Abstract：
BACKGROUND: 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.
METHODS: 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 × 1013 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 ClinicalTrials.gov, number NCT03569891.
RESULTS: 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%]).
CONCLUSIONS: 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.
BACKGROUND: uniQure and CSL Behring.
METHODS: 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 × 1013 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 ClinicalTrials.gov, number NCT03569891.
RESULTS: 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%]).
CONCLUSIONS: 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.
BACKGROUND: uniQure and CSL Behring.
摘要：
背景：Etranacogenedezaparvovec，第一个被批准用于血友病B治疗的基因疗法,在一项3期试验中，在基因治疗后18个月的出血保护方面，显示优于连续预防因子IX的治疗。我们报告了该试验的24个月后疗效和安全性数据，以评估乙型血友病患者使用去血友病的长期疗效。
方法：3期HOPE-B试验招募了18岁或以上患有遗传性乙型血友病的男性，分为重度（血浆因子IX活性水平<1％）或中度重度（血浆因子IX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因子IX预防。参与者接受了单次输注etranacogenedezaparvovec（每公斤体重2×1013个基因组拷贝）的治疗。主端点，以前报道过，在因子IX表达稳定后的52周内（定义为治疗后7-18个月），与参与者接受常规连续因子IX预防的至少6个月导入期相比，年出血率（ABR）的不劣性。并在这里更新到24个月。额外,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，和因子IX的使用，安全性分析在基因治疗后24个月进行.数据在完整的分析集中进行了分析，其中包括接受至少部分剂量基因治疗的54名患者。该试验正在进行中，并在ClinicalTrials.gov注册，编号NCT03569891。
结果：该研究于2018年6月27日开始，参与者在1月之间接受治疗，2019年3月,2020年；数据截止日期为2022年4月21日。54名成年男性（40名白人，两个亚洲人,一个黑人或非裔美国人，11个其他或缺失）接受了一次静脉内输注的异产来扎沃维奇，并随访了中位数为26·51个月（IQR24·54-27·99），在7·13个月的导入期后（6·51-7·82）。在比较基因治疗后7-24个月与导入期的最新分析中，所有出血的平均校正ABR从4·18显著降低至1·51(p=0·0002),因子IX处理的出血的平均校正ABR从3·65显著降低至0·99(p=0·0001)。在基因治疗后的每6个月期间，至少67%的参与者没有经历出血(54人中有36人在0-6个月期间和此后的稳定),在导入期，54人中有14人（26%）。基因治疗24个月后,1名(2%)参与者的一阶段因子IX活性低于5%，而18（33%）的因子IX活性超过40%（非血友病范围），因子IX的平均活性稳定并持续在36·7%（SD19·0%）。54名参与者中有52名(96%)表达了内源性因子IX，在第24个月保持无因子IX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例患者中有9例[17%]）。头痛（八[15%]），流感样疾病(七[13%])，天冬氨酸转氨酶增加（五[9%]）。
结论：通过在基因治疗后24个月提供持久的疾病矫正，etracogenedezaparvovec为重度或中度血友病B患者提供了一种安全有效的治疗选择。
背景：uniQure和CSLBehring。
方法：3期HOPE-B试验招募了18岁或以上患有遗传性乙型血友病的男性，分为重度（血浆因子IX活性水平<1％）或中度重度（血浆因子IX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因子IX预防。参与者接受了单次输注etranacogenedezaparvovec（每公斤体重2×1013个基因组拷贝）的治疗。主端点，以前报道过，在因子IX表达稳定后的52周内（定义为治疗后7-18个月），与参与者接受常规连续因子IX预防的至少6个月导入期相比，年出血率（ABR）的不劣性。并在这里更新到24个月。额外,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，和因子IX的使用，安全性分析在基因治疗后24个月进行.数据在完整的分析集中进行了分析，其中包括接受至少部分剂量基因治疗的54名患者。该试验正在进行中，并在ClinicalTrials.gov注册，编号NCT03569891。
结果：该研究于2018年6月27日开始，参与者在1月之间接受治疗，2019年3月,2020年；数据截止日期为2022年4月21日。54名成年男性（40名白人，两个亚洲人,一个黑人或非裔美国人，11个其他或缺失）接受了一次静脉内输注的异产来扎沃维奇，并随访了中位数为26·51个月（IQR24·54-27·99），在7·13个月的导入期后（6·51-7·82）。在比较基因治疗后7-24个月与导入期的最新分析中，所有出血的平均校正ABR从4·18显著降低至1·51(p=0·0002),因子IX处理的出血的平均校正ABR从3·65显著降低至0·99(p=0·0001)。在基因治疗后的每6个月期间，至少67%的参与者没有经历出血(54人中有36人在0-6个月期间和此后的稳定),在导入期，54人中有14人（26%）。基因治疗24个月后,1名(2%)参与者的一阶段因子IX活性低于5%，而18（33%）的因子IX活性超过40%（非血友病范围），因子IX的平均活性稳定并持续在36·7%（SD19·0%）。54名参与者中有52名(96%)表达了内源性因子IX，在第24个月保持无因子IX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例患者中有9例[17%]）。头痛（八[15%]），流感样疾病(七[13%])，天冬氨酸转氨酶增加（五[9%]）。
结论：通过在基因治疗后24个月提供持久的疾病矫正，etracogenedezaparvovec为重度或中度血友病B患者提供了一种安全有效的治疗选择。
背景：uniQure和CSLBehring。
