S140 RESULTS FROM THE PHASE 3 NORTHSTAR‐3 STUDY EVALUATING LENTIGLOBIN GENE THERAPY IN PATIENTS WITH TRANSFUSION‐DEPENDENT β‐THALASSAEMIA AND A β0 OR IVS‐I‐110 MUTATION AT BOTH ALLELES OF THE HBB GENE

Background: LentiGlobin gene therapy in transfusion‐dependent β‐thalassaemia (TDT) contains autologous CD34+ haematopoietic stem cells (HSCs) transduced ex vivo with the BB305 lentiviral vector (LVV) encoding β‐globin with a T87Q amino acid substitution. Patients with β 0 /β 0 genotypes generally have the most severe phenotype and require higher production of transgenic haemoglobin (Hb) to fully ameliorate symptoms. In the phase 1/2 Northstar study (NCT01745120), 3/8 patients with TDT and β 0 /β 0 genotypes became free from red blood cell (RBC) transfusions and 5/8 patients had a 55% median reduction in annualised RBC transfusion volume. The LentiGlobin drug product (DP) manufacturing process was then refined to improve clinical outcomes. Aims: To evaluate refined LentiGlobin gene therapy in patients with TDT and β 0 or β + IVS‐I‐110 (G→A) mutations on both HBB alleles in the ongoing, international, single‐arm, phase 3 Northstar‐3 study (HGB‐212; NCT03207009). Methods: Patients with TDT undergo HSC mobilisation with G‐CSF and plerixafor. CD34+ HSCs, collected via aphaeresis, are transduced with BB305 LVV. Patients undergo myeloablative, single‐agent, pharmacokinetic‐adjusted conditioning with busulfan and are infused with the transduced cells. The primary endpoint is transfusion reduction (≥60% reduction in transfused RBC volume post‐DP infusion compared to pre‐DP infusion). Patients are followed for 2 years and offered participation in a long‐term follow‐up study. Results: As of 14 September 2018, 10 patients have completed HSC mobilisation and DPs have been manufactured for 7 patients. Three patients (aged 7, 17, 26 yrs) have been treated with LentiGlobin (follow‐up 9.2, 4.2, 1.4 months). In treated patients, the median DP cell dose was 6.1 (min‐max: 5.9–12.9) x10 6 CD34+ cells/kg, the median DP vector copy number (VCN) was 3.3 (min‐max: 2.9–3.9) vector copies/diploid genome, and the median transduction rate was 82% (min‐max: 78–85%). The median time to neutrophil engraftment was 34 (min‐max: 14–38) days. Two patients achieved platelet engraftment at 28 and 50 days. Patient 3 had not achieved platelet engraftment as of the datacut (day +42). The first patient treated (β 0 /β 0 ) has not had any RBC transfusions since DP infusion, maintaining a total Hb of 12.8 g/dL, which consisted of 11.6 g/dL (91%) gene therapy‐derived Hb, HbA T87Q , at month 9. Investigator reported data available as of 19 November 2018 was also analyzed. Patient 1's month 12 total Hb was 13.8 g/dL. Patient 2 (β 0 /IVS‐I‐110) has been transfusion‐free for 4 months with a total Hb of 10.1 g/dL at month 6. Patient 3 (IVS‐I‐110/IVS‐I‐110) was last transfused 1.4 months after DP infusion and had a total Hb of 11.6 g/dL at month 3. Longer follow‐up and results obtained in additional patients will be presented. Non‐haematologic grade ≥3 adverse events (AEs) following DP infusion as of 19 November 2018 included stomatitis (67%) and one AE each of anal inflammation, epistaxis, febrile neutropenia, and pharyngeal inflammation. There were no serious AEs or DP‐related AEs following DP infusion. Summary/Conclusion: Early data from Northstar‐3 suggest that improvements in DP manufacturing are resulting in improved DP VCN, HbA T87Q production, and total Hb levels after treatment with LentiGlobin gene therapy for TDT. The 2 patients with ≥6 months follow‐up have stopped RBC transfusions and total Hb levels are >10 g/dL. Longer follow‐up and data from additional patients are needed to demonstrate whether the manufacturing refinements ultimately translate into improved clinical outcomes for patients with TDT and β 0 /β 0 genotypes.