Lentiglobin Gene Therapy for Transfusion-Dependent β-Thalassemia: Update from the Northstar Hgb-204 Phase 1/2 Clinical Study

BACKGROUND

Allogeneic hematopoietic stem cell (HSC) transplant is potentially curative for patients with β-thalassemia major or, as more broadly defined, transfusion dependent β-thalassemia (TDT). However, HSC transplant is generally restricted to younger patients with matched sibling donors. Gene therapy could provide a transformative treatment for a broader population of patients with TDT, including those who are older or lack an appropriate donor.

HGB-204 is an international, multi-center Phase 1/2 clinical study investigating the safety and efficacy of LentiGlobin Drug Product (DP), a gene therapy product containing autologous HSCs transduced ex vivowith the BB305 lentiviral vector, in patients with TDT. We previously reported initial data in 13 treated patients with 0 to 19 months follow-up. Study enrollment is complete, and all 18 patients have undergone DP infusion. Here, we report new results on the study's full cohort of 18 patients, 14 of whom have ≥ 6 months of follow-up, including 1 who has completed the primary 24-month analysis period.

METHODS

Patients (12 to 35 years of age) with TDT were enrolled at participating sites in the U.S., Australia, and Thailand. HSC mobilization was accomplished with granulocyte colony stimulating factor (G-CSF) and plerixafor, and HSCs were harvested by apheresis. In a centralized manufacturing facility, CD34+-selected stem cells were transduced with the BB305 lentiviral vector, which encodes the human β-globin gene engineered to contain a single point mutation (A^T87Q) and is regulated by the β-globin locus control region. Patients underwent myeloablation with intravenous busulfan, followed by infusion of transduced CD34+ cells (LentiGlobin DP). Patients were monitored for hematologic engraftment, vector copy number (VCN), hemoglobin A^T87Q (HbA^T87Q) expression, and transfusion requirements. Safety assessments including adverse clinical events (AEs), integration site analysis (ISA) and surveillance for replication competent lentivirus (RCL) were evaluated post-infusion.

RESULTS

Eighteen patients with TDT (β⁰/β⁰ [n=8], β⁰/β^E [n=6], β⁰/β⁺ [n=1], β⁰/β^x [n=1] and β⁺/β⁺ [n=2] genotypes) have received LentiGlobin DP. The median age of the 13 female and 5 male patients treated was 20 years (range: 12-35 years). The median DP VCN was 0.7 (range: 0.3-1.5 copies/diploid genome) and the median cell dose was 8.1 x 10⁶ CD34+ cells/kg (range: 5.2-18.1 x 10⁶ cells/kg). Patients engrafted with a median time of 18.5 days (range: 14-30 days) to neutrophil recovery. The toxicity profile observed was typical of myeloablative conditioning with single agent busulfan. There have been no ≥ Grade 3 DP-related AEs and no evidence of clonal dominance or RCL during a median follow-up of 14.4 months post-infusion (range: 3.7-27.0 months; cut-off date: 27 June 2016). To date, patients with at least 6 months of follow-up achieved a median HbA^T87Q level of 4.7 g/dL at 6 months (range: 1.8-8.9 g/dL; n=14), with a median VCN in peripheral blood of 0.4 (range: 0.2−1.0; n=13). Of these, all patients with non-β⁰/β⁰ genotypes and ≥12 months of follow-up (n=5) have remained free of transfusions (median 19.4 months without transfusion; range: 15.3 to 24.0 months) with a median total Hb of 11.6g/dL (range: 9.0-11.9 g/dL) at the most recent follow-up visit. While patients with β⁰/β⁰genotypes and ≥12 months of follow-up (n=5) have continued to require transfusions, annual median transfusion volumes have decreased 60% (from median 171.9 ml/kg/year at baseline [range: 168.1-223.2ml/kg/year] to 67.8 ml/kg/year post-treatment [range: 14.8-123.7 ml/kg/year]).

CONCLUSIONS

In the largest TDT gene therapy trial to date, all patients have demonstrated therapeutic Hb expression without ≥ Grade 3 DP-related AEs. The levels of HbA^T87Q in patients with at least 6 months of follow-up have exceeded the study primary endpoint (≥ 2g/dL) in 13/14 (93%) patients and are sustained in the 10 patients with ≥12 months of follow up. Compared to their baseline, all patients with β⁰/β⁰ genotypes have considerably reduced transfusion requirements. Notably, following a single infusion of LentiGlobin DP, patients with genotypes other than β⁰/β⁰ have discontinued transfusions and remain free of transfusions to date. These early results support the continued development of LentiGlobin DP as a treatment for TDT.