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

Le résumé fourni par la source

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. 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. 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 (β 0 /β 0 vs non-β 0 /β 0 ) 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. 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.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.