BACKGROUNDBetibeglogene autotemcel (beti-cel) gene therapy for transfusion-dependent β-thalassemia contains autologous CD34+ hematopoietic stem cells and progenitor cells transduced with the BB305 lentiviral vector encoding the β-globin (β A-T87Q ) gene. METHODSIn this open-label, phase 3 study, we evaluated the efficacy and safety of beti-cel in adult and pediatric patients with transfusion-dependent β-thalassemia and a non-β 0 /β 0 genotype. Patients underwent myeloablation with busulfan (with doses adjusted on the basis of pharmacokinetic analysis) and received beti-cel intravenously. The primary end point was transfusion independence (i.e., a weighted average hemoglobin level of ≥9 g per deciliter without red-cell transfusions for ≥12 months). RESULTSA total of 23 patients were enrolled and received treatment, with a median followup of 29.5 months (range, 13.0 to 48.2). Transfusion independence occurred in 20 of 22 patients who could be evaluated (91%), including 6 of 7 patients (86%) who were younger than 12 years of age. The average hemoglobin level during transfusion independence was 11.7 g per deciliter (range, 9.5 to 12.8). Twelve months after beti-cel infusion, the median level of gene therapy-derived adult hemoglobin (HbA) with a T87Q amino acid substitution (HbA T87Q ) was 8.7 g per deciliter (range, 5.2 to 10.6) in patients who had transfusion independence. The safety profile of beti-cel was consistent with that of busulfan-based myeloablation. Four patients had at least one adverse event that was considered by the investigators to be related or possibly related to beti-cel; all events were nonserious except for thrombocytopenia (in 1 patient). No cases of cancer were observed. CONCLUSIONSTreatment with beti-cel resulted in a sustained HbA T87Q level and a total hemoglobin level that was high enough to enable transfusion independence in most patients with a non-β 0 /β 0 genotype, including those younger than 12 years of age. (Funded by Bluebird Bio; HGB-207 ClinicalTrials.gov number, NCT02906202.

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Background Transfusion-dependent β-thalassemia (TDT) is a severe genetic disease caused by impaired β-globin production leading to severe anemia and lifelong transfusion dependence. Autologous CD34+ cells encoding a βA-T87Q-globin gene (LentiGlobin for β-thalassemia) is currently being evaluated in patients with TDT. In the phase 1/2 Northstar study, 3/8 patients with β0/β0 genotypes became transfusion independent. The drug product (DP) manufacturing process (CD34+ cell transduction) was then refined to improve clinical outcomes. Interim results are presented here from the ongoing, international, single-arm, phase 3 Northstar-3 study (HGB-212; NCT03207009) evaluating LentiGlobin gene therapy in patients ≤50 years of age with TDT and either β0 or β+ IVS-I-110 mutations on both HBB alleles. Methods Patients with TDT undergo hematopoietic stem cell mobilization with G-CSF and plerixafor. CD34+ cells collected via apheresis are transduced with BB305 lentiviral vector. Patients undergo myeloablative, single-agent, pharmacokinetic-adjusted busulfan conditioning over 4 days and are infused with transduced cells. The primary efficacy endpoint is transfusion reduction (≥60% reduction in transfused red blood cell (RBC) volume post-DP infusion compared with pre-DP infusion). A key secondary endpoint is transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without RBC transfusions for ≥12 months). Patients are followed for 2 years and offered participation in a long-term follow-up study. Summary statistics presented as median (min - max). Results As of 12 April 2019, 11 patients (7 β0/β0, 2 β0/IVS-I-110, 2 homozygous IVS-I-110genotypes) were treated with LentiGlobin and have a median follow-up of 4.6 (1.5 - 15.7) months. Median age at enrollment was 17 (7 - 33) years; 3 patients were <12 years of age. DP vector copy number (VCN) and proportion of transduced cells were higher in Northstar-3 (N=11) compared to Northstar (N=18). In Northstar-3, median DP VCN was 2.5 (1.2 - 4.3) copies/diploid genome (c/dg) compared to 0.7 (0.3 - 1.5) c/dg in Northstar; 74% (34% - 83.5%) and 32% (17% - 58%) of cells were transduced in Northstar-3 versus Northstar, respectively. Median time to neutrophil and platelet engraftment was 26 (14 - 38) days and 36 (25 - 64) days, respectively; 3 patients with 1 - 3 months follow-up had not yet achieved platelet engraftment. There was one grade 3 bleeding adverse event (AE) of epistaxis from DP infusion to platelet engraftment, but no grade ≥ 3 bleeding AEs after platelet engraftment. Non-hematologic grade ≥3 AEs in ≥2 patients after DP infusion were febrile neutropenia, stomatitis, and pharyngeal inflammation. AEs considered possibly related to LentiGlobin were abdominal pain (n=2) and leukopenia and thrombocytopenia in one patient. Serious AEs after DP infusion were pyrexia (n=2), and one event each of febrile neutropenia, headache, neutropenia, stomatitis, thrombocytopenia, and congestive heart failure. Congestive heart failure occurred in a patient (screening cardiac T2* 16.6 msec) who had a fall in left ventricular ejection fraction associated with worsening of cardiac iron pre-engraftment. Three of 4 patients followed for ≥ 6 months have stopped transfusions for ≥ 6 months with total Hb of 10.5 - 13.6 g/dL at last visit. Gene therapy-derived HbAT87Q stabilized approximately 6 months after infusion and was 9.5 - 12.6 g/dL at last assessment. The fourth patient with ≥ 6 months follow-up had a Hb of 8.6 g/dL at last visit after being off transfusions for 2.8 months; however, has since received additional transfusions due to symptomatic anemia. The only patient with ≥12 months follow-up (β0/β0 genotype) achieved transfusion independence. Of the 5 patients with ≥3 to <6 months follow-up, 4 have been off transfusions for ≥2 months and one patient continues to receive transfusions. Longer follow-up and outcomes from additional patients treated will be presented. Summary Interim results from Northstar-3 indicate that refinements in the manufacturing of LentiGlobin gene therapy led to higher DP VCN and proportion of transduced cells. In patients with TDT and either a β0 or IVS-I-110 mutation at both alleles of the HBB gene, 3/4 with ≥ 6 months have stopped transfusions and one patient has achieved the protocol definition of transfusion independence. The safety profile of LentiGlobin gene therapy was generally consistent with myeloablative busulfan conditioning. Disclosures Lal: Terumo Corporation: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Insight Magnetics: Research Funding; Protagonist Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding; Novartis: Research Funding; La Jolla Pharmaceutical Company: Research Funding. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kwiatkowski:Terumo: Research Funding; Novartis: Research Funding; Imara: Consultancy; Apopharma: Research Funding. Kulozik:Bluebird Bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Porter:Celgene: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Protagonism: Honoraria; La Jolla: Honoraria; Vifor: Honoraria; Silence therapeutics: Honoraria; Bluebird bio: Consultancy, Honoraria. Thuret:Celgene: Other: investigators for clinical trials, participation on scientific/medical advisory board; Novartis: Other: investigators for clinical trials, participation on scientific/medical advisory board; Apopharma: Consultancy; BlueBird bio: Other: investigators for clinical trials, participation on scientific/medical advisory board. Elliot:bluebird bio, Inc.: Employment, Equity Ownership. Chen:bluebird bio, Inc.: Consultancy. Colvin:bluebird bio, Inc.: Employment, Equity Ownership. Thompson:bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding.

Background Transfusion-dependent β-thalassemia (TDT) is treated with regular, lifelong red blood cell (RBC) transfusions and despite iron-chelating therapy, carries a risk of serious organ damage from iron overload and other complications. Transplantation with autologous CD34+ cells encoding a βA-T87Q-globin gene (LentiGlobin for β-thalassemia) is being evaluated in patients with TDT. Interim results are presented here from the ongoing, international, single-arm, phase 3 Northstar-2 study (HGB-207; NCT02906202) of LentiGlobin gene therapy in pediatric, adolescent, and adult patients with TDT (defined by receiving ≥100 mL/kg/yr of RBCs or ≥8 RBC transfusions/yr) and non-β0/β0 genotypes. Methods Patients undergo hematopoietic stem cell (HSC) mobilization with G-CSF and plerixafor. Following apheresis, CD34+ cells are transduced with BB305 lentiviral vector and infused into patients after pharmacokinetic-adjusted, single-agent busulfan myeloablation. The primary efficacy endpoint is transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without RBC transfusions for ≥12 months). HSC engraftment, βA-T87Q-globin expression, Hb levels, detection of replication competent lentivirus (RCL), and adverse events (AE) are also assessed. Patients are followed for 2 years and offered participation in a long-term follow-up study. Summary statistics are presented as median (min - max). Results Twenty patients were treated in Northstar-2 as of 13 December 2018 and have been followed for a median of 8.1 (0.5 - 22.2) months. At enrollment, median age was 16 (8 - 34) years; 5 patients were <12 years of age. Median drug product cell dose was 8.0 (5.0 - 19.9) x106 cells/kg and vector copy number was 3.2 (1.9 - 5.6) copies/diploid genome. Time to neutrophil and platelet engraftment in the 18/20 and 15/20 evaluable patients was 22.5 (13 - 32) and 45 (20 - 84) days, respectively. Non-hematologic grade ≥3 AEs in ≥3 patients after LentiGlobin infusion included stomatitis (n=12), febrile neutropenia (n=6), pyrexia (n=4), epistaxis (n=3), and veno-occlusive liver disease (n=3). One serious AE of grade 3 thrombocytopenia was considered possibly related to LentiGlobin. No patient died, had graft failure, or had detection of RCL. No insertional oncogenesis has been observed. Gene therapy-derived HbAT87Q stabilized approximately 6 months after infusion. In adolescent and adult patients treated with LentiGlobin, median HbAT87Q at Months 6, 12 and 18 was 9.5 (n=11), 9.2 (n=8), and 9.5 (n=3) g/dL, respectively. The median total Hb without transfusions at Months 6, 12, and 18 were 11.9 (n=11), 12.4 (n=8), 12.3 (n=2) g/dL, respectively. At Month 6, 91% (10/11) of patients had total Hb of >11 g/dL without transfusions. Five adolescent and adult patients were evaluable for the primary endpoint of transfusion independence, 4 (80%) of whom achieved TI. The median weighted average Hb during TI was 12.4 (11.5 - 12.6) g/dL which compared favorably to pre-transfusion nadir Hb levels before enrollment (median 9.1 g/dL [7.5 - 10.0 g/dL]). At time of analysis, the median duration of TI was 13.6 (12.0 - 18.2) months. One patient who did not achieve TI stopped transfusions for 11.4 months but resumed transfusions due to recurrent anemia. This patient had a 71.4% reduction in RBC transfusion volume from Month 6 to Month 18 compared to baseline. Marrow cellularity and myeloid:erythroid (M:E) ratios were evaluated in 8 adolescent and adult patients with ≥12 months follow-up to assess the effect of LentiGlobin treatment on dyserythropoiesis. Seven of 8 patients had improved marrow M:E ratios at Month 12 (0.63 - 1.90) compared with baseline (0.14 - 0.48). In patients who stopped transfusions, soluble transferrin receptor levels were reduced by a median of 72% (58% - 78%) at Month 12 (n=6). Updated outcomes in adolescents and adults and outcomes in pediatric patients will be reported. Summary In this update of the Northstar-2 study of LentiGlobin gene therapy in patients with TDT and non-β0/β0 genotypes, transfusion independence was observed in 4/5 evaluable adolescent and adults and 10/11 treated patients had total Hb of >11 g/dL without transfusion support 6 months after LentiGlobin infusion. HbAT87Q stabilized approximately 6 months after treatment and patients who stopped RBC transfusions had improved erythropoiesis. A safety profile consistent with busulfan conditioning was observed after LentiGlobin gene therapy. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Walters:TruCode: Consultancy; AllCells, Inc: Consultancy; Editas Medicine: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Terumo: Research Funding; Celgene: Consultancy; Agios: Consultancy; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding. Porter:Protagonism: Honoraria; Celgene: Consultancy, Honoraria; Bluebird bio: Consultancy, Honoraria; Agios: Consultancy, Honoraria; La Jolla: Honoraria; Vifor: Honoraria; Silence therapeutics: Honoraria. Thrasher:Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Generation Bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; 4BIOCapital: Membership on an entity's Board of Directors or advisory committees. Thuret:BlueBird bio: Other: investigators for clinical trials, participation on scientific/medical advisory board; Celgene: Other: investigators for clinical trials, participation on scientific/medical advisory board; Novartis: Other: investigators for clinical trials, participation on scientific/medical advisory board; Apopharma: Consultancy. Elliot:bluebird bio, Inc.: Employment, Equity Ownership. Tao:bluebird bio, Inc.: Employment, Equity Ownership. Colvin:bluebird bio, Inc.: Employment, Equity Ownership. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria.

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