Study Hgb-205: Outcomes of Gene Therapy for Hemoglobinopathies Via Transplantation of Autologous Hematopoietic Stem Cells Transduced Ex Vivo with a Lentiviral βΑ-T87Q-Globin Vector (LentiGlobin® BB305 Drug Product)

Abstract

Background: In patients with β-thalassemia major, hematopoietic stem cell (HSC) gene therapy has the potential to induce production of β-globin, γ-globin or modified β-globin in the red blood cell lineage and reduce or stop the need for blood transfusions. We have previously presented early results for 2 subjects with β0/βE -thalassemia major that 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) resulted in near-normal levels of total hemoglobin (Hb) early after HSC infusion. Herein, we provide additional follow-up data on these two subjects. Subjects and Methods: After obtaining informed consent, subjects with β-thalassemia major underwent HSC collection via peripheral blood apheresis and CD34+ cells were selected. Estimation of the mean ex- vivo vector copy number (VCN) was obtained by quantitative PCR performed on pooled colony-forming progenitors. Subjects underwent myeloablation with intravenous busulfan, followed by infusion of transduced CD34+ cells. Subjects were monitored for hematological 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 were performed. Results: As of 31 July 2014, two subjects with β0/βE thalassemia major (Subjects 1201 and 1202) have undergone infusion with drug product. The outcome of these two subjects to date is shown in Table 1. The initial safety profile is consistent with myeloablation, without serious adverse events or drug product-related adverse events. Both subjects remain transfusion independent. ISA analyses in both the subjects at 3 months shows polyclonal reconstitution. An additional 2 subjects have been enrolled in this study but have not yet undergone drug product infusion. Conclusion: In the first two subjects, early transfusion independence was achieved and has been maintained as of 31 July 2014. Further follow up data on these two subjects and additional data on subjects who have undergone drug product infusion in this study will be presented. Gene therapy using autologous HSC transduced with LentiGlobin BB305 lentiviral vector is a promising approach for the treatment of patients with β-thalassemia major. Abstract 4797. 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 Day of last pRBC transfusion Day of last follow up βA-T87Q-Hb at last follow-up visit /Total Hb (g/dL) VCNa CD34+ cell dose (x106 per kg) 1201 19 F β0/βE 1.5 8.9 Day +13 None Day +10 Day +180 7.2/10.2 1202 16 M β0/βE 2.1 13.6 Day +15 None Day +12 Day +90 6.8/11.0 As of 31 July 2014 a VCN, mean vector copy number Disclosures Payen: bluebird bio, Inc: Consultancy. Beuzard:bluebird bio, Inc: Consultancy, Equity Ownership. Sandler:bluebird bio, Inc: Employment, Equity Ownership. Soni:bluebird bio, Inc.: Employment, Equity Ownership. De Montalembert:Novartis : Speakers Bureau. Leboulch:bluebird bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Gene Therapy of the β-Hemoglobinopathies by Lentiviral Transfer of the βA(T87Q)-GlobinGene

“…Initial results have been presented at scientific meetings but not yet published, and the trial is ongoing. 157–159 All of the four treated β-TM subjects have so far become transfusion independent, and the treated SCD subject shows early clinical benefit.…”

“…The LG001 and HGB-205 were the first gene therapy studies worldwide to treat β-TM and SCD subjects, respectively, achieving the first conversion to long-term transfusion independence of a β-TM subject 15 , 141 , 157 , 158 and the first evidence of clinical benefit in SCD. 159 …”

Current and future alternative therapies for beta-thalassemia major

“…Methods for selecting and amplifying transduced stem cells may be required to maximize efficacy in such a context of reduced conditioning [195] . Finally, although recent gene and cell therapy trials involving LV-mediated gene transfer in HSCs followed by autologous cell transplantation gave excellent outcomes, with no observable toxicity [175] , [184] , [196] , [197] , it is still too early to draw any firm conclusions about the risk of insertional mutagenesis. Gene vector targeting and gene modification by homologous recombination [198] remain suboptimal, but research is continuing.…”

“…Very encouraging results have been obtained for transfusion-dependent beta-thalassemia major patients, and were presented by the corresponding clinical investigators at the annual meeting of the American Society of Hematology (ASH) in December 2014 [184] , [185] . For the HGB-205 trial, transplantation was carried out in two transfusion-dependent β E /β 0 patients.…”

Cell and Gene Therapy for the Beta-Thalassemias: Advances and Prospects

“…Seven thalassemia subjects have been infused with CD34+ cells transduced with BB305, with clinical benefit in patients with b + -or b E -thalassemia but not in patients with b 0 -thalassemia. 27 The New York trial, which has been conducted in close collaboration with Aurelio Maggio in Palermo, Sicily, and Paolo Moi and the late Renzo Galanello in Cagliari, Sardinia, opened in 2012, enrolling adult subjects with transfusion-dependent betathalassemia major who lack an HLA-matched donor. The treatment is based on the administration of autologous CD34 + hematopoietic cells transduced with the TNS9.3.55 vector, a lentiviral vector encoding the wild-type human b-globin gene.…”