279. Clinical Outcomes of Gene Therapy with BB305 Lentiviral Vector for Sickle Cell Disease and β-Thalassemia
Authors: Marina Cavazzana, Jean-Antoine Ribeil, Emmanuel Payen, Fabien Touzot, Bénédicte Neven, Francois Lefrere, Felipe Suarez, Elisa Magrin, Yves Beuzard, Stany Chretien, Philippe Bourget, Fabrice Monpoux, Corinne Pondarré, Pablo Bartolucci, Manfred Schmidt, Christof von Kalle, Laura Sandler, Sandeep Soni, Michaela Semeraro, Wassim El Nemer, Olivier Hermine, Mariane de Montalembert, Stéphane Blanche, Salima Hacein-Bey-Abina, Philippe Leboulch
Journal: Molecular Therapy (2016)

In patients with hemoglobinopathies, transduction of hematopoietic stem cell (HSC) with a β-globin gene may induce production of functional β-globin, potentially reducing or eliminating disease symptoms. LentiGlobin™ BB305 Drug Product (DP), an investigational gene therapy product for the treatment of sickle cell disease (SCD) and β-thalassemia (βT), consists of autologous CD34+ cells transduced with the BB305 lentiviral vector. BB305 is a replication defective, self-inactivating vector using erythroid-specific globin gene regulatory elements. The vector carries an HBB gene with an anti-sickling amino acid substitution found in γ globin (T87Q) that also allows for HPLC monitoring of transgene globin levels in the subjects' blood. HGB-205 is a phase 1/2 clinical study of safety and efficacy of LentiGlobin BB305 DP in severe SCD and transfusion-dependent βT. Subjects undergo HSC collection via bone marrow harvest (SCD) or mobilization and apheresis (βT). CD34+ cells are selected and transduced with BB305 vector to produce the DP. Subjects undergo myeloablation with IV busulfan followed by DP infusion. As of 11/10/15, 5 subjects had been treated: 1 SCD and 4 βT. No replication competent lentivirus has been detected and integration site analysis shows polyclonal reconstitution without clonal dominance at all time points to date (follow-up between 2 and 23 months). No subjects have experienced drug product-related adverse events; safety observations to date are consistent with myeloablative conditioning. The subject with SCD received 5.6 × 106 CD34+ cells/per kg from two DP lots with VCN of 1.0 and 1.2. He achieved neutrophil engraftment on Day +37 and platelet engraftment on Day +91. Prior to study treatment, he had been on prophylactic transfusions to manage severe SCD symptoms including multiple vaso-occlusive crises. He stopped transfusions at Day +88 and at 12 months post DP infusion had a total Hb of 11.7 g/dL, of which approximately 49% is anti-sickling hemoglobin (47%HbAT87Q, 2% HbF). This subject has had no post-infusion pain crises or SCD-related hospitalizations. For the βT subjects the cell dose infused was 8.8 to 13.6 × 106 CD34+ cells/per kg, with VCN between 0.8 and 2.1, with neutrophil engraftment at Day +13 to +28 and platelet engraftment at Day +17 to +24. The first two βT subjects treated had genotype β0/βE. They have been transfusion independent since ~2 weeks after DP infusion, with consistent levels of total Hb (>10g/dL) and HBAT87Q (7-8 g/dL and 9-10 g/dL). The third βT subject is homozygous for the IVS1 nt 110 G>A mutation. This subject at 4.5 months of follow-up had total Hb 8.0 g/dL and had gone ~2 months without transfusion. The fourth βT subject (β0/βE) has less than 2 months follow-up. These interim data suggest that gene therapy with LentiGlobin DP is a promising potential treatment for severe SCD and transfusion-dependent βT.