Improvement in Erythropoiesis Following Treatment with Betibeglogene Autotemcel Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia in the Phase 3 Hgb-207 Study

Background

Transfusion-dependent β-thalassemia (TDT) is a severe genetic disease requiring lifelong packed red blood cell (pRBC) transfusions and regular iron chelation treatment. Transfusions temporarily relieve anemia, but do not restore normal erythropoiesis. The goal of betibeglogene autotemcel (beti-cel; LentiGlobin for β-thalassemia) is to correct ineffective erythropoiesis and enable lifelong production of functional adult hemoglobin (Hb), thereby allowing patients to achieve transfusion independence. Here, we report outcomes of beti-cel gene therapy on ineffective erythropoiesis in the ongoing phase 3 HGB-207 study (Northstar-2; NCT02906202) in patients with TDT and non-β⁰/β⁰ genotypes.

Methods

Patients received G-CSF and plerixafor to mobilize CD34+ cells which were collected via apheresis. Cells were then transduced with BB305 lentiviral vector and infused into patients following single-agent, pharmacokinetic-adjusted, busulfan myeloablation. The primary endpoint is transfusion independence (TI; weighted average Hb ≥9 g/dL without pRBC transfusions for ≥12 months). Improvement of ineffective erythropoiesis was evaluated as an exploratory endpoint. Patients are followed for 2 years and offered participation in a long-term follow-up study, lasting 13 additional years. Data are presented as median (min-max).

Results

As of 3 March 2020, 23 patients were treated and followed for 19.4 (1.2-36.2) months. The median age at enrollment was 15 (4-34) years (<12yrs: n=8; >12 to <18 yrs: n=6; ≥18yrs: n=9). All patients achieved neutrophil engraftment and all except one patient with 1-month follow-up achieved platelet engraftment. Transfusion independence was achieved by 89% (17/19) of evaluable patients (<12 yrs: n=3; >12 to <18 yrs: n=6; ≥18 yrs: n=8) for an ongoing duration of 19.4 (12.3-31.4) months. The weighted average Hb during TI was 11.9 (9.4-12.9) g/dL.

Patients who achieved TI had improved myeloid:erythroid (M:E) ratios post-beti-cel regardless of age at drug product infusion (Table). M:E ratio increased from 1:7.3-1.6:1 at baseline (n=17) to 1:2.7-1.9:1 at Month 12 (n=16) and 1:2.8-1.5:1 at Month 24 (n=8). Normocellular bone marrow samples at Month 12 and Month 24 were observed in 36% (5/14) and 50% (4/8) of patients who achieved TI, respectively, compared to only 13% (2/16) of patients at baseline. Reticulocyte counts in patients who achieved TI improved from baseline to Month 12 and 24, with 69% (11/16) and 75% (6/8) of patients, respectively, within the normal range compared to 44% (7/16) of patients at baseline. Patients who achieved TI also had an improvement in soluble transferrin receptor (sTfR) levels regardless of age cohort (Table). Median sTfR decreased from 135.3 (65.9-235.3) nmol/L at baseline (n=17) to 55.9 (20.0-83.5) nmol/L at Month 12 (n=16) and 49.4 (24.7-67.1) nmol/L at Month 24 (n=9). Erythropoietin levels in patients who achieved TI decreased by 52.1% from 32.2 (10.2-169.6) U/L at baseline (n=16) to 15.1 (4.9-113.8) U/L at Month 12 (n=15), and by 65.1% to 12.4 (7.1-29.5) U/L at Month 24 (n=8). Finally, the hepcidin:ferritin ratio in patients who achieved TI improved from 0.01 (0.00-0.06) at baseline (n=16) to 0.02 (0.00-0.04) at Month 12 (n=17) and 0.02 (0.01-0.06) at Month 24 (n=9).

Post-infusion non-hematologic grade ≥3 treatment-emergent adverse events (AEs) reported in ≥3 patients included stomatitis (n=14), febrile neutropenia (n=8), epistaxis (n=5), pyrexia (n=4), decreased appetite (n=3), and veno-occlusive liver disease (n=3). Adverse events considered related to beti-cel by the investigator included thrombocytopenia (n=2, one event was serious), abdominal pain (n=1), pain in extremity (n=1), and tachycardia (n=1). There were no deaths and no evidence of insertional oncogenesis or hematopoietic clonal dominance.

Summary

Following treatment with betibeglogene autotemcel (beti-cel) gene therapy, 17/19 patients with transfusion-dependent β-thalassemia and non-β⁰/β⁰ genotypes achieved transfusion independence. These patients showed improvements in erythropoiesis as assessed by bone marrow biopsies and biomarkers, suggesting that the bone marrow is in the process of normalizing. The treatment regimen comprised of conditioning and beti-cel infusion had a tolerability profile consistent with the known effects of busulfan myeloablation.