Efficacy and safety of LentiGlobin gene therapy in patients with transfusion-dependent β-thalassemia and non-β0/β0 genotypes: Updated results from the completed phase 1/2 Northstar and ongoing phase 3 Northstar-2 studies

Abstract

Background & Aim Although advances in red blood cell (RBC) transfusion and iron chelation have improved the prognosis of patients with transfusion-dependent β-thalassemia (TDT), allogeneic hematopoietic stem cell (HSC) transplantation is the only curative therapy. LentiGlobin gene therapy is being evaluated in patients with TDT and contains autologous CD34+ cells transduced ex vivo with the BB305 lentiviral vector (LVV) encoding β-globin with a T87Q substitution. The safety and efficacy of LentiGlobin in patients with TDT (≥100 mL/kg/yr RBCs or ≥8 RBC transfusions/yr) and non-β0/β0 genotypes was evaluated in the completed Phase 1/2 Northstar (NCT01745120) study and ongoing Phase 3 Northstar-2 (NCT02906202) study using a refined manufacturing process. Methods, Results & Conclusion HSCs were mobilized (G-CSF, plerixafor), collected through apheresis and transduced with the BB305 LVV. Patients received single-agent busulfan myeloablative conditioning, were infused with transduced cells, and were followed for safety and efficacy. Statistics are presented as median (min-max). As of 14 September 2018, 10 and 16 patients with TDT and non-β0/β0 genotypes have been treated in Northstar (16-34 yrs; follow-up 36.0 [29.3-48.1] months) and Northstar-2 (8-34 yrs; follow-up 9.3 [0.7-20.4] months), respectively. All patients who have >2 months follow-up have achieved neutrophil and platelet engraftment. In Northstar, 8/10 patients with non-β0/β0 genotypes achieved transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without RBC transfusions for ≥12 months). Duration of TI was 38.0 (21.2-43.6) months; all responses are sustained. Weighted average total Hb during TI was 10.2 (9.3-13.2) g/dL. In Northstar-2, 10/11 patients with ≥3 months follow-up stopped RBC transfusions with a median total Hb of 12.0 (11.1-13.3) g/dL comprising 9.3 (7.7-10.6) g/dL gene therapy-derived Hb, HbAT87Q, at last visit. Two patients achieved TI and 5/6 patients with ≥1 year follow-up had improved myeloid:erythroid ratios (1:5.6-1:2.2 to 1:1.3-1.1:1). The most common non-hematologic grade ≥3 adverse events post-infusion (≥3 patients with non-β0/β0 genotypes in either study) were stomatitis, febrile neutropenia, irregular menstruation, epistaxis, pyrexia, and veno-occlusive liver disease. There was no transplant-related mortality or vector-mediated replication of competent lentivirus. No single integration site contributed to ≥30% of all integration sites at any time, this finding being consistent with polyclonal hematopoiesis.