S141 CLINICAL OUTCOMES OF LENTIGLOBIN GENE THERAPY FOR TRANSFUSION‐DEPENDENT β‐THALASSAEMIA (TDT) FOLLOWING COMPLETION OF THE NORTHSTAR (HGB‐204) STUDY

Background: While regular red blood cell (RBC) transfusions extend the lifespan of patients with transfusion‐dependent β‐thalassaemia (TDT), iron overload and end‐organ damage can result. The curative alternate, allogeneic haematopoietic stem cell (HSC) transplantation, is limited by donor availability and transplant‐related risks. LentiGlobin gene therapy in TDT is under investigation as a treatment option that may overcome some of these limitations. LentiGlobin gene therapy contains autologous CD34+ cells transduced ex vivo with the BB305 lentiviral vector (LVV) encoding β‐globin with a T87Q substitution. Aims: To evaluate the safety and efficacy of LentiGlobin gene therapy in adolescents and adults with TDT (≥ 100 mL/kg/yr of RBCs or ≥ 8 RBC transfusions/yr) in the phase 1/2 Northstar study (NCT01745120). Methods: HSCs were mobilised with G‐CSF and plerixafor and enriched CD34+ cells were transduced with the BB305 LVV. Patients received myeloablative busulfan, after which transduced HSCs were infused. Primary efficacy endpoints were sustained production of ≥ 2 g/dL of gene therapy‐derived haemoglobin (Hb), HbA T87Q , between months 18–24 and transfusion independence (TI; weighted average Hb ≥ 9 g/dL without RBC transfusions for ≥ 12 months). Patients were monitored for 2 years and offered participation in the long‐term follow‐up study, LTF‐303. Results: Eighteen patients with TDT (median age 20 [min‐max: 12–35] years) were treated in Northstar. As of 14 September 2018, median follow‐up was 38.9 (29.3–48.1) months. Median time to neutrophil and platelet engraftment was 18.5 (14–30) and 39.5 (19–191) days, respectively. There was no graft failure. Grade ≥ 3 non‐haematologic adverse events (AEs) in ≥ 25% of patients were stomatitis, febrile neutropenia, and pharyngeal inflammation. Serious AEs reported in ≥ 2 patients were thrombosis (n = 2) and liver veno‐occlusive disease (n = 2), all of which resolved. The vector integration site profile in all patients remains polyclonal. Sixteen of 18 (89%) patients met the primary endpoint of sustained production of ≥ 2 g/dL of HbA T87Q from months 18–24. Eight of 10 (80%) patients with non‐β 0 /β 0 genotypes achieved transfusion independence with a median weighted average Hb during TI of 10.2 (min‐max: 9.3–13.2 g/dL). TI has been maintained for a median of 38 (min‐max: 21‐ 44) months. The median time to last RBC transfusion after LentiGlobin infusion was 2.0 (min‐max: 0.3–5.8) months. In the 8 patients who achieved TI, median (min‐max) total Hb, RBC counts, and mean corpuscular volume (MCV) were 10.8 (9.7–14.1) g/dL, 4.1 (2.8–5.8) x10 12 /L, and 83.0 (74.2–108.6) fL at last study visit. Of 8 patients with β 0 /β 0 genotypes, 3 (38%) achieved TI for 16–21 months during any interval post‐infusion. Median time to last RBC transfusion was 19.4 (min‐max: 1.8–19.8) months. At last study visit, median (min‐max) total Hb, RBC counts, and MCV in these 3 patients were 10.3 (9.1–10.9) g/dL, 4.2 (3.4–4.4) x10 12 /L, and 82.8 (78.3–83.8) fL. Liver iron concentration as measured by magnetic resonance imaging in patients who achieved TI is shown in Figure 1. Patients re‐initiated iron chelation therapy at a median of 13 (min‐max: 2–16) months after infusion. Summary/Conclusion: With up to 4 years of follow‐up, we observed durable transfusion independence in 8/10 and 3/8 patients with non‐β 0 /β 0 genotypes and β 0 /β 0 genotypes, respectively, and a safety profile that is consistent with myeloablative conditioning. Two ongoing Phase 3 studies, Northstar‐2 and Northstar‐3, are evaluating refined manufacturing of LentiGlobin with the goal to improve patient outcomes.