Lentiglobin Gene Therapy for Patients with Transfusion-Dependent β-Thalassemia (TDT): Results from the Phase 3 Northstar-2 and Northstar-3 Studies

Background

Transfusion-dependent β-thalassemia (TDT) is a severe genetic disease caused by impaired β-globin production, leading to severe anemia, lifelong transfusion dependence with iron overload and serious comorbidities. Gene therapy (GT) offers a potentially transformative option for these patients. LentiGlobin GT contains autologous CD34+ hematopoietic stem cells (HSCs) 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 was assessed in the phase 1/2 Northstar study in which 8/10 patients with non-β⁰/β⁰ genotypes and 3/8 patients with a β⁰/β⁰ genotype stopped transfusions. A refined manufacturing process to improve drug product (DP) characteristics is being evaluated in the studies presented here.

Methods

Northstar-2 (HGB-207; NCT02906202) and Northstar-3 (HGB-212; NCT03207009) are ongoing, international, single-arm, phase 3 studies in patients with TDT (≥ 100 mL/kg/yr of red blood cells [RBCs] or ≥ 8 RBC transfusions/yr) and non-β⁰/β⁰ genotypes or a β⁰/β⁰ genotype, respectively. HSCs were collected by apheresis after G-CSF and plerixafor mobilization. CD34+ HSCs were transduced with the BB305 LVV using a refined manufacturing process. Patients received single-agent, myeloablative busulfan conditioning and transduced cells were infused. The primary endpoint in Northstar-2 is the proportion of patients achieving transfusion independence (TI, weighted average hemoglobin [Hb] ≥ 9g/dL without RBC transfusions for ≥ 12 months continuously) and in Northstar-3 is the proportion of patients achieving transfusion reduction (≥ 60% reduction in transfused RBC volume post-DP infusion compared to pre-DP infusion). Patients were evaluated for engraftment, DP and peripheral blood vector copy number (VCN), GT-derived Hb (HbA^T87Q), adverse events (AEs), vector integration, and evidence of replication competent lentivirus (RCL). Patients are followed for 2 years and offered participation in a long-term follow-up study.

Results

Eleven patients (median age 20 [min - max: 12 - 24] years) with TDT and non-β⁰/β⁰ genotypes (5 β⁺/β⁰, 4 β^E/β⁰, 2 β⁺/β⁺) have been treated in Northstar-2 as of May 15, 2018 with a median follow-up of 8.5 (min - max: 0.3 - 16.2) months. DPs had a median cell dose of 7.4 x 10⁶ (min - max: 5.0 - 19.4 x 10⁶) CD34+ cells/kg, median VCN of 3.4 (min - max: 2.4 - 5.6) copies/diploid genome (c/dg) and a median of 82% (min - max: 53 - 90%) CD34+ cells were transduced. Median time to neutrophil and platelet engraftment was 21.5 (min - max: 16 - 28) and 44.5 (min - max: 34 - 84) days, respectively, in 10 patients; 1 patient was not yet evaluable. Serious AEs after DP infusion included 2 events of grade 4 liver veno-occlusive disease treated with defibrotide and 1 event each of hypotension, hypoxia, sepsis, and transfusion reaction, all resolved. Only 1 AE (grade 1 abdominal pain) was related to LentiGlobin. There were no deaths or graft failure and no evidence of vector-mediated RCL or clonal dominance.

Of 8 patients with ≥ 6 months follow-up, 7 have stopped RBC transfusions. At last study visit, peripheral blood VCN was 1.1 - 5.0 c/dg and total Hb was 11.1 - 13.3 g/dL of which 7.6 - 10.2 g/dL (68 - 92%) was contributed by HbA^T87Q. Median Hb at month 6 was 11.9 (min - max: 11.2 - 13.3) g/dL. The first treated patient achieved TI. The additional patient with ≥ 6 months follow-up had no transfusions for 11 months, however had a peripheral blood VCN of 0.2 c/dg and resumed transfusions due to symptomatic anemia. Bone marrow assessment of dyserythropoesis and data with longer follow-up will be presented.

Two patients, 26- and 7- years old, have been treated in Northstar-3. Both had 2 DP lots manufactured with DP VCNs of 2.9/3.3 and 3.4/3.9 c/dg and 82%/85% and 78%/78% CD34+ cells were transduced, respectively. Both successfully engrafted. Additional data for these patients will be presented.

Summary

Seven of 8 patients with TDT and non-β⁰/β⁰ genotypes produced sufficient HbA^T87Q to stop chronic transfusions following LentiGlobin GT in Northstar-2. The safety profile appears consistent with busulfan myeloablative conditioning with no grade ≥ 3 DP-related AEs. Initial results show DP characteristics in Northstar-3 are consistent with those in Northstar-2. Additional data from Northstar-3 will determine the impact of HbA^T87Q production on transfusion reduction in patients without endogenous β-globin production.