Introduction

LentiGlobin for SCD GT contains autologous CD34+ hematopoietic stems cells (HSCs) encoding β-globin with the anti-sickling T87Q mutation (β^A-T87Q) and is being evaluated in the ongoing Phase 1/2 HGB-206 Study (NCT02140554) in patients with SCD. Levels of GT-derived hemoglobin (HbA^T87Q) in 7 initial patients (Group A) were suboptimal but were maintained for ≥ 30 months of follow-up post-treatment, suggesting durable transgene expression. To increase HbA^T87Q production, protocol and manufacturing changes were made (Group B; N=2). In addition, HSC collection by plerixafor mobilization and apheresis was instituted in Group C.

Objective

Provide an update on safety and efficacy of LentiGlobin for SCD in HGB-206 Group C.

Methods

Adults with severe SCD (including recurrent vaso-occlusive crisis [VOC] and acute chest syndrome [ACS]) were enrolled. CD34+ HSCs were harvested by apheresis following plerixafor mobilization and transduced with BB305 lentiviral vector (LVV). Patients received myeloablative busulfan conditioning, were infused with LentiGlobin drug product (DP) and monitored for adverse events (AEs), Hb fractions, and other parameters. LVV presence in transduced cells (%LVV+) was measured by qPCR of individual colonies from colony-forming unit assays from pre-infusion DP) and post-infusion from CD34+ bone marrow (BM) HSCs and peripheral blood mononuclear cells (PBMCs). Data are shown as median (min-max).

Results

As of 7 March 2019, 13 Group C patients received DP, with follow-up of 9.0 (1.0-15.2) months. All but 1 patient had neutrophil and platelet engraftment as of the data cut date. Median HbS was ≤50% of total Hb in those with ≥6 months follow-up (n=8; Figure 1). Total unsupported Hb at last visit in patients with ≥6 months of follow-up was 11.5 (10.2-15.0) g/dL, with HbA^T87Q levels of 5.3 (4.5-8.8) g/dL. Six of these 8 patients had a history of VOCs or ACS; the annualized VOC+ACS rate decreased from 5.3 (3-14) pre-treatment to 0 (0-2) post-treatment (Figure 2). A decrease in hemolysis markers was also seen post-DP. Most common non-hematologic Grade ≥ 3 AEs were febrile neutropenia (n=10) and stomatitis (n=7). Serious AEs occurred in 6 patients; the most frequent were nausea and vomiting. To date, there have been no cases of DP-related AEs, graft failure, vector-mediated replication competent lentivirus, or clonal dominance. The %LVV+ colonies from PBMCs at 9 months and BM at 12 months post-DP infusion (n=5) were 79.2 (67.0-88.4) % and 81.5 (60.6-88.1) %, respectively, indicating stable engraftment of transduced cells from DP (%LVV+ was 80 [71-88] %).

Conclusions

Patients in HGB-206 Group C show stable LentiGlobin engraftment, with median total Hb >10 g/dL and median HbS ≤50% of total Hb in those with ≥6 months follow-up. The decrease in SCD-related complications and hemolysis in this cohort demonstrate a strong therapeutic benefit of LentiGlobin in patients with SCD.

中文翻译：

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用于镰状细胞病（SCD）基因治疗（GT）的慢球蛋白：1/2 Hgb-206期研究的C组患者的最新结果

介绍

用于SCD GT的LentiGlobin包含自体CD34 +造血干细胞（HSC），其编码具有抗镰状T87Q突变（βA ^-T87Q）的β-珠蛋白，目前正在进行的1/2 HGB-206期患者研究（NCT02140554）中进行评估与SCD。在最初的7名患者（A组）中，GT衍生的血红蛋白（HbA ^T87Q）水平不理想，但在治疗后的随访中保持≥30个月，表明转基因表达持久。为了增加HbA ^T87Q的产量，对方案和制造进行了更改（B组； N = 2）。此外，在C组中建立了通过plerixa进行动员和单采的HSC收集。

目的

提供有关HGB-206 C组中LentiGlobin用于SCD的安全性和有效性的最新信息。

方法

纳入患有严重SCD（包括复发性血管闭塞性危机[VOC]和急性胸腔综合征[ACS]）的成人。CD34 + HSCs通过采血后动员采血，并用BB305慢病毒载体（LVV）进行转导。患者接受清髓性白消安调理，向患者注射LentiGlobin药物产品（DP）并监测不良事件（AE），Hb分数和其他参数。通过qPCR对转导细胞中LVV的存在情况（％LVV +）进行定量PCR，分别来自输注前DP的集落形成单位测定）和CD34 +骨髓（BM）HSC和外周血单核细胞（PBMC）的输注后集落。数据显示为中位数（最小-最大）。

结果

截至2019年3月7日，C组13例患者接受了DP治疗，随访9.0（1.0-15.2）个月。截至数据截止日期，除1名患者外，所有患者均患有中性粒细胞和血小板移植。在随访≥6个月的患者中，HbS中位数≤总Hb的50％（n = 8；图1）。随访≥6个月的患者最后一次访视时无支持的Hb总数为11.5（10.2-15.0）g / dL，HbA ^T87Q浓度为5.3（4.5-8.8）g / dL。这8例患者中有6例有VOC或ACS病史。年化VOC + ACS率从治疗前的5.3（3-14）降至治疗后的0（0-2）（图2）。DP后也观察到溶血标志物减少。最常见的≥3级非血液学不良事件是发热性中性粒细胞减少症（n = 10）和口腔炎（n = 7）。6例患者发生严重AE。最常见的是恶心和呕吐。迄今为止，还没有DP相关AE，移植失败，载体介导的复制型慢病毒或克隆优势的病例。DP输注后9个月来自PBMC的％LVV +集落和DP输注后12个月（n = 5）的BM分别为79.2（67.0-88.4）％和81.5（60.6-88.1）％，表明从DP导入的转导细胞稳定移植（％LVV +为80 [71-88]％）。

结论

HGB-206 C组患者表现出稳定的LentiGlobin植入，在≥6个月的随访中，中位总Hb> 10 g / dL，中位HbS≤总Hb的50％。该队列中SCD相关并发症的减少和溶血表明LentiGlobin对SCD患者具有强大的治疗益处。