Initial Results from the Northstar Study (HGB-204): A Phase 1/2 Study of Gene Therapy for β-Thalassemia Major Via Transplantation of Autologous Hematopoietic Stem Cells Transduced Ex Vivo with a Lentiviral βΑ-T87Q -Globin Vector (LentiGlobin BB305 Drug Product)
Authors: Thompson Alexis A. , Rasko John E , Hongeng Suradej , Kwiatkowski Janet L. , Schiller Gary , von Kalle Christof , Cavazzana Marina , Leboulch Philippe , Petrusich Alexandria , Soni Sandeep , Walters Mark C. 
Published: October 2019

Abstract
Background: Hematopoietic stem cell (HSC) gene therapy has the potential to induce globin production and mitigate the need for blood transfusions in β-thalassemia major. Promising early results for 2 subjects with β0/βE -thalassemia major in the ongoing HGB-205 study suggested that transplantation with autologous CD34+ cells transduced with a replication-defective, self-inactivating LentiGlobin BB305 lentiviral vector containing an engineered β-globin gene (βA-T87Q) can be safe and yield robust production of βA-T87Qglobin resulting in rapid transfusion independence. The Northstar study (HGB-204), which uses the same lentivirus vector and analogous study design as study HGB-205, is multi-center and multi-national, and centralizes drug product manufacturing. Herein, we provide the initial data on subjects enrolled and treated in this study.
Subjects and Methods: Transfusion-dependent subjects with β-thalassemia major undergo HSC collection via mobilized peripheral blood apheresis and CD34+ cells are selected. Estimation of the mean ex-vivo vector copy number (VCN) is obtained by quantitative PCR performed on pooled colony-forming progenitors. Subjects undergo myeloablation with intravenous busulfan, followed by infusion of transduced CD34+ cells. Subjects are monitored for hematologic engraftment, βA-T87Q -globin expression (by high performance liquid chromatography) and transfusion requirements. Integration site analysis (ISA, by linear amplification-mediated PCR and high-throughput sequencing on nucleated cells) and replication-competent lentivirus (RCL) assays are performed for safety monitoring.
Results: As of 31 July 2014, 3 subjects have undergone HSC collection and ex-vivo LentiGlobin BB305 gene transfer. One subject (Subject 1102) has undergone myeloablation and drug product infusion. Outcomes data are shown in Table 1. The initial safety profile is consistent with myeloablation, without serious adverse events or gene therapy-related adverse events. This subject has increasing production of βA-T87Q-globin: the proportion of βA-T87Qglobin was 1.5%, 10.9% and 19.5% of total Hb at 1, 2 and 3 months post-infusion, respectively. This subject received pRBCs on Day +14 following drug product infusion and required no further transfusions until a single unit of pRBC was transfused on Day +96 for a Hb of 8.6 g/dL and fatigue. Two additional subjects have undergone drug product manufacture and are awaiting transplantation. Safety data related to ISA and RCL assays are pending.
Abstract 549. Table 1 Preliminary results of dosing parameters and transplantation outcomes Subject Age (years) and Gender Genotype BB305 Drug Product Day of Neutrophil Engraftment Drug Product- related Adverse Events βA-T87Q-Hb at last follow-up visit /Total Hb (g/dL) VCN CD34+ cell dose (x106 per kg) 1102 18 F β0/βE 1.0/1.1a 6.5 Day +17 None 1.77/8.6 1104 21 F β0/βE 0.7/0.7a 5.4 P P P 1106 20 F β0/β0 1.5 12.3 P P P As of 31 July 2014; P, pending a If more than one drug product were manufactured, the VCN of each drug product lot is presented.
Conclusion: The first subject treated on the Northstar study has safely undergone drug product infusion with autologous HSCs transduced with LentiGlobin BB305 lentiviral vector and is producing steadily increasing amounts of βA-T87Q-globin. Additional follow-up of this subject plus data on additional subjects who undergo drug product infusion will be presented at the meeting. Ex-vivo gene transfer of βA-T87Q-globin to autologous HSCs is a promising approach for the treatment of patients with β-thalassemia major.

Disclosures
Thompson: ApoPharma: Consultancy; Novartis: Consultancy, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding; Mast: Research Funding; Eli Lilly: Research Funding. Kwiatkowski:Shire Pharmaceuticals and Sideris Pharmaceuticals: Consultancy. Schiller:Sunesis, Amgen, Pfizer, Bristol Myers Squibb: Research Funding. Leboulch:bluebird bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Petrusich:bluebird bio, Inc.: Employment, Equity Ownership. Soni:bluebird bio, Inc.: Employment. Walters:Via Cord and AllCells, Inc.: Medical Director Other.