allogeneic hematopoietic stem cell transplantation, and death, and is evaluating the need for further regulatory action. Given the risk of hematologic malignancy, providers should carefully consider alternative therapies, including allogeneic hematopoietic stem cell transplant for patients who have a suitable, willing, and available human leukocyte antigen (HLA)-matched donor, prior to deciding to treat a child with Skysona."

FDA event • Gene Therapies

Blood Cancers Reported in Seven Children Dosed with SKYSONA™. (PubMed, Hum Gene Ther) - No abstract available

Journal • Hematological Malignancies • Oncology

Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy. (PubMed, N Engl J Med) - P, P2/3, P3 | "Hematologic cancer developed in a subgroup of patients who were treated with eli-cel; the cases are associated with clonal vector insertions within oncogenes and clonal evolution with acquisition of somatic genetic defects. (Funded by Bluebird Bio; ALD-102, ALD-104, and LTF-304 ClinicalTrials.gov numbers, NCT01896102, NCT03852498, and NCT02698579, respectively.)."

Gene therapy • Journal • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • CD34 • CDKN2A • CDKN2B • KRAS • MECOM • NRAS • PRDM16 • RUNX1 • WT1

Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy. (PubMed, N Engl J Med) - P, P2/3 | "At a median follow-up of 6 years after lentiviral gene therapy, most patients with early cerebral adrenoleukodystrophy and MRI abnormalities had no major functional disabilities. However, insertional oncogenesis is an ongoing risk associated with the integration of viral vectors. (Funded by Bluebird Bio; ALD-102 and LTF-304 ClinicalTrials.gov numbers NCT01896102 and NCT02698579, respectively.)."

Gene therapy • Journal • Bone Marrow Transplantation • CNS Disorders • Gene Therapies • Genetic Disorders • Hematological Malignancies • Inflammation • Myelodysplastic Syndrome • Oncology • Transplantation • CD34

Secondary failure of Lentiviral Vector Gene Therapy in a Cerebral Adrenoleukodystrophy Patient with an ABCD1 Whole-Gene Deletion. (PubMed, Mol Ther) - "He underwent hemopoietic cell transplant (HCT) with autologous CD34+ cells transduced with an ABCD1-expressing lentiviral vector (eli-cel, elivaldogene autotemcel) as part of the ALD-104 clinical trial...The coincident VCN loss and appearance of antibody to the ABCD1 gene product is of interest, and we postulate that it is related to the patient's whole ABCD1 gene deletion. We suggest close monitoring of loss of gene therapy efficacy due to immune response in patients with full deletions who are considering gene therapy."

Gene therapy • Journal • Viral vector • Gene Therapies • Genetic Disorders • Transplantation • CD34

Association Between Potency Critical Quality Attributes and Clinical Efficacy Across Lentiviral Vector Cell and Gene Therapy Products (ASGCT 2024) - P1/2, P2/3, P3 | "Betibeglogene autotemcel (beti-cel), lovotibeglogene autotemcel (lovo-cel), and elivaldogene autotemcel (eli-cel) are distinct CGT products with differentiated safety and efficacy profiles that leverage lentiviral gene addition in CD34+ hematopoietic stem and progenitor cells for treatment of severe genetic diseases. Our findings indicate that all three products (beti-cel, lovo-cel, and eli-cel) share measures of transduction efficiency as the common potency-associated CQAs that highly correlate with product efficacy. These results highlight the value of transduction efficiency assays as surrogate potency measurements and can help guide the establishment of rigorous and meaningful product quality acceptance criteria for complex CGT products."

Clinical • Gene therapy • Viral vector • Beta-Thalassemia • Gene Therapies • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Sickle Cell Disease • CD34

Stargazer: A Study of Participants With Cerebral Adrenoleukodystrophy (CALD) Treated With Elivaldogene Autotemcel (clinicaltrials.gov) - P=N/A | N=120 | Recruiting | Sponsor: bluebird bio | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders

Viral Vectors in Gene Replacement Therapy. (PubMed, Biochemistry (Mosc)) - "Special attention is given to successful preclinical and clinical studies that have led to the approval of gene therapies: six AAV-based (Glybera® for lipoprotein lipase deficiency, Luxturna® for retinal dystrophy, Zolgensma® for spinal muscular atrophy, Upstaza® for AADC, Roctavian® for hemophilia A, and Hemgenix® for hemophilia B) and three LV-based (Libmeldy® for infantile metachromatic leukodystrophy, Zynteglo® for β-thalassemia, and Skysona® for ALD). The review also discusses the problems that arise in the development of gene therapy treatments, which, nevertheless, do not overshadow the successes of already developed gene therapies and the hope these treatments give to long-suffering patients and their families."

Journal • Review • Viral vector • Beta-Thalassemia • CNS Disorders • Gene Therapies • Genetic Disorders • Hematological Disorders • Hemophilia • Inherited Retinal Dystrophy • Metabolic Disorders • Movement Disorders • Muscular Atrophy • Muscular Dystrophy • Ophthalmology • Rare Diseases • LPL

LTF-304: Long-term Follow-up of Participants With Cerebral Adrenoleukodystrophy Who Were Treated With Lenti-D Drug Product (clinicaltrials.gov) - P=N/A | N=64 | Active, not recruiting | Sponsor: bluebird bio | Trial completion date: May 2037 ➔ Aug 2038 | Trial primary completion date: May 2037 ➔ Aug 2038

Trial completion date • Trial primary completion date • Genetic Disorders

Evaluation of Mobilization, Apheresis, and Conditioning Regimen and Engraftment in Patients Receiving One-Time Gene Therapy with Elivaldogene Autotemcel (Eli-cel) for Cerebral Adrenoleukodystrophy (CALD) (TCT-ASTCT-CIBMTR 2024) - P2/3, P3 | " ALD-102 and ALD-104 enrolled boys aged ≤17 y with active CALD to undergo HSC mobilization with granulocyte colony-stimulating factor with or without plerixafor (mandated in ALD-104; physician discretion in ALD-102)...Transduced cells (eli-cel) were infused following myeloablation conditioning with intravenous (IV) busulfan (1.1 mg/kg [≤12 kg] or 0.8 mg/kg [>12 kg] every 6 hours ×4 days with level monitoring) with IV cyclophosphamide (50 mg/kg ×4 days; ALD-102) or IV fludarabine (40 mg/m2 ×4 days; ALD-104)... In ALD-102 and ALD-104, the mobilization, apheresis, and conditioning protocols used were effective. The AE profile was consistent with the expected effects of mobilization, apheresis, and myeloablation. These data demonstrate the utility of these approaches in achieving sufficient CD34+ cell yields and engraftment for CALD gene therapy."

Clinical • Gene therapy • CNS Disorders • Epilepsy • Gene Therapies • Genetic Disorders • Hematological Malignancies • Hepatology • Myelodysplastic Syndrome • Oncology • Transplantation • CD34

Stargazer: A Study of Participants With Cerebral Adrenoleukodystrophy (CALD) Treated With Elivaldogene Autotemcel (clinicaltrials.gov) - P=N/A | N=120 | Not yet recruiting | Sponsor: bluebird bio

New trial • Genetic Disorders

A Clinical Study to Assess the Efficacy and Safety of Gene Therapy for the Treatment of Cerebral Adrenoleukodystrophy (CALD) (clinicaltrials.gov) - P3 | N=35 | Completed | Sponsor: bluebird bio | Active, not recruiting ➔ Completed | Trial completion date: Feb 2024 ➔ Jul 2023 | Trial primary completion date: Feb 2024 ➔ Jul 2023

Gene therapy • Trial completion • Trial completion date • Trial primary completion date • Gene Therapies • Genetic Disorders

LTF-304: Long-term Follow-up of Participants With Cerebral Adrenoleukodystrophy Who Were Treated With Lenti-D Drug Product (clinicaltrials.gov) - P=N/A | N=64 | Active, not recruiting | Sponsor: bluebird bio | Enrolling by invitation ➔ Active, not recruiting

Enrollment closed • Genetic Disorders

"@bluebirdbio - #FDA Priority rev for its #genetherapy 4 #sicklecelldisease by Dec 20 Days behind @VertexPharma & @CRISPRTX dec on Dec 8 Could be @bluebirdbio's 3rd approval after Zynteglo for beta-thalassemia & Skysona for cerebral adrenoleukodystrophy https://t.co/dfVPdaBaOk" (@Gayathri_Vijayk)

FDA event • Gene therapy • Beta-Thalassemia • Gene Therapies • Genetic Disorders • Hematological Disorders • Sickle Cell Disease

Bluebird's Experience with Accelerated Approval and Efficacy Data - Discussion on the Skysona (eli-cel) Experience (ASGCT 2023) - No abstract available

Clinical

Hematopoietic stem-cell gene therapy is associated with restored white matter microvascular function in cerebral adrenoleukodystrophy. (PubMed, Nat Commun) - P2/3 | "We analyzed cerebral perfusion imaging in boys with CALD treated with autologous hematopoietic stem-cells transduced with the Lenti-D lentiviral vector that contains ABCD1 cDNA as part of a single group, open-label phase 2-3 safety and efficacy study (NCT01896102) and patients treated with allogeneic hematopoietic stem cell transplantation...Inverse correlation between gene dosage and lesion growth suggests that corrected cells contribute long-term to remodeling of brain microvascular function. Further studies are needed to explore the longevity of these effects."

Gene therapy • Journal • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Transplantation

Comparison of Outcomes in Patients with Cerebral Adrenoleukodystrophy (CALD) Receiving Elivaldogene Autotemcel (eli-cel; Lenti-D) Gene Therapy in Clinical Trials Versus Those Receiving Allogeneic Hematopoietic Stem Cell Transplant in a Contemporaneous Comparator Study (TCT-ASTCT-CIBMTR 2022) - "As of August 2021, 2 events of myelodysplastic syndrome (MDS) occurred in ALD-104. Although 2 recent MDS events are likely related to vector insertion, eli-cel appears to offer a meaningful alternative to allo-HSCT for early CALD, without immunologic complications of allo-HSCT."

Clinical • Bone Marrow Transplantation • CNS Disorders • Gene Therapies • Genetic Disorders • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Myelodysplastic Syndrome • Oncology • Transplantation • CD34

[VIRTUAL] Elivaldogene Autotemcel (eli-cel, Lenti-D) Gene Therapy for the Treatment of Cerebral Adrenoleukodystrophy: Updated Results from the Phase 2/3 ALD-102 Study and First Report on Safety Outcomes from the Phase 3 ALD-104 Study (TCT-ASTCT-CIBMTR 2021) - "Here, we report updated results from the fully enrolled ALD-102 study and initial data from study ALD-104 investigating an alternative myeloablative protocol utilizing busulfan/fludarabine in lieu of busulfan/cyclophosphamide. Boys with CALD (≤17 years) underwent hematopoietic stem cells (HSCs) mobilization with granulocyte colony-stimulating factor +/- plerixafor, followed by apheresis collection...The treatment showed a favorable benefit/risk profile with up to 71 months follow-up in ALD-102/LTF-304. Additional data from ALD-102/LTF-304 and ALD-104 will allow further insights into the clinical impact of eli-cel in CALD."

Clinical • P2/3 data • P3 data • CNS Disorders • Gene Therapies • Graft versus Host Disease • Hematological Disorders • Immunology • Oncology • Pediatrics • CD34

Safety of Autologous Hematopoietic Stem Cell Transplantation with Gene Addition Therapy for Transfusion-Dependent β-Thalassemia, Sickle Cell Disease, and Cerebral Adrenoleukodystrophy (TCT-ASTCT-CIBMTR 2020) - P=N/A; "Ex vivo gene addition therapy using lentiviral vectors (LVV) is being evaluated in patients with transfusion-dependent β-thalassemia (TDT) using betibeglogene autotemcel (beti-cel, LentiGlobin for TDT) in the HGB-204, -205, -207, and -212 studies, sickle cell disease (SCD) using LentiGlobin for SCD in HGB-205 and -206, and cerebral adrenoleukodystrophy (CALD) using Lenti-D in ALD-102...After myeloablation with busulfan (SCD, TDT) or busulfan/cyclophosphamide (CALD), patients are infused with LVV-transduced CD34+ HSCs...Summary Data from 110 patients followed for up to 5 years supports that the safety profile of gene-modified autologous HSCT does not carry the risks of GVHD, graft rejection, and long-term immunosuppression attendant to allo-HSCT. While the safety profile beyond 5-years is still being established, these data suggest that HSC gene therapy may be an acceptable therapy for patients with TDT, SCD, and CALD, particularly in patients at increased risk of..."

Clinical • CD34

Lenti-D Hematopoietic Stem Cell Gene Therapy Stabilizes Neurologic Function in Boys with Cerebral Adrenoleukodystrophy (TCT-ASTCT-CIBMTR 2020) - "Lenti-D DP appears to stabilize neurologic disease progression and continues to show favorable safety with the longest follow-up at 60.2 months. Additional follow-up is ongoing to assess durability of effects and long-term safety."

CD34

"Some drugs for #RareDisease approved in 2022 by @US_FDA 🧬Zynteglo for beta-thalassemia 🧬Skysona for adrenoleukodystrophy 💊Pyrukynd and Enjaymo for hemolytic anemia 💊Camzyos for hypertrophic cardiomyopathy 💊Relyvrio for #ALS 💉Amvuttra for amyloidosis 🩸Xenpozyme for #ASMD" (@Info_Rares)

Amyloidosis • Amyotrophic Lateral Sclerosis • Anemia • Beta-Thalassemia • Cardiomyopathy • Cardiovascular • Genetic Disorders • Hematological Disorders • Hypertrophic Cardiomyopathy • Rare Diseases

Real-World Assessment of Orphan Drugs via the New Joint Clinical Assessment Route in Europe (ISPOR-EU 2022) - "One additional publication highlighted that only one advanced therapy medicinal product (ATMP) had been approved via the new JCA route, elivaldogene autotemcel for the treatment of cerebral adrenoleukodystryophy. This review identified that no novel ODs were assessed via the new JCA EMA route for rare diseases in the pilot phase. The new EMA JCA route could provide a more homogenous clinical assessment across EU countries that could enable faster pricing and reimbursement negotiations specific to rare diseases."

Clinical • Orphan drug • Real-world evidence • Rare Diseases