Itepekimab治疗中度至重度哮喘患者的疗效和安全性
2021/11/24
摘要
背景：靶向IgE、白介素4和白介素13以及白介素5的单克隆抗体可有效治疗重度2型哮喘，但我们仍需寻找新的八点。Itepekimab是靶向上游警报素白介素-33的新型单克隆抗体。Itepekimab单药治疗以及itepekimab与度普利尤单抗联合治疗对哮喘患者的疗效和安全性尚未明确。
方法：在一项2期试验中，我们以1：1：1：1的比例将接受吸入型糖皮质激素+长效β受体激动剂（LABA）治疗的中度至重度哮喘成人患者随机分组，四组分别接受itepekimab皮下给药（剂量为300mg）、itepekimab+度普利尤单抗（剂量均为300mg；联合治疗）、度普利尤单抗（300mg）或安慰剂治疗，每2周一次，治疗12周。随机分组后，LABA在第4周停药，吸入型糖皮质激素在第6周至第9周期间逐渐减量停药。主要终点是与安慰剂组相比，在itepekimab组和联合治疗组中评估的哮喘失去控制事件。次要终点和其他终点包括肺功能、哮喘控制、生活质量、2型生物标志物和安全性。
结果：截止12周时，itepekimab组22%的患者、联合治疗组27%的患者和度普利尤单抗组19%的患者发生了哮喘失去控制事件，而安慰剂组的这一比例为41%；与安慰剂组相比，各组的相应比值比如下：itepekimab组0.42（95%置信区间CI，0.20-0.88；P=0.02）；联合治疗组0.52（95%CI，0.26-1.06；P=0.07）；度普利尤单抗组0.33（95%CI，0.15-0.70）。与安慰剂组相比，在itepekimab和度普利尤单抗单药治疗组中，使用支气管扩张剂之前的第1秒用力呼气量增加，而联合治疗组的第1秒用力呼气量未增加。与安慰剂相比，itepekima改善了哮喘控制和生活质量，并且更大幅降低了平均血液嗜酸性粒细胞计数。四个实验组的不良事件发生率均相似。
结论：在中度至重度哮喘患者中，与安慰剂相比，使用itepekimab阻断白介素-33降低了哮喘失去控制事件的发生率，并改善了肺功能。
Efficacy and Safety of Itepekimab in Patients with Moderate-to-Severe Asthma
Michael E Wechsler , Marcella K Ruddy, Ian D Pavord , Elliot Israel , Klaus F Rabe, Linda B Ford , Jorge F Maspero , Raolat M Abdulai, Chih-Chi Hu, Renata Martincova , Andreas Jessel , Michael C Nivens, Nikhil Amin, David M Weinreich, George D Yancopoulos, Helene Goulaouic
Abstract
Background: Monoclonal antibodies targeting IgE, interleukin-4 and -13, and interleukin-5 are effective in treating severe type 2 asthma, but new targets are needed. Itepekimab is a new monoclonal antibody against the upstream alarmin interleukin-33. The efficacy and safety of itepekimab as monotherapy, as well as in combination with dupilumab, in patients with asthma are unclear.
Methods: In a phase 2 trial, we randomly assigned, in a 1:1:1:1 ratio, adults with moderate-to-severe asthma receiving inhaled glucocorticoids plus long-acting beta-agonists (LABAs) to receive subcutaneous itepekimab (at a dose of 300 mg), itepekimab plus dupilumab (both at 300 mg; combination therapy), dupilumab (300 mg), or placebo every 2 weeks for 12 weeks. After randomization, LABA was discontinued at week 4, and inhaled glucocorticoids were tapered over weeks 6 through 9. The primary end point was an event indicating a loss of asthma control, assessed in the itepekimab group and the combination group, as compared with the placebo group. Secondary and other end points included lung function, asthma control, quality of life, type 2 biomarkers, and safety.
Results: A total of 296 patients underwent randomization. By 12 weeks, an event indicating a loss of asthma control occurred in 22% of the patients in the itepekimab group, 27% of those in the combination group, and 19% of those in the dupilumab group, as compared with 41% of those in the placebo group; the corresponding odds ratios as compared with placebo were as follows: in the itepekimab group, 0.42 (95% confidence interval [CI], 0.20 to 0.88; P = 0.02); in the combination group, 0.52 (95% CI, 0.26 to 1.06; P = 0.07); and in the dupilumab group, 0.33 (95% CI, 0.15 to 0.70). As compared with placebo, the forced expiratory volume in 1 second before bronchodilator use increased with the itepekimab and dupilumab monotherapies but not with the combination therapy. Itepekimab treatment improved asthma control and quality of life, as compared with placebo, and led to a greater reduction in the mean blood eosinophil count. The incidence of adverse events was similar in all four trial groups.
Conclusions: Interleukin-33 blockade with itepekimab led to a lower incidence of events indicating a loss of asthma control than placebo and improved lung function in patients with moderate-to-severe asthma.
背景：靶向IgE、白介素4和白介素13以及白介素5的单克隆抗体可有效治疗重度2型哮喘，但我们仍需寻找新的八点。Itepekimab是靶向上游警报素白介素-33的新型单克隆抗体。Itepekimab单药治疗以及itepekimab与度普利尤单抗联合治疗对哮喘患者的疗效和安全性尚未明确。
方法：在一项2期试验中，我们以1：1：1：1的比例将接受吸入型糖皮质激素+长效β受体激动剂（LABA）治疗的中度至重度哮喘成人患者随机分组，四组分别接受itepekimab皮下给药（剂量为300mg）、itepekimab+度普利尤单抗（剂量均为300mg；联合治疗）、度普利尤单抗（300mg）或安慰剂治疗，每2周一次，治疗12周。随机分组后，LABA在第4周停药，吸入型糖皮质激素在第6周至第9周期间逐渐减量停药。主要终点是与安慰剂组相比，在itepekimab组和联合治疗组中评估的哮喘失去控制事件。次要终点和其他终点包括肺功能、哮喘控制、生活质量、2型生物标志物和安全性。
结果：截止12周时，itepekimab组22%的患者、联合治疗组27%的患者和度普利尤单抗组19%的患者发生了哮喘失去控制事件，而安慰剂组的这一比例为41%；与安慰剂组相比，各组的相应比值比如下：itepekimab组0.42（95%置信区间CI，0.20-0.88；P=0.02）；联合治疗组0.52（95%CI，0.26-1.06；P=0.07）；度普利尤单抗组0.33（95%CI，0.15-0.70）。与安慰剂组相比，在itepekimab和度普利尤单抗单药治疗组中，使用支气管扩张剂之前的第1秒用力呼气量增加，而联合治疗组的第1秒用力呼气量未增加。与安慰剂相比，itepekima改善了哮喘控制和生活质量，并且更大幅降低了平均血液嗜酸性粒细胞计数。四个实验组的不良事件发生率均相似。
结论：在中度至重度哮喘患者中，与安慰剂相比，使用itepekimab阻断白介素-33降低了哮喘失去控制事件的发生率，并改善了肺功能。
(中日友好医院呼吸与危重症医学科 张清 摘译 林江涛 审校)
(N Engl J Med. 2021 Oct 28;385(18):1656-1668. doi: 10.1056/NEJMoa2024257.)
(N Engl J Med. 2021 Oct 28;385(18):1656-1668. doi: 10.1056/NEJMoa2024257.)
Efficacy and Safety of Itepekimab in Patients with Moderate-to-Severe Asthma
Michael E Wechsler , Marcella K Ruddy, Ian D Pavord , Elliot Israel , Klaus F Rabe, Linda B Ford , Jorge F Maspero , Raolat M Abdulai, Chih-Chi Hu, Renata Martincova , Andreas Jessel , Michael C Nivens, Nikhil Amin, David M Weinreich, George D Yancopoulos, Helene Goulaouic
Abstract
Background: Monoclonal antibodies targeting IgE, interleukin-4 and -13, and interleukin-5 are effective in treating severe type 2 asthma, but new targets are needed. Itepekimab is a new monoclonal antibody against the upstream alarmin interleukin-33. The efficacy and safety of itepekimab as monotherapy, as well as in combination with dupilumab, in patients with asthma are unclear.
Methods: In a phase 2 trial, we randomly assigned, in a 1:1:1:1 ratio, adults with moderate-to-severe asthma receiving inhaled glucocorticoids plus long-acting beta-agonists (LABAs) to receive subcutaneous itepekimab (at a dose of 300 mg), itepekimab plus dupilumab (both at 300 mg; combination therapy), dupilumab (300 mg), or placebo every 2 weeks for 12 weeks. After randomization, LABA was discontinued at week 4, and inhaled glucocorticoids were tapered over weeks 6 through 9. The primary end point was an event indicating a loss of asthma control, assessed in the itepekimab group and the combination group, as compared with the placebo group. Secondary and other end points included lung function, asthma control, quality of life, type 2 biomarkers, and safety.
Results: A total of 296 patients underwent randomization. By 12 weeks, an event indicating a loss of asthma control occurred in 22% of the patients in the itepekimab group, 27% of those in the combination group, and 19% of those in the dupilumab group, as compared with 41% of those in the placebo group; the corresponding odds ratios as compared with placebo were as follows: in the itepekimab group, 0.42 (95% confidence interval [CI], 0.20 to 0.88; P = 0.02); in the combination group, 0.52 (95% CI, 0.26 to 1.06; P = 0.07); and in the dupilumab group, 0.33 (95% CI, 0.15 to 0.70). As compared with placebo, the forced expiratory volume in 1 second before bronchodilator use increased with the itepekimab and dupilumab monotherapies but not with the combination therapy. Itepekimab treatment improved asthma control and quality of life, as compared with placebo, and led to a greater reduction in the mean blood eosinophil count. The incidence of adverse events was similar in all four trial groups.
Conclusions: Interleukin-33 blockade with itepekimab led to a lower incidence of events indicating a loss of asthma control than placebo and improved lung function in patients with moderate-to-severe asthma.
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