Improvement in Iron Burden in Patients with Transfusion-Dependent β-Thalassemia (TDT) Treated with Betibeglogene Autotemcel (Beti-cel) Gene Therapy: Up to 9 Years of Follow-up

Introduction: Beti-cel is an approved, one-time gene therapy treatment for adult and pediatric patients with TDT. Beti-cel consists of autologous hematopoietic stem and progenitor cells transduced with the BB305 lentiviral vector encoding a modified β-globin gene (β^A-T87Q), which produces functional hemoglobin (Hb) and addresses the underlying genetic cause of TDT. While transfusion independence (TI) remains a critical component for assessing patient response to gene therapy, other measures, including markers of iron overload, are important for evaluating the impact of therapy and management of disease burden over time. Previously, we demonstrated that iron markers stabilized in patients who achieved TI and stopped chelation therapy. Here, we report iron management outcomes in patients who completed either a phase 1/2 or phase 3 beti-cel parent study and subsequently enrolled in the long-term follow-up study.

Methods: Patients with TDT who completed a parent beti-cel study (phase 1/2 studies: HGB-204 [NCT01745120]; HGB-205 [NCT02151526]; phase 3 studies: HGB-207 [NCT02906202]; HGB-212 [NCT03207009]) could enroll in a long-term study (LTF‑303 [NCT02633943]) for up to an additional 13 years of follow-up. In these studies, TI was defined as a weighted average Hb ≥9 g/dL without packed red blood cell transfusions for ≥12 months. Iron removal therapy was at the discretion of the treating physician. Liver and cardiac magnetic resonance imaging evaluated liver iron concentration (LIC) and cardiac T2*; serum ferritin and transferrin receptor (TfR) were assessed at regular intervals according to protocol.

Results: As of January 30, 2023, 63 patients received beti-cel; median (range) follow-up was 60.1 (23.8-109.5) months. In phase 3 studies, 37/41 (90%) patients achieved TI and maintained TI through the last follow-up, which was 5+ years for 10 patients (Figure 1). In phase 1/2 studies, 15/22 (68%) patients achieved TI; 14 of these patients maintained TI through the last follow-up, which was 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. In total, 51 patients across phase 1/2 and 3 studies achieved and maintained TI through last follow-up with 35/51 (69%) patients off chelation. Thirty of 51 patients had an LIC measurement at month 48. Of these 30 patients, 21 had an LIC <5 mg/g at month 48 post infusion. Among these 21 patients, 5 never restarted chelation after infusion (2 received phlebotomy only), 11 restarted chelation and then were able to discontinue after iron stores normalized (1 also received phlebotomy), and 5 continue to receive chelation (none had phlebotomy). The other 9 patients who had an LIC measurement at month 48 had an iron burden ≥5 mg/g. All 9 of these patients restarted chelation; 4 were able to discontinue (2 had phlebotomy) and 5 continue to receive chelation (1 had phlebotomy). Analysis of iron marker stabilization after discontinuation of chelation will be presented. The median (range) change from baseline in LIC levels at month 48 was -3.9 (-22.3 to 10.5) mg Fe/g dry weight; the median (range) change from baseline in serum ferritin was -2119.0 (-7211 to 3889) pmoL/L. Reductions from baseline in serum TfR were observed at month 36; cardiac T2* remained stable at month 48 (Table 1). Safety of beti-cel treatment largely reflected the known side effects of hematopoietic stem cell collection and the busulfan conditioning regimen.

Conclusion: In this analysis with up to 9 years of follow up, patients treated with beti-cel who achieved TI also demonstrated sustained improvements in iron burden, and the majority of patients were able to stop chelation. Collectively, these results demonstrate the long-term durability and stability of response after beti-cel gene therapy in patients with TDT.