A Multicentre, Randomized, Double-Blind, Placebo-Controlled, Crossover Study To Investigate the Efficacy, Safety, Tolerability, and Pharmacokinetics of Repeat Doses of Inhaled Nemiralisib in Adults with Persistent, Uncontrolled Asthma
A Multicentre, Randomized, Double-Blind, Placebo-Controlled, Crossover Study To Investigate the Efficacy, Safety, Tolerability, and Pharmacokinetics of Repeat Doses of Inhaled Nemiralisib in Adults with Persistent, Uncontrolled Asthma
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DOI：
10.1124/jpet.118.249516
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发表时间：
2018-12-01
影响因子：
3.5
通讯作者：
Hessel, Edith M.
中科院分区：
文献类型：
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作者：
Khindri, Sanjeev;Cahn, Anthony;Hessel, Edith M.
磷酸肌醇3-激酶δ（PI3K δ）是一种参与白细胞募集和活化的脂质激酶。PI3K δ的激活与气道炎症和哮喘发病机制有关。这项随机、双盲、安慰剂对照、交叉研究研究了PI3K δ抑制剂nemiralisib（GSK 2269557）在持续性、不受控制的哮喘患者中的疗效、安全性、耐受性和药代动力学。患者（n = 50）接受每日一次吸入nemiralisib（1000 μ g）或安慰剂，持续28天，在4周洗脱期后交叉至替代治疗。肺量测定显示，在第28天（主要终点），nemiralisib和安慰剂治疗之间1秒用力呼气量谷值（FEV1）与基线（校正后验中位数7 ml; 95%可信区间-83，102 ml）相比无明显差异。这些结果得到了大多数次要终点的支持，包括第28天的加权平均FEV1（0 - 4小时）和用力肺活量谷值变化。Nemiralisib通常耐受良好，除吸入后咳嗽外，副作用很少（Nemiralisib：35%;安慰剂：9%）。在第14天，当与安慰剂比较时，痰中白细胞介素（IL）-5、IL-13、IL-6和IL-8水平分别降低了17%、7%、15%和8%的中位数[n = 15（IL-5，IL-8）或16（IL-6，IL-13）;真实比率> 0%的后验概率分别为：78%，64%，76%和63%]。这些结果表明，nemiralisib局部抑制PI3K δ;然而，这并没有转化为有意义的临床改善。进一步的研究将调查内米拉利西布对具有其他特定更严重表型的哮喘患者的潜在疗效，包括那些被细菌定植并经常恶化的哮喘患者。
Phosphoinositide 3-kinase delta (PI3K delta) is a lipid kinase involved in leukocyte recruitment and activation. Activation of PI3K delta has been linked to airway inflammation and asthma pathogenesis. This randomized, double-blind, placebo-controlled, crossover study investigated the efficacy, safety, tolerability, and pharmacokinetics of a PI3K delta inhibitor, nemiralisib (GSK2269557), in patients with persistent, uncontrolled asthma. Patients (n = 50) received once-daily inhaled nemiralisib (1000 mu g) or placebo for 28 days, with a crossover to the alternative treatment following a 4-week washout period. Spirometry demonstrated no discernible difference in trough forced expiratory volume in 1 second (FEV1) from baseline (adjusted posterior median 7 ml; 95% credible interval -83, 102 ml) between nemiralisib and placebo treatment at day 28 (primary endpoint). These results were supported by most secondary endpoints, including weighted mean FEV1 (0-4 hours) and change in trough forced vital capacity at day 28. Nemiralisib was generally well-tolerated, with few side effects except for post-inhalation cough (nemiralisib: 35%; placebo: 9%). At day 14, sputum interleukin (IL)-5, IL-13, IL-6, and IL-8 levels were reduced by a median of 17%, 7%, 15%, and 8%, respectively, when comparing nemiralisib with placebo [n = 15 (IL-5, IL-8) or 16 (IL-6, IL-13); posterior probability of a true ratio >0%: 78%, 64%, 76%, and 63%, respectively]. These results suggest that nemiralisib inhibited PI3K delta locally; however, this did not translate into meaningful clinical improvement. Further studies will investigate the potential efficacy of nemiralisib in patients with asthma with other specific more severe phenotypes, including those who are colonized with bacteria and frequently exacerbate.