NORTHSTAR-2 and 3 phase III trials of Lentiglobin show efficacy to month 16 in beta-thalassemia

bluebird bio announced new data from the Phase III Northstar-2 (HGB-207) and Phase III Northstar-3 (HGB-212) clinical studies of its LentiGlobin gene therapy for patients with transfusion-dependent beta-thalassemia (TDT). As of December 13, 2018, 20 patients who do not have beta0/beta0 genotypes have been treated in the Phase III Northstar-2 study. Patient age ranged from 8–34 years, with five pediatric (<12 years) and 15 adolescent/adult (at least 12 years) patients. Four of five evaluable patients achieved TI and maintained a median weighted average Hb of 12.4 g/dL (min–max: 11.5–12.6 g/dL). These four patients continued to maintain TI for a median duration of 13.6 months (min–max: 12–18.2 months) at the time of the data cut off. Thirteen of 14 patients with at least three months of follow-up were free from transfusions for at least three months. Total Hb levels in these patients ranged from 8.8–13.3 g/dL at the time of the last study visit. HbAT87Q levels were stable over time in patients who were free from transfusions; at Month 6 (n=10) median HbAT87Q was 9.5 g/dL and at Month 12 (n=7) median HbAT87Q was 9.3 g/dL.

An exploratory analysis was conducted with bone marrow from seven patients with 12 months of follow-up after treatment. The samples were evaluated for cellularity and myeloid to erythroid ratio. A low myeloid to erythroid ratio is a key feature of dyserythropoesis, or abnormal bone marrow red blood cell (RBC) production, characteristic of patients with TDT. In these seven patients, all of whom had stopped chronic transfusions, an increase in the myeloid to erythroid ratio was observed, suggesting improvement in RBC production.

As of April 12, 2019, 11 patients with TDT and a beta0/beta0 genotype or an IVS-I-110 mutation had been treated in the Phase III Northstar-3 study. The one patient evaluable for TI achieved and maintained it and had a total Hb of 13.6 g/dL at the Month 16 follow-up. Five patients had stopped transfusions for at least three months and had Hb levels of 10.2–13.6 g/dL at the time of the last study visit (5 – 16 months post-treatment). Of these patients, all of those who reached six months of follow-up (n=4) had HbAT87Q levels of at least 8 g/dL. Non-serious adverse events (AEs) observed during clinical studies that were attributed to LentiGlobin for TDT were hot flush, dyspnoea, abdominal pain, pain in extremities and non-cardiac chest pain. One serious adverse event (SAE) of thrombocytopenia was considered possibly related to LentiGlobin for TDT. Additional AEs observed in clinical studies were consistent with the known side effects of HSC collection and bone marrow ablation with busulfan, including SAEs of veno-occlusive disease. Data were presented at the 24th European Hematology Association (EHA) Congress in Amsterdam, the Netherlands.