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Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia

医学 地中海贫血 临床终点 胎儿血红蛋白 内科学 输血 胃肠病学 儿科 外科 临床试验 生物 胎儿 怀孕 遗传学
作者
Franco Locatelli,Peter Lang,Selim Corbacioglu,Donna A. Wall,Roland Meisel,Amanda M. Li,Josu de la Fuente,Ami J. Shah,Ben Carpenter,Janet L. Kwiatkowski,Markus Y. Mapara,Robert I. Liem,Maria Domenica Cappellini,Mattia Algeri,Antonis Kattamis,Sujit Sheth,Stephan A. Grupp,Puja Kohli,Daoyuan Shi,Leorah Ross
出处
期刊:Blood [Elsevier BV]
卷期号:142 (Supplement 1): 1053-1053 被引量:2
标识
DOI:10.1182/blood-2023-190534
摘要

Background: Exagamglogene autotemcel (exa-cel) is a non-viral cell therapy designed to reactivate fetal hemoglobin (HbF) via ex vivo CRISPR-Cas9 gene-editing of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) at the erythroid-specific enhancer region of BCL11A in patients (pts) with transfusion-dependent β-thalassemia (TDT). Here we report that in a pre-specified interim analysis, the pivotal CLIMB THAL-111 trial of exa-cel met primary and key secondary endpoints. Methods: CLIMB THAL-111 is an ongoing, 24-month (mo), phase 3 trial of exa-cel in pts age 12-35y with TDT and a history of ≥100 mL/kg/y or ≥10 U/y packed red blood cell (RBC) transfusions in the 2y before screening. Primary endpoint is transfusion independence defined as proportion of pts maintaining a weighted average hemoglobin (Hb) ≥9 g/dL without RBC transfusion for ≥12 consecutive mos (TI12). Key secondary endpoint is proportion of pts maintaining a weighted average Hb ≥9 g/dL without RBC transfusion for ≥6 consecutive mos (TI6). Evaluable pts had ≥16 mos of follow-up after exa-cel infusion. Evaluation of TI12 and TI6 started 60 days after last RBC transfusion for post-transplant support or TDT management. Pts completing trial enrolled in long-term follow-up Study 131. Mean (SD) shown except where noted. Results: As of 16 Jan 2023, 52 pts (mean age 21.5[range 12-35]y; 18[34.6%] age ≥12 to <18y; 31[59.6%] with severe genotypes [β 0/β 0 or β 0/β 0-like], median annualized transfusion volume 201.0 mL/kg) received exa-cel; median follow-up 20.4 (range 2.1-48.1) mos. Following infusion, all pts engrafted neutrophils and platelets (median 29 and 44 days, respectively). Of the 35 pts evaluable for primary and key secondary endpoints, 32 (91.4%) achieved TI12 and TI6 (95% CI: 76.9%, 98.2%; P<0.0001). Pts achieving TI12 stopped transfusions 35.2 (SD, 18.5) days after exa-cel infusion and remained transfusion independent for 22.5 (range, 13.3, 45.1) mos (Fig). For 3 pts not achieving TI12, one had reductions in annualized RBC transfusion volume of 83.9%, while the others have been transfusion-free for 7.3 mos and 4.0 mos starting 60 days after the last transfusion. For all pts, total Hb was 11.4 g/dL at Month 3 (≥12g/dL Month 6 onward) and HbF was 7.7 g/dL at Month 3 (≥ 10 g/dL Month 6 onward) with pancellular distribution (≥95% RBCs expressing HbF Month 6 onward). Proportion of edited BCL11A alleles was stable over time in bone marrow CD34 + and peripheral blood nucleated cells. Pts not yet evaluable and with sufficient follow-up were also transfusion-free. Quality-of-life (QOL) measures showed clinically significant improvements. All pts had ≥1 adverse event (AE), most were Grade 1 or 2; 46 (88.5%) pts had AEs of Grade 3 or 4 severity. Most common AEs were febrile neutropenia (61.5%), headache (53.8%), and stomatitis (50.0%). Most AEs and serious AEs (SAEs) occurred within first 6 mos after infusion. Two pts had SAEs considered related to exa-cel: headache, hemophagocytic lymphohistiocytosis (HLH), acute respiratory distress syndrome and idiopathic pneumonia syndrome (latter also considered related to busulfan) all in the context of HLH (n=1) and delayed engraftment and thrombocytopenia (both also considered related to busulfan) (n=1), which all resolved. There were no deaths, discontinuations, or malignancies. Conclusions: The CLIMB THAL-111 trial met primary and key secondary endpoints, with exa-cel treatment resulting in early and sustained increases in Hb and HbF leading to transfusion independence in >90% of pts with TDT and improved QOL. Safety profile of exa-cel was generally consistent with myeloablative busulfan conditioning and autologous transplantation. These results show exa-cel has the potential to deliver a one-time functional cure to pts with TDT.
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