Interim Results from the Phase 3 Hgb-207 (Northstar-2) and Hgb-212 (Northstar-3) Studies of Betibeglogene Autotemcel Gene Therapy (LentiGlobin) for the Treatment of Transfusion-Dependent β-Thalassemia

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<h3>Introduction</h3> A phase 1/2 study of betibeglogene autotemcel (beti-cel; LentiGlobin for β-thalassemia) gene therapy in patients with transfusion-dependent β-thalassemia (TDT) demonstrated stable transgene expression with up to 4.5 years follow-up and enabled some patients to achieve transfusion independence. The interim results of two phase 3 studies, HGB-207 (NCT02906202; non-β⁰/β⁰ genotypes) and HGB-212 (NCT03207009; β⁰/β⁰, β⁰/β^{+ IVS-I-110} or β^{+ IVS-I-110}/β^{+ IVS-I-110} genotypes), are presented here. <h3>Methods</h3> After G-CSF and plerixafor mobilization, autologous hematopoietic stem cells were collected via apheresis. Using a refined manufacturing process compared to the phase 1/2 study, CD34+ cells were transduced with BB305 lentiviral vector. Patients were infused with transduced cells following pharmacokinetic-adjusted, single-agent busulfan myeloablation. Target busulfan AUC was 3800–4500 (once daily) or 950–1125 (Q6H) μM*min. Statistics are shown as median (min–max). <h3>Results</h3> As of 13 Dec 2018 and 12 Apr 2019, 31 patients were treated in HGB-207 and HGB-212 with a follow-up of 8.1 (0.5–22.2) and 4.6 (1.5–15.7) months, respectively. Daily average busulfan AUC was 4450 (3709–9087) μM*min. Neutrophil and platelet engraftment were achieved at 25 (13–38) and 44 (20–84) days, respectively. Hospitalization from conditioning to discharge ranged from 30–92 days. In HGB-207, 10/11 patients followed for ≥6 months have stopped transfusions for ≥5.9 months (Figure 1). HbA^T87Q levels at Months 6 (n=11), 12 (n=8) and 18 (n=3) were 9.5, 9.2, and 9.5 g/dL, respectively, which contributed to total hemoglobin (Hb) of 11.9, 12.4, and 11.3 g/dL at these time points, respectively. Marrow myeloid:erythroid ratios in 7/8 patients at Month 12 were 0.63–1.90 versus 0.14–0.48 at baseline, indicating improved erythropoiesis. In HGB-212, 3/4 patients followed for ≥6 months stopped transfusions for ≥6 months. Total Hb at last visit ranged from 10.5–13.6 g/dL and HbA^T87Q was 9.5–12.6 g/dL at last assessment. Transfusion independence (weighted average Hb ≥9 g/dL without transfusions for ≥12 months) was achieved in 4/5 evaluable patients in HGB-207 and in the only evaluable patient in HGB-212. Post-infusion non-hematologic grade ≥3 adverse events (AEs) in ≥3 patients in either study were stomatitis (n=17), febrile neutropenia (n=11), pyrexia (n=4), epistaxis (n=3), and veno-occlusive liver disease (VOD; n=3). VOD prophylaxis with ursodiol or ursodiol/defibrotide was used in 24/31 patients. One beti-cel-related serious AE of thrombocytopenia was reported; platelet count was 63 × 10⁹/L at last visit (Month 7). All patients remain alive. <h3>Summary</h3> Following treatment with beti-cel gene therapy, 10/11 and 3/4 patients with ≥6 months follow-up have stopped transfusions in HGB-207 and HGB-212, respectively. The safety profile of treatment with beti-cel is consistent with busulfan myeloablation.