Background

Transfusion-dependent β-thalassaemia (TDT) is a severe disease, resulting in lifelong blood transfusions, iron overload, and associated complications. Betibeglogene autotemcel (beti-cel) gene therapy uses autologous haematopoietic stem and progenitor cells (HSPCs) transduced with BB305 lentiviral vector to enable transfusion independence.

Methods

HGB-212 was a non-randomised, multicentre, single-arm, open-label, phase 3 study of beti-cel in patients with TDT conducted at eight centres in France, Germany, Greece, Italy, the UK, and the USA. Patients with β⁰/β⁰, β⁰/β^+IVS-I-110, or β^+IVS-I-110/β^+IVS-I-110 genotypes, clinically stable TDT, and a transfusion history of at least 100 mL/kg per year of packed red blood cells (pRBCs) or at least eight transfusions of pRBCs per year in the 2 years before enrolment were eligible for participation. After undergoing HSPC mobilisation and busulfan-based, pharmacokinetic-adjusted myeloablative conditioning, patients were infused with beti-cel and followed up for 24 months. The primary efficacy outcome was transfusion independence, defined as weighted average haemoglobin level of 9 g/dL or above without pRBC transfusions for 12 or more months. The primary outcome was measured in all patients who received an infusion of beti-cel (transplant population); safety was evaluated in all patients who initiated study treatment (intention-to-treat population). Patients were eligible to enrol in the ongoing 13-year long-term follow-up study (for a total of 15 years), LTF-303 (registered at ClinicalTrials.gov, NCT02633943). This trial, HGB-212, was registered at ClinicalTrials.gov (NCT03207009), and is complete.

Findings

From June 8, 2017, to March 12, 2020, 20 patients were screened for eligibility. One patient was ineligible and one withdrew consent before HSPC mobilisation and myeloablative conditioning. Of the 18 patients who received beti-cel, ten (56%) were male and eight (44%) were female; 13 (72%) were younger than 18 years at the time of informed consent, and five (28%) were older than 18 years. 12 (67%) patients had β⁰/β⁰ genotypes, three (17%) had β⁰/ β^+IVS-I-110, and three (17%) had β^+IVS-I-110/β^+IVS-I-110. As of Jan 30, 2023, all patients enrolled in the long-term follow-up study and the median follow-up was 47·9 months (range 23·8–59·0). All 18 patients were evaluable for transfusion independence, with 16 (89%) of 18 reaching and maintaining transfusion independence to last follow=up (estimated effect size 89·9% [95% CI 65·3–98·6]). All patients had at least one adverse event after beti-cel infusion. There were no serious adverse events considered to be related to beti-cel, and no deaths.

Interpretation

These data demonstrate that beti-cel can allow patients with genotypes that cause severe β-thalassaemia (β⁰/β⁰, β⁰/β^+IVS-I-110, or β^+IVS-I-110/β^+IVS-I-110) to reach transfusion independence. Beti-cel offers the potential to attain near-normal haemoglobin levels for those with severe forms of TDT, and a potentially curative option without the risks and limitations of allogeneic HSPC transplantation. Patients are being followed up for a total of 15 years to assess the durability of transfusion independence and long-term safety profile of beti-cel.

Funding

Bluebird Bio, Somerville, MA, USA.

中文翻译：

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输血依赖性严重基因型 β-地中海贫血患者的 Betibeglogene autotemcel 基因治疗 （HGB-212）：一项非随机、多中心、单臂、开放标签、单剂量、3 期试验

 背景

输血依赖性 β-地中海贫血 （TDT） 是一种严重的疾病，可导致终生输血、铁超负荷和相关并发症。Betibeglogene autotemcel （beti-cel） 基因疗法使用用 BB305 慢病毒载体转导的自体造血干细胞和祖细胞 （HSPC） 来实现不依赖性输血。

 方法

HGB-212 是一项非随机、多中心、单臂、开放标签的 3 期研究，在法国、德国、希腊、意大利、英国和美国的八个中心进行，用于治疗 TDT 患者。β⁰/β⁰、β⁰/β^+IVS-I-110 或 β^+IVS-I-110/β^+IVS-I-110 基因型、临床稳定的 TDT 以及每年至少 100 mL/kg 浓缩红细胞 （pRBC） 或每年至少 8 次输血 pRBC 的患者入组前 2 年有资格参加。在接受 HSPC 动员和基于白消安的、药代动力学调整的清髓性预处理后，患者接受 beti-cel 输注并随访 24 个月。主要疗效结局是不依赖输血，定义为加权平均血红蛋白水平为 9 g/dL 或以上，12 个月或更长时间未输注 pRBC。在所有接受 beti-cel 输注的患者 （移植人群） 中测量主要结局;在所有开始研究治疗的患者 （意向治疗人群） 中评估安全性。患者有资格参加正在进行的 13 年长期随访研究 （总共 15 年），LTF-303 （注册于 ClinicalTrials.gov，NCT02633943）。这项试验 HGB-212 于 ClinicalTrials.gov （NCT03207009） 注册，现已完成。

 发现

从 2017 年 6 月 8 日至 2020 年 3 月 12 日，对 20 名患者进行了资格筛选。1 名患者不符合条件，1 名患者在 HSPC 动员和清髓性预处理之前撤回同意。在接受 beti-cel 治疗的 18 例患者中，10 例 （56%） 为男性，8 例 （44%） 为女性;13 例 （72%） 在知情同意时未满 18 岁，5 例 （28%） 年龄在 18 岁以上。12 例 （67%） 患者有 β⁰/β⁰ 基因型，3 例 （17%） β⁰/ β^+IVS-I-110,3 例 （17%） β^+IVS-I-110/β^+IVS-I-110。截至 2023 年 1 月 30 日，所有患者均参加了长期随访研究，中位随访时间为 47·9 个月（范围 23·8-59·0）。所有 18 例患者均可评估输血不依赖性，18 例患者中有 16 例 （89%） 达到并保持输血独立性至最后一次随访 = （估计效应量 89·9% [95% CI 65·3–98·6]）。所有患者在输注 beti-cel 后都至少发生了 1 次不良事件。没有被认为与 beti-cel 相关的严重不良事件，也没有死亡。

 解释

这些数据表明，beti-cel 可以使导致重度β地中海贫血（β⁰/β⁰、β⁰/β^+IVS-I-110 或 β^+IVS-I-110/β^+IVS-I-110）的基因型患者达到不依赖输血。Beti-cel 有可能使重度 TDT 患者达到接近正常的血红蛋白水平，并且是一种潜在的治愈选择，而没有同种异体 HSPC 移植的风险和局限性。患者接受了总共 15 年的随访，以评估 beti-cel 的输血独立性和长期安全性的持久性。

 资金

Bluebird Bio，美国马萨诸塞州萨默维尔。