Initial Results from Study Hgb-206: A Phase 1 Study Evaluating Gene Therapy By Transplantation of Autologous CD34+ Stem Cells Transduced Ex Vivo with the Lentiglobin BB305 Lentiviral Vector in Subjects with Severe Sickle Cell Disease

Background: Hematopoietic stem cell (HSC) gene transfer has the potential to reduce or eliminate the symptoms of severe sickle cell disease (SCD). Previously reported early results in a single subject with severe SCD from the ongoing study HGB-205 suggested that transplantation with autologous CD34⁺ cells transduced with a replication-defective, self-inactivating LentiGlobin BB305 lentiviral vector containing an engineered β^A-T87Q-globin gene (LentiGlobin BB305 Drug Product) is well-tolerated and yields robust production of anti-sickling HbA^T87Qat 6 months post-transplant. Here we provide initial data on subjects with severe SCD enrolled in the multi-center HGB-206 Study.

Subjects and Methods: Subjects with severe SCD undergo HSC collection via bone marrow harvest. CD34⁺ cells are selected and transduced with LentiGlobin BB305 lentiviral vector. Subjects undergo myeloablation with intravenous busulfan, followed by infusion of LentiGlobin BB305 transduced cells. Subjects are monitored for hematologic engraftment, vector copy number (VCN), β^A-T87Q -globin expression and adverse events. Integration site analysis (ISA) and replication-competent lentivirus (RCL) assays are also performed. Prophylactic pRBC transfusions are continued in subjects with SCD who are on chronic transfusion pre-transplant to maintain HbS <30%, followed by gradual taper over time.

Results: As of 31 July 2015, LentiGlobin BB305 drug product has been manufactured for 2 subjects with severe SCD, and 1 subject has been infused. Additional subjects are undergoing screening. Patient data are presented in Table 1. To date, the safety profile is consistent with autologous transplantation, without ≥ Grade 3 LentiGlobin BB305 Drug Product related adverse events. Follow-up of the infused subject and available data on additional subjects who may have undergone drug product infusion in the coming months will be presented.

Conclusions: LentiGlobin BB305 transduced cells have been manufactured for 2 subjects with severe SCD, and 1 subject has been infused with the drug product. LentiGlobin BB305 gene therapy is a promising approach to decrease the HbS levels in patients with severe sickle cell disease.

Table 1           Preliminary dosing parameters and transplantation outcomes
Subject	Age (years)/ Sex (M/F)	Genotype	VCN in Drug Producta	CD34+ cell dose (x106 /kg)	Day of Neutrophil Engraftment	Drug Product- related Adverse Events	Last Study Visit (Months Post-infusion)
206-113-1301	25/F	βS/βS	0.5/0.6	2.7	NA	NA	Pending infusion
206-114-1303	42/M	βS/βS	1.3	2.9	Day +16	None	1M
As of 31 July 2015. F=female; M= Male for gender, and months post-infusion for visit; NA, not applicable; VCN, vector copy number; a If more than one drug product was manufactured, the VCN of each drug product lot is presented.