Clinical Outcomes up to 3 Years Following Lentiglobin Gene Therapy for Transfusion-Dependent β-Thalassemia in the Northstar Hgb-204 Study

BACKGROUND: Autologous hematopoietic stem cell (HSC) gene therapy could be an effective treatment for transfusion-dependent β-thalassemia (TDT) without some of the limitations and risks associated with allogeneic HSC transplantation. LentiGlobin Drug Product (DP) contains autologous HSC (CD34+ cells) transduced ex vivo with the betibeglogene darolentivec (BB305) lentiviral vector encoding a human β-globin gene with the anti-sickling T87Q mutation (HbA^T87Q). The Northstar Study(HGB-204; NCT01745120) is an international, multi-center phase 1/2 clinical trial examining the safety and efficacy of LentiGlobin investigational gene therapy in patients with TDT. As of the most recent data cut (June 2, 2017), all patients have 1 to 3 years of follow-up post DP infusion.

METHODS: Patients (12-35 years of age) with TDT were enrolled at participating sites in the U.S., Australia, and Thailand. Autologous CD34+ cells were collected by mobilization and apheresis and transduced with the BB305 vector in a centralized facility. Patients underwent myeloablative conditioning with intravenous busulfan prior to infusion of transduced cells. Patients were monitored for hematologic engraftment, vector copy number (VCN), levels of HbA^T87Q, and red blood cell (RBC) transfusion requirements post-infusion. Safety data, including adverse events (AEs), vector integration site analysis, and surveillance for replication competent lentivirus (RCL), were evaluated post-infusion. The primary analysis period for the study is 24 months following infusion; patients then transition into a long-term study for an additional 13 years of follow-up.

RESULTS: Eighteen patients with TDT (8 with β⁰/β⁰ and 10 with non-β⁰/β⁰ genotypes; aged 12-35 years) received LentiGlobin DP. The median DP VCN was 0.7 (range: 0.3-1.5) copies/diploid genome, the median cell dose was 8.1 x 10⁶ (range: 5.2-18.1 x 10⁶) CD34+ cells/kg, and the proportion of transduced CD34+ cells was 17-58%. The toxicity profile observed to date has been typical of myeloablative conditioning. During a follow-up period of up to 38.3 months post-infusion (median 25.5 months; range: 14.9-38.3 months), there have been no ≥ grade 3 DP-related AEs and no evidence of clonal dominance or RCL. Serious AEs occurring after DP infusion have been reported in 6/18 (33%) patients: venoocclusive liver disease (n=2) and 1 case each of cellulitis, diarrhea, gastroenteritis, Klebisella infection, cardiac ventricular thrombosis, device-related thrombosis, and hyperglycemia. No serious AEs were considered related to DP.

Of the 10 patients with non-β⁰/β⁰ genotypes, 8 have been free of transfusions for a median of 27.1 (range 12.5-35.2) months. At their latest study visit (n=8: Months 15-36), their total Hb level ranged from 9.3-13.7 g/dL, and their HbA^T87Q level was 3.6-9.6 g/dL. The peripheral VCN ranged from 0.1−1.0. Notably, of these 8 patients, 6 have achieved "transfusion independence" (TI), defined as ≥12 months without transfusions with a weighted average Hb ≥9 g/dL. The 2 patients with non-β⁰/β⁰ genotypes who still require intermittent transfusions had annual transfusion volumes reduced by 30% and 94%; both received DP with a VCN in the lower range (DP VCNs: 0.3 and 0.4).

Two patients with β⁰/β⁰ genotypes have not received a transfusion in more than a year. At the patients' last study visit (Month 24/Month 12), total Hb levels were 9.0 and 10.2 g/dL, HbA^T87Q levels were 8.4 and 6.8 g/dL, and peripheral VCNs were 0.9 and 0.6, respectively. Six patients with β⁰/β⁰ genotypes have continued transfusions. However, their annual transfusion volumes have decreased by a median of 63% (range: 19% to 81%), from an annualized volume of 124.4-261.3 ml/kg/year at baseline to an annualized volume of 31.4-212.6 ml/kg/year (from 6 months post-infusion to data cut).

CONCLUSIONS: With up to 3 years of follow-up, the Northstar Study is the largest international gene therapy trial in TDT to date. All patients, 9 of whom have at least 2 years of follow-up, have demonstrated ongoing clinical benefit with a manageable safety profile. A total of 10 patients (8/10 with non-β⁰/β⁰, 2/10 with β⁰/β⁰ genotypes) have been able to discontinue RBC transfusions and remain clinically well. The 8/18 patients still receiving transfusions have significantly reduced annualized transfusion volumes (up to 81% and 94% in patients with β⁰/β⁰ and non-β⁰/β⁰ genotypes, respectively).