Coppens Michiel, Pipe Steven W, Miesbach Wolfgang, Astermark Jan, Recht Michael, van der Valk Paul, Ewenstein Bruce, Pinachyan Karen, Galante Nicholas, Le Quellec Sandra, Monahan Paul E, Leebeek Frank W G
Department of Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, Netherlands; Amsterdam Cardiovascular Sciences, Pulmonary Hypertension & Thrombosis, Amsterdam, Netherlands.
University of Michigan, Ann Arbor, MI, USA.
Lancet Haematol. 2024 Apr;11(4):e265-e275. doi: 10.1016/S2352-3026(24)00006-1. Epub 2024 Mar 1.
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 ClinicalTrials.gov, number NCT03569891.
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.
艾曲泊帕乙醇胺是首个获批用于治疗B型血友病的基因疗法，在一项3期试验中，基因治疗18个月后，在预防出血方面，其疗效优于持续预防性输注凝血因子IX。我们报告了该试验事后分析的24个月疗效和安全性数据，以评估艾曲泊帕乙醇胺对B型血友病患者的长期影响。
3期HOPE-B试验纳入了18岁及以上患有遗传性B型血友病的男性，这些患者被分类为重度（血浆凝血因子IX活性水平<1%）或中度重度（血浆凝血因子IX活性水平≥1%且≤2%），具有严重出血表型，且正在接受稳定的持续凝血因子IX预防性治疗。参与者接受单次输注艾曲泊帕乙醇胺（每千克体重2×10基因组拷贝）。先前报告的主要终点是在稳定的凝血因子IX表达期间（定义为治疗后7-18个月）的年化出血率（ABR）不劣于至少6个月的导入期，在此导入期内参与者接受其常规的持续凝血因子IX预防性治疗，此处更新至24个月。在基因治疗24个月后进行了额外的事后疗效分析，包括调整后的ABR、凝血因子IX活性、处于凝血因子IX范围内的参与者以及凝血因子IX的使用情况，以及安全性分析。在全分析集（包括接受至少部分剂量基因治疗的54名患者）中对数据进行了分析。该试验正在进行中，并已在ClinicalTrials.gov上注册，编号为NCT03569891。
该研究于2018年6月27日开始，参与者于2019年1月至2020年3月接受治疗；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名其他或信息缺失）接受了单次静脉输注艾曲泊帕乙醇胺，并在7.13个月（6.51-7.82）的导入期后，中位随访26.51个月（IQR 24.54-27.99）。在将基因治疗后7-24个月与导入期进行比较的更新分析中，所有出血的平均调整后ABR从4.18显著降至1.51（p=0.0002），凝血因子IX治疗的出血从3.65降至0.99（p=0.0001）。在基因治疗后的每个6个月期间，至少67%的参与者无出血（0-6个月期间54名参与者中有36名，此后保持稳定），而导入期54名参与者中有14名（26%）无出血。基因治疗24个月后，1名（2%）参与者的一期凝血因子IX活性低于5%，而18名（33%）参与者的凝血因子IX活性高于40%（非血友病范围），平均凝血因子IX活性稳定并维持在36.7%（SD 19.0%）。54名参与者中有52名（96%）表达内源性凝血因子IX，在24个月时无需凝血因子IX预防性治疗。未发现新的安全问题，未发生与治疗相关的严重不良事件或与治疗相关的死亡。最常见的与治疗相关的不良事件是丙氨酸转氨酶升高（54名患者中有9名[17%]）、头痛（8名[15%]）、流感样疾病（7名[13%]）和天冬氨酸转氨酶升高（5名[9%]）。
通过在基因治疗后的24个月内提供持久的疾病纠正，艾曲泊帕乙醇胺为重度或中度重度B型血友病患者提供了一种安全有效的治疗选择。
uniQure和CSL Behring。
