Betibeglogene Autotemcel (Beti-cel) Gene Addition Therapy Results in Durable Hemoglobin A (HbA) Production with up to 10 Years of Follow-up in Participants with Transfusion-Dependent β-Thalassemia

Introduction

Beti-cel gene addition therapy is a one-time treatment for transfusion-dependent β-thalassemia (TDT) that adds functional copies of the β-globin gene (β^T87Q) to address the underlying cause of disease. Here, we report long-term outcomes of participants treated with beti-cel.

Methods

After completion of a 2-year phase 1/2 (HGB-204 [NCT01745120]; HGB-205 [NCT02151526]) or phase 3 (HGB-207 [NCT02906202]; HGB-212 [NCT03207009]) beti-cel study, participants were eligible for the long-term, 13-year follow-up study, LTF-303 (NCT02633943). Clinical efficacy, iron homeostasis, health-related quality of life, and safety are reported through last follow-up.

Results

As of Feb 2024, 63 participants (median [range] age: 17 [4-35] y) received beti-cel and subsequently enrolled in LTF-303 (median [range] follow-up: 71.2 [34.5-121.4] mo); 2 participants had 10 y of follow-up, 51 (81.0%) had at least 5 y, and 1 withdrew consent after 39 mo for personal reasons. Peripheral blood vector copy number and HbA^T87Q levels were stable by month 6, sustained across studies up to 10 y, and were higher in phase 3 vs phase 1/2 following beti-cel drug product manufacturing optimization, which is similar to the commercial process. In phase 1/2, 15/22 (68.2%) participants achieved transfusion independence (TI; median [range] weighted average hemoglobin (Hb) during TI, 10.24 [9.1-13.1] g/dL). In phase 3, 37/41 (90.2%) participants achieved TI (Figure; weighted average Hb, 11.24 [9.8-13.9] g/dL). Transduction efficiency, pharmacodynamics, TI rate, and weighted average Hb were similar across genotypes (β⁰/β⁰ vs non-β⁰/β⁰) and ages. Among phase 1/2 and phase 3 participants who achieved TI, median (range) change from baseline in serum ferritin at month 60 was -1951.0 (-7079 to 1345) ng/mL (n=39), and liver iron concentration (LIC) was -2.9 (-20.6 to 9.6) mg Fe/g dry weight (dw; n=31). At physician discretion, 28/37 (75.7%) phase 3 participants were no longer receiving iron chelation therapy, and 22 of those 28 (78.6%) had LIC <5 mg Fe/g dw. Clinically meaningful improvements in the Short Form-36 Health Survey Questionnaire (SF-36) mental component summary at month 24 and SF-36 physical component summary and Pediatric Quality of Life Inventory total score at month 36 were sustained above the normative population mean at month 60. All 26 participants who completed a questionnaire reported an overall benefit with beti-cel. No beti-cel–related serious adverse events occurred >2 y after infusion. No malignancies, insertional oncogenesis, or vector-derived replication-competent lentivirus were reported.

Conclusion

Beti-cel is a potentially curative therapy for patients with TDT across genotypes and ages through achievement of durable TI and a favorable safety profile up to 10 y. These data will inform real-world treatment decisions.