New data from Phase 1/II HGB-206 study of LentiGlobin gene therapy in patients with sickle cell disease.-bluebird bio.

bluebird bio, Inc. announced new data from patients in Group C of its ongoing Phase 1/II HGB-206 study of the company�s investigational LentiGlobin gene therapy in patients with sickle cell disease (SCD) at the 60th Annual Meeting of the American Society of Hematology (ASH). SCD is a serious, progressively debilitating and life-threatening genetic disease. SCD results from production of abnormal sickle hemoglobin (HbS), which leads to sickled red blood cells (RBCs) and hemolysis.

�After patients with sickle cell disease were treated with LentiGlobin they began to produce gene-therapy derived HbAT87Q, which was associated with lower levels of sickling hemoglobin, the type of hemoglobin that damages red blood cells,� said David Davidson, M.D., chief medical officer, bluebird bio. �These clinical findings were consistent with results in newly developed exploratory assays used to evaluate patient samples that demonstrated reduction of HbS in most red blood cells, and a reduction in sickling comparable to sickle-trait, suggesting the potential for LentiGlobin to fundamentally improve the underlying red blood cell pathology responsible for the clinical consequences of sickle cell disease.

Many patients with SCD live with severe anemia and vaso-occlusive events which include severe, recurrent pain crises that lead to organ damage and shortened life span..

HGB-206: Phase 1/II Study of LentiGlobin for Sickle Cell Disease : HGB-206 is an ongoing, Phase 1/II open-label study designed to evaluate the efficacy and safety of LentiGlobin gene therapy for the treatment of adults with SCD. A total of nine patients were treated with LentiGlobin in Group C in HGB-206. As of the data cut-off of September 14, 2018, data was available for seven patients who were at least three months post treatment.A refined LentiGlobin manufacturing process intended to increase vector copy number (VCN) as well as changes to improve engraftment of gene-modified stem cells, was used for Group C. Group C patients also received LentiGlobin gene therapy made from hematopoietic stem cells (HSCs) collected from peripheral blood after mobilization with plerixafor rather than via bone marrow harvest.

HGB-206: Group C Efficacy: In patients who were six months post treatment (n=4), the production of gene therapy-derived hemoglobin, HbAT87Q, ranged from 4.8 � 8.8 g/dL and were comparable to or exceeded the levels of sickle hemoglobin, HbS. These patients did not receive a blood transfusion during this time and had total hemoglobin ranging from 9.9 � 13.7 g/dL at their last visit. No vaso-occlusive events were reported as of the data cut-off (up to nine months post treatment with LentiGlobin). In an exploratory analysis, key markers of hemolysis, including reticulocyte counts, lactate dehydrogenase (LDH) and total bilirubin concentration had decreased compared to baseline.

To help assess the distribution of HbAT87Q in the red blood cells, bluebird bio has developed an antibody that recognizes betaS, the protein present in HbS. Using this antibody, the amount of betaS was measured in the red blood cells obtained from healthy donors (betaA/betaA), sickle cell trait donors (betaS/betaA) and patients with sickle cell disease (betaS/betaS). Clear and distinct distribution of ?S was observed in these control samples, with highest expression in the betaS/betaS samples, followed by betaS/betaA and no expression of betaS in the healthy donor (betaA/betaA) samples. Initial results from two patients treated with LentiGlobin gene therapy, who were nine months post treatment, showed that nearly all their red blood cells had lower amounts of betaS than the betaS/betaS and the betaS/betaA control samples. Given that these patients were no longer receiving any blood transfusions, this suggests betaS expression was reduced in these patients due to the production of HbAT87Q following treatment with LentiGlobin.

HGB-206 Safety : As of the data cut-off date, the safety profile of LentiGlobin remains generally consistent with underlying SCD and myeloablative conditioning. A serious adverse event (SAE) of myelodysplasia syndrome was reported in a patient who received LentiGlobin approximately three years ago in Group A of the Phase 1/II HGB-206 study. Analysis of the patient�s cells showed no evidence of vector mediated insertional oncogenesis, and the independent data monitoring committees, along with the treating physician, agreed the SAE was unlikely related to LentiGlobin gene therapy.

Comment:Bluebird plans to expand the cohort that is treated with the modified version of LentiGlobin in its HGB-206 study and aims to begin a Phase III U.S. study in sickle cell next year..