Results from the Hgb-207 (Northstar-2) Trial: A Phase 3 Study to Evaluate Safety and Efficacy of Lentiglobin Gene Therapy for Transfusion-Dependent β-Thalassemia (TDT) in Patients with Non-β⁰/β⁰ Genotypes

Background

Gene therapy with LentiGlobin Drug Product (DP), which contains autologous CD34+ hematopoietic stem cells transduced with the betibeglogene darolentivec (BB305) lentiviral vector, has been shown to eliminate red blood cell (RBC) transfusions in most patients with TDT with non-β⁰/β⁰ genotypes in the prior HGB-204 (Northstar) phase 1/2 study, with a safety profile consistent with myeloablative conditioning. A key finding in HGB-204 was that the average number of therapeutic gene copies per CD34+ cell (i.e. vector copy number [VCN] per diploid genome; median 0.7, range 0.3-1.5) in the DP correlated with peripheral HbA^T87Q (transgenic hemoglobin [Hb]) expression at 6 months. To optimize the proportion of patients able to achieve "transfusion independence" and increase unsupported Hb levels after treatment, a refined manufacturing process for LentiGlobin DP was used, to increase the DP VCN and the proportion of transduced cells. Herein, we report initial data from the phase 3 HGB-207 (Northstar-2) trial, recently initiated to evaluate safety and efficacy of autologous transplantation with LentiGlobin DP, using this refined manufacturing process, in patients with TDT and a non-β⁰/β⁰ genotype (NCT02906202).

Methods

The HGB-207 study is enrolling patients (12-50 years old) with TDT (≥100 mL/kg/year of packed RBCs or ≥8 pRBC transfusions/year) and a non-β⁰/β⁰ genotype. Following mobilization with G-CSF + plerixafor, CD34+ cells are harvested via apheresis. After individualized DP manufacture, patients receive myeloablative conditioning with single-agent busulfan, followed by infusion of LentiGlobin DP. Patients are followed for 2 years after infusion and can then be enrolled in a 13-year follow-up study. The primary endpoint is proportion of patients who achieve transfusion independence after DP infusion, defined as a weighted average Hb ≥9g/dL without pRBC transfusions for ≥12 months continuously. Additional endpoints include time to engraftment, adverse events (AEs), and biological parameters, including peripheral blood VCN and HbA^T87Q levels over time.

Results

As of June 2017, 17 patients have been consented; mobilization and DP manufacturing has been completed for 6 patients. DP VCN and percent CD34+ transduced cells in these 6 patients were consistently higher than those observed in the 18 patients treated in the initial HGB-204 study (Figure 1). Three female patients have been treated with LentiGlobin DP, including two 20-year-olds with β⁰/β^E and one 22-year-old homozygous for IVS-I-5 (G>C) β⁺ mutation. These 3 patients had pre-study pRBC transfusion volumes of 159-193 mL/kg/year and 2 had substantial liver iron overload at baseline. At a median follow-up of 3 (range 2-6) months, all 3 treated patients had successful engraftment; no significant veno-occlusive disease of the liver or infections and no DP-related AEs were observed. Grade ≥3 non-hematologic AEs were observed in 2 patients: hypotension (considered serious) and epistaxis in 1 and mucositis in the other. Total Hb; HbA^T87Q; and peripheral blood VCN in the 3 patients with 6, 3 and 2 months follow-up was 13.3, 8.4 and 11.2 g/dL; 9.5, 1.6 and 4.6 g/dL; and 3.4, 0.3 and 2.2, respectively. The first patient treated has been transfusion-free for 5 months. Since the time of this data cut, 2 more patients have been treated.

Summary

The refined manufacturing process used in the Northstar-2 trial yields, on average, DPs with higher VCNs and proportion of transduced cells. These improved DP parameters may translate into higher in vivo VCN and HbA^T87Q production than has been previously seen while maintaining a safety profile consistent with myeloablative conditioning. Longer follow-up on the 3 treated patients and data from approximately 5 additional treated patients will be presented.

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