Safety and Efficacy of Autologous CD34+ Base Edited Hematopoietic Stem Cells (BEAM-101) for the Treatment of Sickle Cell Disease with Severe Vaso-Occlusive Crises: Results from the Ongoing Phase 1/2 Beacon Study

IF 3.6 3区 医学 Q2 HEMATOLOGY
Ashish O. Gupta MD, MPH , Akshay Sharma MBBS, MSc , Haydar Frangoul MD, MS , Jignesh Dalal MD , Julie Kanter MD , Asif Alavi MD , John F. DiPersio MD, PhD , Mary Eapen MRCPI, MBBS, MS , Dr. Jennifer J. Jaroscak MD , Ernesto Ayala MD , Edward D. Ziga MD, MPH , Stacey Rifkin-Zenenberg DO , Alex C. Minella MD , Guo Chen PhD , Yinzhong Chen PhD , Priya S. Chockalingam PhD , Ling Lin PhD , Marcelyne Joseney-Antoine , Leanne Ianniello MPH , Beth Gardner BSc, EMBA, PMP , Matthew M. Heeney MD
{"title":"Safety and Efficacy of Autologous CD34+ Base Edited Hematopoietic Stem Cells (BEAM-101) for the Treatment of Sickle Cell Disease with Severe Vaso-Occlusive Crises: Results from the Ongoing Phase 1/2 Beacon Study","authors":"Ashish O. Gupta MD, MPH ,&nbsp;Akshay Sharma MBBS, MSc ,&nbsp;Haydar Frangoul MD, MS ,&nbsp;Jignesh Dalal MD ,&nbsp;Julie Kanter MD ,&nbsp;Asif Alavi MD ,&nbsp;John F. DiPersio MD, PhD ,&nbsp;Mary Eapen MRCPI, MBBS, MS ,&nbsp;Dr. Jennifer J. Jaroscak MD ,&nbsp;Ernesto Ayala MD ,&nbsp;Edward D. Ziga MD, MPH ,&nbsp;Stacey Rifkin-Zenenberg DO ,&nbsp;Alex C. Minella MD ,&nbsp;Guo Chen PhD ,&nbsp;Yinzhong Chen PhD ,&nbsp;Priya S. Chockalingam PhD ,&nbsp;Ling Lin PhD ,&nbsp;Marcelyne Joseney-Antoine ,&nbsp;Leanne Ianniello MPH ,&nbsp;Beth Gardner BSc, EMBA, PMP ,&nbsp;Matthew M. Heeney MD","doi":"10.1016/j.jtct.2025.01.040","DOIUrl":null,"url":null,"abstract":"<div><div>BEAM-101 is an investigational base edited autologous cell therapy for the treatment (tx) of SCD through upregulation of anti-sickling fetal hemoglobin (HbF). We present initial data from BEACON (NCT05456880), a Phase 1/2, single-arm, open-label study evaluating the safety and efficacy of BEAM-101 in patients (pts) with SCD with severe vaso-occlusive crises (sVOCs).</div><div>Pts aged 18–35 with SCD and ≥4 sVOCs in the 2 years pre-screening were eligible per trial criteria. After plerixafor mobilization, autologous CD34+ HSPCs were collected by leukapheresis and edited with an adenine base editor. After myeloablative conditioning with busulfan, pts received a single infusion of BEAM-101 (≥3.0 × 10<sup>6</sup> viable CD34+ cells/kg) and are monitored for 24 months (m).</div><div>As of July 2, 2024, 6 pts have been dosed. Demographics: 5/6 β<sup>S</sup>/β<sup>S</sup>, 1/6 β<sup>S</sup>/β<sup>0</sup>, 50% female, 19–27 years. Half (n=3) required a single mobilization cycle and half required 2. Pts received a mean BEAM-101 dose of 11.9 × 10<sup>6</sup> (5.2–23.4) viable CD34+ cells/kg.</div><div>Besides safety data that include all pts dosed (n=6), the following data are from pts dosed with ≥1m of follow up (n=4; 6, 5, 2, and 1m[s] post-tx, each). All 4 pts with ≥1m of follow up achieved neutrophil and platelet engraftment at a median of 17 (15–19) and 20 (11–34) days, respectively. One pt died due to respiratory failure, likely related to busulfan conditioning, 4m after infusion. In all pts dosed (n=6), there have been no ≥Grade 3 AEs or serious AEs related to BEAM-101.</div><div>Using central lab data, pts’ total Hb increased from baseline (mean 9.3 [7.9–10.9] g/dL) to 17.9, 18.2, 11.0, and 11.8 g/dL at last time point available (LTPA) for P1, P2, P3, and P4, respectively. No signs/symptoms or interventions were needed for high total Hb. All pts achieved &gt;60% HbF of non-transfused (NT) Hb (total Hb − HbA) at Month (M) 1 and sustained this elevation to the LTPA. By M1, HbS% in NT blood dropped to ≤36% in all 4 pts and was sustained through LTPA. In total blood, % F-cells were 99.6% in P1 at M6, 94.4% in P2 at M4, 52.0% in P3 at M2, and 13.3% in P4 at M1 with all pts having &gt;19 pg HbF/F-cell at LTPA. Peripheral blood editing in nucleated cells, measured in P1 (at M6) and P2 (at M3), was 69.9% and 76.1%, respectively. Markers of hemolysis have normalized or improved for all pts. No VOCs have been reported by investigators following BEAM-101 tx.</div><div>These initial data show a safety profile for BEAM-101 consistent with busulfan conditioning and autologous HSCT. Tx with BEAM-101 resulted in rapid engraftment and marked improvement of anemia in all 4 dosed pts. We observed rapid and robust HbF induction in NT blood in all post-tx assessments. No VOCs were reported by investigators post-tx. These initial data support base editing of the <em>HBG1/2</em> promoters as an effective therapeutic modality for the tx of SCD and will continue to be investigated in the ongoing BEACON study. Updated data to be presented. <em>© American Society of Hematology (2024). Reused with permission.</em></div></div>","PeriodicalId":23283,"journal":{"name":"Transplantation and Cellular Therapy","volume":"31 2","pages":"Page S22"},"PeriodicalIF":3.6000,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Transplantation and Cellular Therapy","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2666636725000624","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"HEMATOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

BEAM-101 is an investigational base edited autologous cell therapy for the treatment (tx) of SCD through upregulation of anti-sickling fetal hemoglobin (HbF). We present initial data from BEACON (NCT05456880), a Phase 1/2, single-arm, open-label study evaluating the safety and efficacy of BEAM-101 in patients (pts) with SCD with severe vaso-occlusive crises (sVOCs).
Pts aged 18–35 with SCD and ≥4 sVOCs in the 2 years pre-screening were eligible per trial criteria. After plerixafor mobilization, autologous CD34+ HSPCs were collected by leukapheresis and edited with an adenine base editor. After myeloablative conditioning with busulfan, pts received a single infusion of BEAM-101 (≥3.0 × 106 viable CD34+ cells/kg) and are monitored for 24 months (m).
As of July 2, 2024, 6 pts have been dosed. Demographics: 5/6 βSS, 1/6 βS0, 50% female, 19–27 years. Half (n=3) required a single mobilization cycle and half required 2. Pts received a mean BEAM-101 dose of 11.9 × 106 (5.2–23.4) viable CD34+ cells/kg.
Besides safety data that include all pts dosed (n=6), the following data are from pts dosed with ≥1m of follow up (n=4; 6, 5, 2, and 1m[s] post-tx, each). All 4 pts with ≥1m of follow up achieved neutrophil and platelet engraftment at a median of 17 (15–19) and 20 (11–34) days, respectively. One pt died due to respiratory failure, likely related to busulfan conditioning, 4m after infusion. In all pts dosed (n=6), there have been no ≥Grade 3 AEs or serious AEs related to BEAM-101.
Using central lab data, pts’ total Hb increased from baseline (mean 9.3 [7.9–10.9] g/dL) to 17.9, 18.2, 11.0, and 11.8 g/dL at last time point available (LTPA) for P1, P2, P3, and P4, respectively. No signs/symptoms or interventions were needed for high total Hb. All pts achieved >60% HbF of non-transfused (NT) Hb (total Hb − HbA) at Month (M) 1 and sustained this elevation to the LTPA. By M1, HbS% in NT blood dropped to ≤36% in all 4 pts and was sustained through LTPA. In total blood, % F-cells were 99.6% in P1 at M6, 94.4% in P2 at M4, 52.0% in P3 at M2, and 13.3% in P4 at M1 with all pts having >19 pg HbF/F-cell at LTPA. Peripheral blood editing in nucleated cells, measured in P1 (at M6) and P2 (at M3), was 69.9% and 76.1%, respectively. Markers of hemolysis have normalized or improved for all pts. No VOCs have been reported by investigators following BEAM-101 tx.
These initial data show a safety profile for BEAM-101 consistent with busulfan conditioning and autologous HSCT. Tx with BEAM-101 resulted in rapid engraftment and marked improvement of anemia in all 4 dosed pts. We observed rapid and robust HbF induction in NT blood in all post-tx assessments. No VOCs were reported by investigators post-tx. These initial data support base editing of the HBG1/2 promoters as an effective therapeutic modality for the tx of SCD and will continue to be investigated in the ongoing BEACON study. Updated data to be presented. © American Society of Hematology (2024). Reused with permission.
自体CD34+碱基编辑造血干细胞(BEAM-101)治疗镰状细胞病伴严重血管闭塞危像的安全性和有效性:来自正在进行的1/2期信标研究的结果
BEAM-101是一种研究性碱基编辑的自体细胞疗法,通过上调抗镰状胎儿血红蛋白(HbF)来治疗SCD。我们提供了来自BEACON (NCT05456880)的初步数据,这是一项1/2期、单臂、开放标签研究,评估BEAM-101治疗伴有严重血管闭塞危像(sVOCs)的SCD患者的安全性和有效性。年龄在18-35岁的SCD患者,在2年的预筛查中,sVOCs≥4的患者符合试验标准。动员后,用白细胞分离法收集自体CD34+造血干细胞,用腺嘌呤碱基编辑器编辑。在用busulfan进行清髓调节后,患者接受单次BEAM-101输注(≥3.0 × 106个活CD34+细胞/kg),并监测24个月(m)。截至2024年7月2日,已有6名患者服用了该药。人口统计学:5/6 βS/βS, 1/6 βS/β0,女性占50%,19-27岁。一半(n=3)需要一个动员周期,一半需要2个。患者接受的BEAM-101平均剂量为11.9 × 106(5.2-23.4)个活CD34+细胞/kg。除安全性数据包括所有给药患者(n=6)外,以下数据来自给药≥1m的患者(n=4;6、5、2和1m[s]后,每个)。随访时间≥1m的4例患者中位时间分别为17(15-19)天和20(11-34)天,均实现了中性粒细胞和血小板的植入。1例患者在输注4m后因呼吸衰竭死亡,可能与磺胺调节有关。在所有给药的患者中(n=6),没有与BEAM-101相关的≥3级ae或严重ae。根据中心实验室数据,P1、P2、P3和P4患者的总Hb从基线(平均9.3 [7.9-10.9]g/dL)分别增加到最后可用时间点(LTPA)的17.9、18.2、11.0和11.8 g/dL。高总血红蛋白不需要任何体征/症状或干预。在第(M) 1个月,所有患者的非输注(NT) Hb(总Hb − HbA) HbF均达到60%,并维持这一升高至LTPA。到M1时,所有4例患者NT血中HbS%降至≤36%,并持续至LTPA。在整个血液中,P1在M6处有99.6%的f细胞,P2在M4处有94.4%,P3在M2处有52.0%,P4在M1处有13.3%,所有患者在LTPA处都有19 pg HbF/ f细胞。有核细胞的外周血编辑,在P1 (M6)和P2 (M3)测量,分别为69.9%和76.1%。所有患者的溶血指标均恢复正常或改善。这些初步数据表明,BEAM-101的安全性与磺胺调节和自体HSCT一致。在所有4个给药患者中,BEAM-101的Tx可快速植入并显著改善贫血。在所有治疗后评估中,我们观察到NT血液中HbF的快速和强劲诱导。调查人员未发现挥发性有机化合物。这些初步数据支持HBG1/2启动子的碱基编辑作为SCD tx的有效治疗方式,并将在正在进行的BEACON研究中继续进行研究。将提供更新的数据。©美国血液学学会(2024)。在获得许可的情况下重用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
7.00
自引率
15.60%
发文量
1061
审稿时长
51 days
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信