Lentiglobin Gene Therapy for Transfusion-Dependent β-Thalassemia: Outcomes from the Phase 1/2 Northstar and Phase 3 Northstar-2 Studies

Introduction Transfusion-dependent β-thalassemia (TDT) is a severe genetic disease characterized by anemia, iron overload and serious comorbidities for which gene therapy may be an effective treatment option. LentiGlobin gene therapy contains autologous CD34+ hematopoietic stem cells (HSCs) transduced ex vivo with the BB305 lentiviral vector (LVV) encoding β-globin with a T87Q substitution. Objective Evaluate the efficacy and safety of LentiGlobin in patients with TDT in the phase 1/2 Northstar (HGB-204; NCT01745120) and phase 3 Northstar-2 (HGB-207; NCT02906202) studies. Methods Patients with TDT (≥100 mL/kg/yr of red blood cells [RBCs] or ≥8 RBC transfusions/yr) received G-CSF and plerixafor for mobilization and HSCs were transduced with the BB305 LVV. Patients underwent single agent busulfan myeloablative conditioning, were infused with transduced cells, and were followed for engraftment, safety, and efficacy. Statistics are presented as median (min – max). Results As of March 7, 2018, 18 patients (12 – 35 yrs) were treated in Northstar (follow-up 32.1 [23.1 – 41.9] months) and as of May 15, 2018, 11 patients (12 – 24 yrs) were treated in Northstar-2 (follow-up 8.5 [0.3 – 16.2] months). Patients received a median cell dose of 8.0 (5.0 – 19.4) CD34+ cells × 10 6 /kg in both studies. The median time to neutrophil and platelet engraftment in both studies was 19 (14 – 30) days and 44 (19 – 191) days, respectively; 1 patient in Northstar-2 (0.3 months follow-up) had not engrafted at time of analysis. Of 6 patients with platelet engraftment ≥ Day 60, 4 had non-serious bleeding events prior to engraftment. All 6 had intact spleens and 3/6 received G-CSF between Days 0 – 21. Both factors appeared associated with time to platelet engraftment. In Northstar, 8/10 patients with non-β 0 /β 0 genotypes and 2/8 patients with β 0 /β 0 genotypes achieved transfusion independence (TI; weighted average hemoglobin [Hb] ≥ 9 g/dL without RBC transfusions for ≥ 12 months). Median Hb during TI was 10.0 (9.3 – 13.1) g/dL. In Northstar-2, 7/8 patients with non-β 0 /β 0 genotypes and ≥ 6 months follow-up stopped RBC transfusions with Hb of 11.1 – 13.3 g/dL at last visit; the first patient treated achieved TI. Non-hematologic grade ≥ 3 adverse events post-infusion in ≥ 5/29 (15%) patients were stomatitis, febrile neutropenia, and pharyngeal inflammation. Veno-occlusive liver disease attributed to busulfan occurred in 4/29 patients (Table 1). There was no transplant-related mortality, vector-mediated replication competent lentivirus, or clonal dominance. Conclusion In Northstar, 80% of patients with non-β 0 /β 0 genotypes achieved TI and early Northstar-2 data suggest that patients can achieve near-normal Hb without transfusions. The safety profile of LentiGlobin is consistent with myeloablative busulfan conditioning.  Longer time to platelet engraftment was observed in few patients, but no graft failure or deaths were reported.