Northstar-3: Interim Results from a Phase 3 Study Evaluating Lentiglobin Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia and Either a β0 or IVS-I-110 Mutation at Both Alleles of the HBB Gene

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. 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.