Clinical Outcomes Following Autologous Hematopoietic Stem Cell Transplantation with Betibeglogene Autotemcel Gene Therapy in the Phase 3 Northstar-2 and Northstar-3 Studies for Transfusiondependent b-Thalassemia (TDT)

Introduction: In a phase 1/2 study of betibeglogene autotemcel (beticel; LentiGlobin for β-thalassemia), 8/10 patients with TDT and nonβand0/βand0 genotypes and 3/8 patients with βand0/βand0 genotypes achieved transfusion independence (TI, defined as weighted average Hb of ≥9 g/dL without RBC transfusions for ≥12 months). For patients achieving TI, reductions from baseline to Month 48 were observed in median liver iron concentration (6.3 [n=11] to 2.0 [n=7] mg/g dw), median serum ferritin levels (4829 [n=10] to 937 [n=7] pmol/L) and median transferrin saturation (96.5 [n=10] to 49.0% [n=4]). At up to 5-year follow-up, vector integration was polyclonal. We present interim results of two phase 3 studies, Northstar-2 (NCT02906202; non-βand0/βand0 genotypes) and Northstar-3 (NCT03207009; βand0/βand0, βand0/βand+IVS-I-110 or βand+IVS-I110/βand+IVS-I-110 genotypes). Methods: CD34+ hematopoietic stem cells collected via mobilization/apheresis were transduced with BB305 lentiviral vector. Patients were infused with transduced cells following PK-adjusted, single-agent busulfan myeloablation. Statistics presented as median (min/max). Results: As of 12 Jun and 30 Sept 2019, 34 patients were treated in Northstar-2 and-3 with a follow-up of 11.6 (0.9a-26.3) and 8.8 (2.5a- 20.0) months; 24 patients were aged ≥12 years. Non-hematologic grade ≥3 AEs post-infusion in ≥3 patients in either study were stomatitis (n=17), febrile neutropenia (n=14), pyrexia (n=3), epistaxis (n=3), and liver veno-occlusive disease (VOD; n=3). Drug product-related AEs were abdominal pain (n=3), thrombocytopenia (n=3), leukopenia (n=1), neutropenia (n=1), and pain in extremity (n=1). All patients are alive and a polyclonal vector integration profile was demonstrated. In Northstar-2, 18/20 patients (>5 months follow-up) have not received a transfusion in >3.5 months. The primary endpoint of transfusion independence TI was achieved by 9/10 evaluable patients; duration was 15.2 (12.1a-21.3) months. Weighted average Hb during TI was 12.2 (11.4a- 12.8) g/dL. HbAandT87Q levels were 8.7, 9.3, and 9.4 at Month 6 (n=17), 12 (n=11), 18 (n=8), respectively. Myeloid:erythroid ratios in patients who achieved TI were 0.6a-1.9 at Month 12 (n=9) and 0.8a-0.9 at Month 24 (n=2) versus 0.1a-0.7 at baseline, indicating reduction of ineffective erythropoiesis. In Northstar-3, 9/11 patients followed for >6 months have stopped transfusions for ≥3 months. At Months 6 and 12, total unsupported Hb was 10.2 (8.5a-13.2) (n=10) and 13.8 (10.3a-14.0) g/dL (n=3), while HbAandT87Q was 8.3 (0a-12.0) (n=11) and 11.1 (8.8a-12.6) g/dL (n=3), respectively. Two evaluable patients achieved TI. Conclusions: After beti-cel gene therapy in Northstar-2 and-3, 18/20 patients with TDT and non-βand0/βand0 genotypes and 9/11 patients with βand0/βand0, βand0/βand+IVS-I-110 or βand+IVS-I-110/βand+IVS-I-110 genotypes, with ≥6 months of follow-up, have stopped transfusions. In Northstar2, 90% of patients achieved TI. The safety profile is consistent with that of single-agent busulfan myeloablation.