Betibeglogene Autotemcel (beti-cel) Gene Addition Therapy Results in Durable Hemoglobin a Production with up to 10 Years of Follow-up with Transfusion-Dependent β-Thalassemia
Authors: Thompson Alexis , Kwiatkowski Janet L. , Schneiderman Jennifer , Thuret Isabelle , Kulozik Andreas E. , Yannaki Evangelia , Cavazzana Marina , Hongeng Suradej , Olson Timothy S. , Sauer Martin G. , Thrasher Adrian J. , Lal Ashutosh , Rasko John E. J. , Ali Shamshad , Tao Ge , Thakar Himal L. , Deora Ami , Paramore Clark , Witthuhn Niki , Walters Mark C. , Locatelli Franco 
Published: December 2024

Drs. Thompson and Kwiatkowski contributed equally.
Introduction: Beti-cel gene therapy is a one-time treatment for transfusion-dependent β-thalassemia (TDT) that adds functional copies of the β-globin gene (βT87Q) to address the underlying cause of disease. Here, we report long-term outcomes of participants treated with beti-cel with up to 10 years of follow-up.
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 parent study, treated participants were eligible for the long-term, 13-year follow-up study LTF-303 (NCT02633943). Clinical efficacy, iron homeostasis, health-related quality of life (HRQOL), and safety are reported through last follow-up visit. Key outcomes were also examined by genotype (β0/β0 vs non-β0/β0) and by participant age at enrollment (pediatric: &lt;12 years; adolescent: ≥12 years to &lt;18 years; adult: ≥18 years).
Results:As of Feb 2024, 63 participants (median [range] age: 17 [4-35] years) had received beti-cel and subsequently enrolled in LTF-303 (median [range] follow-up: 71.2 [34.5-121.4] months); 2 participants had 10 years of follow-up, 51 (81.0%) participants had at least 5 years of follow-up, and 1 participant withdrew consent after 39 months of follow-up due to personal reasons. Peripheral blood vector copy number (PB VCN) and HbAT87Q levels were stable by month 6 after infusion, sustained across studies up to 10 years, and were higher in phase 3 versus phase 1/2 studies following beti-cel drug product manufacturing optimization, which is similar to the commercial process. At last follow-up, median (range) PB VCN was 0.4 (0.1-4.9) c/dg and 1.6 (0.1-4.8) c/dg in phase 1/2 and phase 3, respectively. Among participants who achieved transfusion independence (TI) in phase 1/2 studies (15/22 [68.2%]), median (range) HbAT87Q was 7.6 (3.9-10.8) g/dL and weighted average hemoglobin (Hb) during TI was 10.24 (9.1-13.1) g/dL. In phase 3 studies, 37/41 (90.2%) participants achieved TI, median (range) HbAT87Q was 9.8 (5.1-14.3) g/dL, and weighted average Hb during TI was 11.24 (9.8-13.9) g/dL. Transduction efficiency, pharmacodynamics, TI rate, and weighted average Hb were similar across genotypes and ages. While iron overload management was at the physician's discretion, 28/37 (78.4%) phase 3 participants who achieved TI are no longer receiving iron-chelation therapy, and of those 28, 22 (78.6%) had liver iron concentration (LIC) &lt;5 mg Fe/g dry weight (dw). Among phase 1/2 and phase 3 participants who achieved and maintained TI and had baseline data, median (range) change from baseline in serum ferritin at month 24 was -907.9 (-5014 to 5539) ng/mL (n=51). At month 60, median (range) change from baseline in serum ferritin and LIC were -1951.0 (-7079 to 1345) ng/mL (n=39) and -2.2 (-20.6 to 9.6) mg Fe/g dw (n=30), respectively, indicating improvement in iron overload. Cardiac T2* remained stable and was &gt;20 msec at last follow-up in all participants who achieved TI, including 2 participants with cardiac T2* ≤20 msec at baseline. Among participants who achieved TI and had HRQOL data, clinically meaningful improvements were reported in Short Form-36 Health Survey Questionnaire (SF-36) scores at month 24 for the mental component summary and at month 36 for physical component summary (mean score increase &gt;2). Participants had sustained SF-36 physical and emotional scores above the normative population mean (50) at month 60. Clinically meaningful improvements in Pediatric Quality of Life Inventory total scores were reported at month 36, and scores remained above the normative population mean (81) at month 60. All 26 participants who achieved TI and completed a questionnaire reported an overall benefit with beti-cel. No beti-cel-related serious adverse events were reported &gt;2 years after infusion through last follow-up. No malignancies, insertional oncogenesis, or vector-derived replication-competent lentivirus were reported.
Conclusion: These data provide evidence of the sustained favorable benefit-risk profile of gene addition therapy with beti-cel in participants with TDT and will inform real-world treatment decisions.Beti-cel is a potentially curative gene addition therapy for patients with TDT across genotypes and ages through achievement of durable TI, normal or near-normal Hb, and a favorable long-term safety profile with up to 10 years of follow-up.