Lentiglobin Gene Therapy in Patients with Sickle Cell Disease: Updated Interim Results from Hgb-206

Introduction β-globin gene transfer may reduce or eliminate complications in patients with sickle cell disease (SCD). LentiGlobin gene therapy (GT) comprises drug product (DP) made from autologous hematopoietic stem cells (HSCs) transduced with the BB305 lentiviral vector (LVV) encoding β-globin with an anti-sickling T87Q substitution (HbA T87Q ). The safety and efficacy of LentiGlobin GT in adults with SCD is being evaluated in a phase 1 study, HGB-206 (NCT02140554). Patients were initially treated with DP made from bone marrow harvested (BMH) HSCs (Group [Grp] A, fully enrolled), then from DP made from BMH HSCs but using a refined manufacturing process (Grp B, fully enrolled), and subsequently from plerixafor mobilized HSCs (Grp C, currently enrolling). Objective Assess safety and feasibility of plerixafor mobilization in patients with SCD and describe outcomes of LentiGlobin GT in the HGB-206 study. Methods Adults with severe SCD (history of recurrent vaso-occlusive crisis, acute chest syndrome, stroke, or tricuspid regurgitant jet velocity of >2.5 m/s) were enrolled. Autologous CD34+ cells, collected by BMH or apheresis following mobilization with 240 µg/kg plerixafor, were transduced with BB305 LVV. After myeloablative busulfan conditioning (area under the curve goal of 5000 [range 4400—5400] µM*min daily), patients were infused with the transduced cells and monitored for safety and efficacy. Summary statistics are median (min-max). Results As of May 15, 2018, 22 patients had HSCs collected, 18 patients had DP made and 15 patients were treated. BMH was performed in 11 patients (9 in Grp A, 2 in Grp B) and mobilization/apheresis in 12 patients (1 in Grp B [also had BMH], 11 in Grp C). Median of 4.3 (0.1—10.8) × 10 6 and 10.4 (3.8—21.6) × 10 6 CD34+ cells/kg were collected per BMH (N=26) and per mobilization cycle (N=17), respectively. Eighteen grade 3 adverse events (AEs) in 6 patients were attributed to BMH and 5 grade 3 AEs in 3 patients to mobilization/apheresis. DP and treatment characteristics are shown in Table 1. DP characteristics were improved in Grp B and Grp C vs Grp A. The safety profile post-DP infusion was consistent with myeloablative conditioning and underlying SCD; most common non-hematologic grade ≥3 AEs were stomatitis, febrile neutropenia, and vaso-occlusive pain. At last visit (Table 1), HbA T87Q levels were higher in Grp B (3.2—7.2 g/dL) vs Grp A (0.5—1.2 g/dL). In 4 Grp C patients at the 3-month visit, HbA T87Q (4.1 [3.2—6.0] g/dL) levels were equal to or exceeded HbS levels (3.3 [2.8—3.8] g/dL). In 1 Grp C patient at the 6-month visit, HbA T87Q was 8.8 g/dL and total Hb was 14.2 g/dL. Conclusion These data support the safety and feasibility of plerixafor-mediated HSC collection in patients with SCD. HGB-206 protocol changes have improved LentiGlobin DP characteristics yielding higher HbA T87Q levels. Additional data will determine the clinical effect of increased HbA T87Q /HbS ratios.