右普拉克索治疗嗜酸性粒细胞性哮喘（EXHALE）的安全性和有效性：一项随机对照试验
2023/06/25
摘要
背景：需要新的、有效的口服哮喘疗法。右普拉克索，一种口服的降低嗜酸性粒细胞的药物，以前没有在哮喘中进行过研究。
目的：评价右普拉克索降低嗜酸性哮喘患者血液和气道嗜酸性粒细胞的安全性和有效性。
方法：我们对患有控制不足的中重度哮喘且血液嗜酸性粒细胞绝对计数（AEC）≥300/μL的成年人进行了一项随机、双盲、安慰剂对照的概念验证试验。受试者被随机分配（1:1:1:1）给右普拉克索37.5、75或150 mg BID或安慰剂。主要终点是从基线到第12周AEC的相对变化。支气管扩张剂前FEV1第12周与基线相比的变化是一个关键的次要终点。鼻嗜酸性粒细胞过氧化物酶（EPX）是一个探索性终点。
结果：103名受试者被随机分为右普拉克索37.5（N=22）、75（N=26）或150 mg BID（N=28）或安慰剂（N=27）。在150 mg BID剂量组（比值0.23，95%CI 0.12-0.43，p<0.0001）和75 mg BID给药组（0.34，95%CI 0.18-0.65，p=0.0014）中，右普拉克索显著降低了安慰剂校正的AEC第12周与基线的比值，分别降低了77%和66%。在150 mg BID（中位数0.11，p=0.020）和75 mg BID组（中位数0.17，p=0.021）中，右普拉克索降低了鼻EPX第12周与基线比率的探索终点。从第4周开始观察到安慰剂校正的FEV1增加（无显著性）。右普拉克索显示出良好的安全性。
结论：右普拉克索能有效降低嗜酸性粒细胞，耐受性良好。需要更多更大规模的临床试验来了解右普拉克索治疗哮喘的临床疗效。
Safety and efficacy of dexpramipexole in eosinophilic asthma (EXHALE): a randomized controlled trial
Salman Siddiqui, Sally E Wenzel, Michael E Bozik, Donald G Archibald, Steven I Dworetzky, James L Mather, Randall Killingsworth, Natasha Ghearing, Justin T Schwartz, Sergei I Ochkur, Elizabeth A Jacobsen, William W Busse, Reynold A Panettieri, Calman Prussin
Abstract
Background: There is a need for new and effective oral asthma therapies. Dexpramipexole, an oral eosinophil-lowering drug, has not previously been studied in asthma.
Objectives: To evaluate the safety and efficacy of dexpramipexole in lowering blood and airway eosinophilia in subjects with eosinophilic asthma.
Methods: We performed a randomized, double-blind, placebo-controlled proof of concept trial in adults with inadequately controlled moderate-to-severe asthma and blood absolute eosinophil count (AEC) ≥300/μL. Subjects were randomly assigned (1:1:1:1) to dexpramipexole 37.5, 75, or 150 mg BID or placebo. The primary endpoint was the relative change in AEC from baseline to week 12. Pre-bronchodilator FEV1 week 12 change from baseline was a key secondary endpoint. Nasal eosinophil peroxidase (EPX) was an exploratory endpoint.
Results: 103 subjects were randomly assigned to dexpramipexole 37.5 (N=22), 75 (N=26), or 150 mg BID (N=28), or placebo (N=27). Dexpramipexole significantly reduced placebo-corrected AEC week 12 ratio to baseline, in both the 150 mg BID (ratio 0.23, 95% CI 0.12-0.43, p<0.0001) and 75 mg BID dose groups (0.34, 95% CI 0.18-0.65, p=0.0014), corresponding to 77% and 66% reductions, respectively. Dexpramipexole reduced the exploratory endpoint of nasal EPX week 12 ratio to baseline in the 150 mg BID (median 0.11, p=0.020) and 75 mg BID groups (median 0.17, p=0.021). Placebo corrected FEV1 increases were observed starting at week 4 (non-significant). Dexpramipexole displayed a favorable safety profile.
Conclusions: Dexpramipexole demonstrated effective eosinophil lowering and was well tolerated. Additional larger clinical trials are needed to understand dexpramipexole clinical efficacy in asthma.
背景：需要新的、有效的口服哮喘疗法。右普拉克索，一种口服的降低嗜酸性粒细胞的药物，以前没有在哮喘中进行过研究。
目的：评价右普拉克索降低嗜酸性哮喘患者血液和气道嗜酸性粒细胞的安全性和有效性。
方法：我们对患有控制不足的中重度哮喘且血液嗜酸性粒细胞绝对计数（AEC）≥300/μL的成年人进行了一项随机、双盲、安慰剂对照的概念验证试验。受试者被随机分配（1:1:1:1）给右普拉克索37.5、75或150 mg BID或安慰剂。主要终点是从基线到第12周AEC的相对变化。支气管扩张剂前FEV1第12周与基线相比的变化是一个关键的次要终点。鼻嗜酸性粒细胞过氧化物酶（EPX）是一个探索性终点。
结果：103名受试者被随机分为右普拉克索37.5（N=22）、75（N=26）或150 mg BID（N=28）或安慰剂（N=27）。在150 mg BID剂量组（比值0.23，95%CI 0.12-0.43，p<0.0001）和75 mg BID给药组（0.34，95%CI 0.18-0.65，p=0.0014）中，右普拉克索显著降低了安慰剂校正的AEC第12周与基线的比值，分别降低了77%和66%。在150 mg BID（中位数0.11，p=0.020）和75 mg BID组（中位数0.17，p=0.021）中，右普拉克索降低了鼻EPX第12周与基线比率的探索终点。从第4周开始观察到安慰剂校正的FEV1增加（无显著性）。右普拉克索显示出良好的安全性。
结论：右普拉克索能有效降低嗜酸性粒细胞，耐受性良好。需要更多更大规模的临床试验来了解右普拉克索治疗哮喘的临床疗效。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2023 Jun 3;S0091-6749(23)00709-1. doi: 10.1016/j.jaci.2023.05.014.)
(J Allergy Clin Immunol. 2023 Jun 3;S0091-6749(23)00709-1. doi: 10.1016/j.jaci.2023.05.014.)
Safety and efficacy of dexpramipexole in eosinophilic asthma (EXHALE): a randomized controlled trial
Salman Siddiqui, Sally E Wenzel, Michael E Bozik, Donald G Archibald, Steven I Dworetzky, James L Mather, Randall Killingsworth, Natasha Ghearing, Justin T Schwartz, Sergei I Ochkur, Elizabeth A Jacobsen, William W Busse, Reynold A Panettieri, Calman Prussin
Abstract
Background: There is a need for new and effective oral asthma therapies. Dexpramipexole, an oral eosinophil-lowering drug, has not previously been studied in asthma.
Objectives: To evaluate the safety and efficacy of dexpramipexole in lowering blood and airway eosinophilia in subjects with eosinophilic asthma.
Methods: We performed a randomized, double-blind, placebo-controlled proof of concept trial in adults with inadequately controlled moderate-to-severe asthma and blood absolute eosinophil count (AEC) ≥300/μL. Subjects were randomly assigned (1:1:1:1) to dexpramipexole 37.5, 75, or 150 mg BID or placebo. The primary endpoint was the relative change in AEC from baseline to week 12. Pre-bronchodilator FEV1 week 12 change from baseline was a key secondary endpoint. Nasal eosinophil peroxidase (EPX) was an exploratory endpoint.
Results: 103 subjects were randomly assigned to dexpramipexole 37.5 (N=22), 75 (N=26), or 150 mg BID (N=28), or placebo (N=27). Dexpramipexole significantly reduced placebo-corrected AEC week 12 ratio to baseline, in both the 150 mg BID (ratio 0.23, 95% CI 0.12-0.43, p<0.0001) and 75 mg BID dose groups (0.34, 95% CI 0.18-0.65, p=0.0014), corresponding to 77% and 66% reductions, respectively. Dexpramipexole reduced the exploratory endpoint of nasal EPX week 12 ratio to baseline in the 150 mg BID (median 0.11, p=0.020) and 75 mg BID groups (median 0.17, p=0.021). Placebo corrected FEV1 increases were observed starting at week 4 (non-significant). Dexpramipexole displayed a favorable safety profile.
Conclusions: Dexpramipexole demonstrated effective eosinophil lowering and was well tolerated. Additional larger clinical trials are needed to understand dexpramipexole clinical efficacy in asthma.
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共病导致的治疗效果改变：120项随机对照试验的个体参与者数据荟萃分析
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