Abstract：
Hereditary angioedema (HAE) is a potentially fatal disease characterized by unpredictable, recurrent, often disabling swelling attacks. In a randomized phase 2 study, donidalorsen reduced HAE attack frequency and improved patient quality-of-life (ISIS721744-CS2, NCT04030598). We report the 2-year interim analysis of the phase 2 open-label extension (OLE) study (ISIS 721744-CS3, NCT04307381).
In the OLE, the on-treatment study period consisted of fixed (weeks 1-13, donidalorsen 80 mg subcutaneously every 4 weeks [Q4W]) and flexible (weeks 17-105, donidalorsen 80 mg Q4W, 80 mg every 8 weeks [Q8W], or 100 mg Q4W) dosing periods. The primary outcome was incidence and severity of treatment-emergent adverse events (TEAEs). The secondary outcomes included efficacy, pharmacodynamic, and quality-of-life assessments.
Seventeen patients continued in the OLE study. No serious TEAEs or TEAEs leading to treatment discontinuation were reported. Mean monthly HAE attack rate was 96% lower than the study run-in baseline rate (mean, 0.06/month; 95% confidence interval [CI], 0.02-0.10; median, 0.04 on-treatment vs. mean, 2.70/month; 95% CI, 1.94-3.46; median, 2.29 at baseline). Mean monthly attack rate for Q8W dosing (n = 8) was 0.29 (range, 0.0-1.7; 95% CI, -0.21 to 0.79; median, 0.00). Mean plasma prekallikrein and D-dimer concentrations decreased, and Angioedema Quality of Life Questionnaire total score improved from baseline to week 105 with donidalorsen.
The 2-year interim results of this phase 2 OLE study of donidalorsen in patients with HAE demonstrated no new safety signals; donidalorsen was well tolerated. There was durable efficacy with a 96% reduction in HAE attacks.
In the OLE, the on-treatment study period consisted of fixed (weeks 1-13, donidalorsen 80 mg subcutaneously every 4 weeks [Q4W]) and flexible (weeks 17-105, donidalorsen 80 mg Q4W, 80 mg every 8 weeks [Q8W], or 100 mg Q4W) dosing periods. The primary outcome was incidence and severity of treatment-emergent adverse events (TEAEs). The secondary outcomes included efficacy, pharmacodynamic, and quality-of-life assessments.
Seventeen patients continued in the OLE study. No serious TEAEs or TEAEs leading to treatment discontinuation were reported. Mean monthly HAE attack rate was 96% lower than the study run-in baseline rate (mean, 0.06/month; 95% confidence interval [CI], 0.02-0.10; median, 0.04 on-treatment vs. mean, 2.70/month; 95% CI, 1.94-3.46; median, 2.29 at baseline). Mean monthly attack rate for Q8W dosing (n = 8) was 0.29 (range, 0.0-1.7; 95% CI, -0.21 to 0.79; median, 0.00). Mean plasma prekallikrein and D-dimer concentrations decreased, and Angioedema Quality of Life Questionnaire total score improved from baseline to week 105 with donidalorsen.
The 2-year interim results of this phase 2 OLE study of donidalorsen in patients with HAE demonstrated no new safety signals; donidalorsen was well tolerated. There was durable efficacy with a 96% reduction in HAE attacks.
摘要：
背景：遗传性血管性水肿（HAE）是一种潜在的致命疾病，其特征是不可预测的，经常性,经常致残肿胀发作。在一项随机的2期研究中,donidalorsen降低了HAE发作频率并改善了患者生活质量(ISIS721744-CS2,NCT04030598)。我们报告了2期开放标签扩展（OLE）研究（ISIS721744-CS3，NCT04307381）的2年中期分析。
方法：在OLE中，治疗期间包括固定（1-13周，donidalorsen80mg皮下每4周[Q4W]）和灵活（17-105周，donidalorsen80mgQ4W，每8周80毫克[Q8W]，或100毫克Q4W）给药期。主要结果是治疗引起的不良事件（TEAE）的发生率和严重程度。次要结果包括疗效，药效学，和生活质量评估。
结果：17名患者继续参与OLE研究。没有报告严重的TEAE或导致治疗中断的TEAE。平均每月HAE发作率比研究运行基线率低96%(平均值，0.06/月；95%置信区间[CI]，0.02-0.10；中位数，0.04治疗与意思是，2.70/月；95%CI，1.94-3.46；中位数，2.29在基线)。Q8W给药（n=8）的平均每月发作率为0.29（范围，0.0-1.7；95%CI，-0.21至0.79；中位数，0.00).平均血浆前激肽释放酶和D-二聚体浓度降低，使用donidalorsen，从基线到第105周，血管性水肿生活质量问卷总分有所改善。
结论：这项关于donidalorsen在HAE患者中的2期OLE研究的2年中期结果表明没有新的安全性信号；donidalorsen耐受性良好。有持久的疗效，HAE发作减少了96％。
方法：在OLE中，治疗期间包括固定（1-13周，donidalorsen80mg皮下每4周[Q4W]）和灵活（17-105周，donidalorsen80mgQ4W，每8周80毫克[Q8W]，或100毫克Q4W）给药期。主要结果是治疗引起的不良事件（TEAE）的发生率和严重程度。次要结果包括疗效，药效学，和生活质量评估。
结果：17名患者继续参与OLE研究。没有报告严重的TEAE或导致治疗中断的TEAE。平均每月HAE发作率比研究运行基线率低96%(平均值，0.06/月；95%置信区间[CI]，0.02-0.10；中位数，0.04治疗与意思是，2.70/月；95%CI，1.94-3.46；中位数，2.29在基线)。Q8W给药（n=8）的平均每月发作率为0.29（范围，0.0-1.7；95%CI，-0.21至0.79；中位数，0.00).平均血浆前激肽释放酶和D-二聚体浓度降低，使用donidalorsen，从基线到第105周，血管性水肿生活质量问卷总分有所改善。
结论：这项关于donidalorsen在HAE患者中的2期OLE研究的2年中期结果表明没有新的安全性信号；donidalorsen耐受性良好。有持久的疗效，HAE发作减少了96％。
