Sustained Efficacy and Safety in Adult and Pediatric Patients with Transfusion-Dependent β-Thalassemia up to 9 Years Post Treatment with Betibeglogene Autotemcel (Beti-cel)

Beti-cel gene therapy addresses the underlying cause of transfusion-dependent β-thalassemia (TDT) via autologous transplantation of hematopoietic stem and progenitor cells transduced with a functional version of the β-globin gene to produce normal adult hemoglobin (Hb), HbAT87Q. Here, we report long-term outcomes from patients treated with beti-cel. Patients with TDT who completed either a phase 1/2 (HGB-204 [NCT01745120]; HGB-205 [NCT02151526]) or phase 3 (HGB-207 [NCT02906202]; HGB-212 [NCT03207009]) beti-cel parent study and subsequently participated in the long-term, 13-year follow-up study LTF-303 (NCT02633943) were included. Efficacy (including transfusion independence [TI], defined as a weighted average Hb ≥9 g/dL without packed red blood cell transfusions for ≥12 months) and safety are reported through last follow-up. Key outcomes were also examined based on patient age at enrollment (pediatric: <18 years; adult: ≥18 years). As of January 30, 2023, 63 patients (median [range] age: 17 [4-35] years) had received beti-cel and enrolled in LTF-303, with a median (range) follow-up of 60.1 (23.8-109.5) months. In phase 3 studies, which used the commercial drug product (DP) manufacturing process, 37/41 (90.2%) patients achieved and maintained TI through last follow-up (up to 6 years; Table). In phase 1/2 studies that used an older DP manufacturing process, 15/22 (68.2%) patients achieved TI, and 14/15 sustained TI through last follow-up (up to 9 years). One patient no longer meets protocol-defined TI as a result of Hb level <9g/dL at year 6 due to acute health events unrelated to β-thalassemia, which were not attributed to loss of beti-cel treatment effect. Among all 63 patients, ≈80% of pediatric and adult patients required only 1 mobilization cycle to achieve the DP dose. Median percentage of transduced DP cells was comparable between adult and pediatric populations (78% and 80%, respectively), as were month 6 median peripheral blood vector copy number (1.4 c/dg and 1.1 c/dg) and HbAT87Q (9.4 g/dL and 8.3 g/dL). Overall, 12/63 (19.0%) patients experienced ≥1 beti-cel–related adverse event (AE); beti-cel–related AEs occurring in ≥3 patients included abdominal pain (5/63 [7.9%]) and thrombocytopenia (3/63 [4.8%]). Five patients experienced serious veno-occlusive liver disease; all 5 received defibrotide and recovered. No malignancies, insertional oncogenesis, or vector-derived replication-competent lentivirus were reported. Beti-cel is a potentially curative gene therapy for patients with TDT across ages and genotypes through achievement of TI and normal or near-normal Hb. These data will inform real-world beti-cel treatment decisions for patients with TDT.