Etranacogene dezaparvovec, the first gene therapy approved for haemophilia B treatment, was shown to be superior to treatment with continuous prophylactic factor IX in terms of bleeding protection 18 months after gene therapy in a phase 3 trial. We report post-hoc 24-month efficacy and safety data from this trial to evaluate the longer-term effects of etranacogene dezaparvovec in individuals with haemophilia B. The phase 3 HOPE-B trial enrolled males aged 18 years or older with inherited haemophilia B, classified as severe (plasma factor IX activity level <1%) or moderately severe (plasma factor IX activity level ≥1% and ≤2%), with a severe bleeding phenotype and who were on stable continuous factor IX prophylaxis. Participants were treated with a single infusion of etranacogene dezaparvovec (2 × 10 genome copies per kg of bodyweight). The primary endpoint, reported previously, was non-inferiority of the annualised bleeding rate (ABR) during the 52 weeks following stable factor IX expression (defined as months 7–18 after treatment) versus an at least 6-month lead-in period in which participants received their usual continuous factor IX prophylaxis, and is updated here up to month 24. Additional, post-hoc efficacy analyses, including adjusted ABR, factor IX activity, participants within factor IX ranges, and factor IX use, and safety analyses were performed at 24 months after gene therapy. Data were analysed in the full analysis set, which comprised the 54 patients who received at least a partial dose of gene therapy. The trial is ongoing and is registered with , number . The study began on June 27, 2018, and participants were treated between January, 2019, and March, 2020; the date of data cutoff was April 21, 2022. 54 adult males (40 White, two Asian, one Black or African American, 11 other or missing) received a single intravenous infusion of etranacogene dezaparvovec and were followed for a median of 26·51 months (IQR 24·54–27·99), after a lead-in period of 7·13 months (6·51–7·82). In the updated analysis comparing months 7–24 after gene therapy to the lead-in period, mean adjusted ABR significantly reduced from 4·18 to 1·51 (p=0·0002) for all bleeds and from 3·65 to 0·99 (p=0·0001) for factor IX-treated bleeds. During each 6-month period after gene therapy, at least 67% of participants experienced no bleeding (36 of 54 during months 0–6 and stable thereafter), compared with 14 (26%) of 54 during the lead-in period. 24 months after gene therapy, 1 (2%) participant had one-stage factor IX activity less than 5%, whereas 18 (33%) had factor IX activity more than 40% (non-haemophilia range), with mean factor IX activity stable and sustained at 36·7% (SD 19·0%). 52 (96%) of 54 participants expressed endogenous factor IX, remaining free of factor IX prophylaxis at month 24. No new safety concerns were identified and no treatment-related serious adverse events or treatment-related deaths occurred. The most common treatment-related adverse events were an increase in alanine aminotransferase (nine [17%] of 54 patients), headache (eight [15%]), influenza-like illness (seven [13%]), and an increase in aspartate aminotransferase (five [9%]). By providing durable disease correction throughout the 24 months after gene therapy, etranacogene dezaparvovec provides a safe and effective therapeutic option for patients with severe or moderately severe haemophilia B. uniQure and CSL Behring.

中文翻译：

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Etranacogene dezaparvovec 治疗 B 型血友病的基因疗法 (HOPE-B)：来自单臂、多中心、3 期试验的 24 个月事后疗效和安全性数据

Etranacogene dezaparvovec 是第一个被批准用于治疗 B 型血友病的基因疗法，在一项 3 期试验中，在基因治疗后 18 个月的出血保护方面，其表现优于持续预防性因子 IX 的治疗。我们报告了该试验的事后 24 个月疗效和安全性数据，以评估 etranacogen dezaparvovec 对 B 型血友病患者的长期影响。3 期 HOPE-B 试验招募了 18 岁或以上患有遗传性 B 型血友病的男性，分为重度（血浆 IX 因子活性水平 <1%）或中重度（血浆 IX 因子活性水平≥1%且≤2%），具有严重出血表型并且正在接受稳定的连续 IX 因子预防。参与者接受单次输注 etranacogen dezaparvovec（每公斤体重 2 × 10 个基因组拷贝）的治疗。先前报道的主要终点是因子 IX 稳定表达后 52 周（定义为治疗后 7-18 个月）内的年化出血率 (ABR) 与至少 6 个月的导入期相比不劣势。参与者接受了通常的连续因子 IX 预防，并在此更新至第 24 个月。额外的事后疗效分析，包括调整后的 ABR、因子 IX 活性、因子 IX 范围内的参与者以及因子 IX 使用和安全性分析基因治疗后 24 个月进行。在完整分析集中对数据进行了分析，其中包括 54 名接受至少部分剂量基因治疗的患者。审判正在进行中，注册号为 。该研究于2018年6月27日开始，参与者在2019年1月至2020年3月期间接受治疗；数据截止日期为 2022 年 4 月 21 日。54 名成年男性（40 名白人、2 名亚洲人、1 名黑人或非裔美国人、11 名其他或失踪）接受了单次静脉输注 etranacogen dezaparvovec，随访中位数为 26·51几个月 (IQR 24·54–27·99)，经过 7·13 个月 (6·51–7·82) 的导入期。在比较基因治疗后 7-24 个月与导入期的更新分析中，所有出血的平均调整 ABR 从 4·18 显着降低至 1·51 (p=0·0002)，从 3·65 显着降低至 0· 99 (p=0·0001) 对于因子 IX 处理的出血。在基因治疗后的每 6 个月期间，至少 67% 的参与者没有出现出血情况（54 名参与者中有 36 名在第 0-6 个月期间出现出血，此后稳定），而在导入期，54 名参与者中有 14 名（26%）没有出血。基因治疗后 24 个月，1 名 (2%) 参与者的一期因子 IX 活性低于 5%，而 18 名 (33%) 参与者的因子 IX 活性超过 40%（非血友病范围），平均因子 IX 活性稳定并持续在 36·7% (SD 19·0%)。 54 名参与者中有 52 名 (96%) 表达内源性 IX 因子，在第 24 个月时仍未接受 IX 因子预防。没有发现新的安全问题，也没有发生与治疗相关的严重不良事件或与治疗相关的死亡。最常见的治疗相关不良事件是丙氨酸转氨酶升高（54 名患者中的 9 名 [17%]）、头痛（8 名 [15%]）、流感样疾病（7 名 [13%]）以及天冬氨酸转氨酶（五[9%]）。通过在基因治疗后 24 个月内提供持久的疾病纠正，etranacogen dezaparvovec 为重度或中重度血友病 B. uniQure 和 CSL Behring 患者提供了安全有效的治疗选择。