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1102 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)

Program: Oral and Poster Abstracts
Session: 112. Thalassemia and Globin Gene Regulation: Poster I
Hematology Disease Topics & Pathways:
Biological therapies, Genetic Disorders, Thalassemia, Hemoglobinopathies, Diseases, Gene Therapy, Therapies
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Alexis A. Thompson, MD, MPH1,2, Timothy S. Olson, MD, PhD1,3, Mark C. Walters, MD4, John B. Porter, MD5*, Jennifer Schneiderman, MD, MS6, Suradej Hongeng, MD7*, Andreas Kulozik, MD, PhD8, Marina Cavazzana, MD, PhD9,10,11, Martin G. Sauer, MD12, Adrian J. Thrasher, MD, PhD13*, Isabelle Thuret, MD14*, Ashutosh Lal, MD15, John E. J. Rasko, MBBS, PhD16,17,18, Evangelia Yannaki, MD19*, Shamshad Ali, MS, MStat20*, Gloria Tao, PhD20*, Himal L. Thakar, MD20*, Ami Deora, PhD20*, Katiana Gruppioni, MPH20*, Richard A. Colvin, MD20*, Franco Locatelli, MD, PhD21,22 and Janet L. Kwiatkowski, MD, MSCE1,23

1Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
2Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA
3Cellular Therapy and Transplant Section, Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA
4UCSF Benioff Children's Hospital, Oakland, CA
5Research Department of Haematology, University College London Hospital, London, GBR
6Division of Hematology, Oncology, Neuro-oncology and Stem Cell Transplantation, Department of Pediatrics, Ann & Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL
7Department of Pediatrics, Ramathibodi Hospital, Mahidol University, Bangkok, THA
8Department of Pediatric Oncology, Hematology, and Immunology and Hopp-Children’s Tumor Center, University of Heidelberg and DKFZ, Heidelberg, Germany
9Pediatric Immunology, Imagine Institute, Paris, FRA
10Department of Biotherapy, Hospital Necker, University Paris Descartes, Paris, France
11Biotherapy Clinical Investigation Center, Inserm Assistance Publique Hôpitaux de Paris, Paris, France
12Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
13Section of Molecular and Cellular Immunology, University College London Great Ormond Street Institute of Child Health, London, GBR
14Department of Pediatrics, Hospital Timone, Marseille, France
15Division of Hematology, UCSF Benioff Children’s Hospital, Oakland, CA
16Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, Australia
17Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
18Department of Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney, NSW, AUS
19Gene and Cell Therapy Center, Hematology Department-Hematopoietic Cell Transplantation Unit, G. Papanikolaou Hospital, Thessaloniki, Greece
20bluebird bio, Inc., Somerville, MA
21Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
22Department of Pediatrics, Catholic University of the Sacred Heart, Rome, Italy
23Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA

Introduction: Beti-cel gene therapy addresses the underlying cause of transfusion-dependent β-thalassemia (TDT) by adding functional copies of a modified β-globin gene to autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) via a third-generation, self-inactivating lentiviral vector (LVV), BB305, which produces functional adult hemoglobin (Hb), HbAT87Q, in red blood cells (RBCs). Here, we report efficacy, safety, and quality of life (QOL) data from adult and pediatric patients treated with beti-cel who were followed for up to 9 years after treatment. These outcomes may inform patient selection for real-world treatment with beti-cel.

Methods: Patients with TDT who completed either a phase 1/2 (HGB-204 [NCT01745120]; HGB-205 [NCT02151526]) or phase 3 (HGB-207 [NCT02906202]; HGB-212 [NCT03207009]) beti-cel parent study and subsequently participated in the long-term, 13-year follow-up study LTF-303 (NCT02633943) were included in this analysis. Analyses were performed with data collected through January 30, 2023. Efficacy (including transfusion independence [TI], defined as a weighted average Hb ≥9 g/dL without packed RBC transfusions for ≥12 months) and safety are reported through last follow-up. QOL data are reported for studies HGB-204, HGB-207, and HGB-212 through month 36. Statistical analyses were conducted to examine key outcomes in subgroups based on patient age at enrollment (pediatric: <18 years; adult: ≥18 years).

Results: As of January 30, 2023, 63 patients (median [range] age: 17 [4-35] years) had received beti-cel in a phase 1/2 or 3 study and enrolled in LTF-303, with a median (range) follow-up of 60.1 (23.8-109.5) months. Phase 3 studies used the commercial drug product manufacturing process. Ninety percent (37/41) of phase 3 patients achieved and maintained TI through last follow-up (up to 6 years; Table 1). TI rates by study, genotype, and age for phase 3 patients are also presented in Table 1. In phase 1/2 studies that used an older drug manufacturing process, 68.2% (15/22) of patients achieved TI; 14 of these patients sustained TI through last follow-up (up to 9 years). One patient no longer meets protocol-defined TI as a result of Hb level <9g/dL at year 6 due to acute health events unrelated to β-thalassemia, which were not attributed to loss of beti-cel treatment effect. Approximately 80% of pediatric and adult patients required only one mobilization cycle to achieve the drug product dose. The median percentage of drug product cells transduced with the BB305 LVV was comparable between adult and pediatric populations (78% and 80%, respectively), as were the month 6 median peripheral blood vector copy number (1.4 c/dg and 1.1 c/dg) and HbAT87Q (9.4 g/dL and 8.3 g/dL). Adult patients reported improvements in QOL up to month 36 as assessed by the Short Form-36 Health Survey Questionnaire mental and physical component summary scores, Functional Assessment of Cancer Therapy, and EuroQol (Table 2). Pediatric Quality of Life Inventory scores will be reported at the time of presentation.

Overall, 19% (12/63) of patients experienced ≥1 beti-cel–related adverse event (AE); the most common beti-cel–related AEs (occurring in ≥3 patients) were abdominal pain (experienced in 5/63 [7.9%] patients) and thrombocytopenia (3/63 [4.8%] patients). Five patients experienced serious veno-occlusive liver disease; all 5 received defibrotide and recovered. No malignancies, insertional oncogenesis, or vector-derived replication-competent lentivirus were reported. Age subgroup safety analysis as of last follow-up will be reported in the final presentation.

Conclusion: 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.

Disclosures: Thompson: Editas: Consultancy, Research Funding; CRISPR/Vertex: Consultancy, Research Funding; Novartis: Research Funding; global blood therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Beam: Consultancy, Research Funding; bluebird bio, Inc.:: Consultancy, Research Funding. Olson: Bluebird Bio: Consultancy; Elixirgen Therapeutics: Other: DSMB; Vertex Pharmaceuticals: Consultancy, Speakers Bureau. Walters: Vertex Pharmaceuticals: Consultancy; BioChip Labs: Consultancy, Other: Medical Director; AllCells, Inc: Consultancy, Other: Medical Director; Ensoma, Inc: Consultancy. Porter: BMS, Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene, bluebird bio, Agios: Consultancy, Honoraria; Protagonism, VIFOR, Silence Therapeutics, La Jolla Pharmaceuticals: Honoraria; Silence Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Vifor: Honoraria, Membership on an entity's Board of Directors or advisory committees. Schneiderman: Therakos Mallinckrodt: Consultancy; bluebird bio, Inc: Membership on an entity's Board of Directors or advisory committees. Thrasher: Orchard Therapeutics, Rocket Pharmaceuticals, 4bio capital: Consultancy; Generation Bio: Consultancy, Current equity holder in publicly-traded company. Thuret: bluebird bio, Inc, Celgene, Novartis pharma:: Other: Participation to clinical trials; Vertex Pharmaceuticals:: Membership on an entity's Board of Directors or advisory committees. Lal: La Jolla Pharmaceuticals, Novartis: Research Funding; Bristol Myers Squibb, Forma Therapeutics, Agios, bluebird bio, Inc, Celgene,: Research Funding; Graphite Bio: Consultancy. Rasko: BeiGene: Honoraria; Rarecyte: Current holder of stock options in a privately-held company, Honoraria; Novartis: Honoraria; Bluebird Bio: Honoraria; Spark Therapeutics: Honoraria; Cynata: Honoraria; Pfizer: Consultancy, Honoraria; Woke: Current holder of stock options in a privately-held company. Ali: bluebird bio, Inc: Current Employment. Tao: bluebird bio, Inc: Current Employment, Current equity holder in publicly-traded company. Thakar: bluebird bio, Inc: Current Employment, Current equity holder in publicly-traded company. Deora: bluebird bio, Inc: Current Employment, Current equity holder in publicly-traded company. Gruppioni: bluebird bio, Inc: Current Employment, Current equity holder in private company. Colvin: bluebird bio, Inc: Current Employment, Current equity holder in publicly-traded company. Kwiatkowski: Regeneron Pharmaceuticals: Consultancy; Bluebird Bio: Research Funding; Agios Pharmaceuticals: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Chiesi Farmaceutici: Consultancy; Forma Therapeutics: Consultancy, Research Funding; BioMarin Pharmaceutical: Consultancy; Vertex Pharmaceuticals: Consultancy; Editas Medicine: Research Funding; Pfizer: Research Funding.

*signifies non-member of ASH