Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA.
Krefting Research Centre, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
Clin Exp Allergy. 2021 Feb;51(2):273-283. doi: 10.1111/cea.13765. Epub 2020 Nov 3.
Upper respiratory tract infections (URTIs) are important triggers for asthma exacerbations. We hypothesized that inhalation of the anti-viral cytokine, interferon (IFN)-β, during URTI, could prevent these exacerbations.
To evaluate the efficacy of on-demand inhaled IFN-β1a (AZD9412) to prevent severe asthma exacerbations following symptomatic URTI.
This was a randomized, double-blind, placebo-controlled trial in which patients with severe asthma (GINA 4-5; n = 121) reporting URTI symptoms were randomized to 14 days of once-daily nebulized AZD9412 or placebo. The primary endpoint was severe exacerbations during treatment. Secondary endpoints included 6-item asthma control questionnaire (ACQ-6) and lung function. Exploratory biomarkers included IFN-response markers in serum and sputum, blood leucocyte counts and serum inflammatory cytokines.
Following a pre-planned interim analysis, the trial was terminated early due to an unexpectedly low exacerbation rate. Asthma worsenings were generally mild and tended to peak at randomization, possibly contributing to the lack of benefit of AZD9412 on other asthma endpoints. Numerically, AZD9412 did not reduce severe exacerbation rate, ACQ-6, asthma symptom scores or reliever medication use. AZD9412 improved lung function (morning peak expiratory flow; mPEF) by 19.7 L/min. Exploratory post hoc analyses indicated a greater mPEF improvement by AZD9412 in patients with high blood eosinophils (>0.3 × 10 /L) at screening and low serum interleukin-18 relative change at pre-treatment baseline. Pharmacodynamic effect of AZD9412 was confirmed using IFN-response markers.
CONCLUSIONS & CLINICAL RELEVANCE: Colds did not have the impact on asthma patients that was expected and, due to the low exacerbation rate, the trial was stopped early. On-demand AZD9412 treatment did not numerically reduce the number of exacerbations, but did attenuate URTI-induced worsening of mPEF. Severe asthma patients with high blood eosinophils or low serum interleukin-18 response are potential subgroups for further investigation of inhaled IFN-β1a.
上呼吸道感染（URTIs）是哮喘恶化的重要诱因。我们假设在 URTI 期间吸入抗病毒细胞因子干扰素（IFN）-β可以预防这些恶化。
评估按需吸入 IFN-β1a（AZD9412）预防有症状 URTI 后严重哮喘恶化的疗效。
这是一项随机、双盲、安慰剂对照试验，纳入了报告 URTI 症状的严重哮喘（GINA 4-5；n=121）患者，随机接受为期 14 天的每日一次雾化 AZD9412 或安慰剂治疗。主要终点是治疗期间的严重恶化。次要终点包括 6 项哮喘控制问卷（ACQ-6）和肺功能。探索性生物标志物包括血清和痰中的 IFN 反应标志物、白细胞计数和血清炎症细胞因子。
在进行了计划中的中期分析后，由于出乎意料的低恶化率，试验提前终止。哮喘恶化通常较轻，且往往在随机分组时达到峰值，这可能是 AZD9412 对其他哮喘终点没有益处的原因。数值上，AZD9412 并未降低严重恶化率、ACQ-6、哮喘症状评分或缓解药物使用。AZD9412 改善了肺功能（晨峰呼气流量；mPEF）19.7 L/min。事后探索性分析表明，在筛选时血嗜酸性粒细胞较高（>0.3×10 /L）和治疗前基线时血清白细胞介素-18 相对变化较低的患者中，AZD9412 改善 mPEF 的效果更大。使用 IFN 反应标志物证实了 AZD9412 的药效学作用。
感冒对哮喘患者的影响并未达到预期，由于恶化率较低，试验提前终止。按需 AZD9412 治疗并未在数值上减少恶化次数，但减轻了 URTI 引起的 mPEF 恶化。血嗜酸性粒细胞较高或血清白细胞介素-18 反应较低的严重哮喘患者可能是进一步研究吸入 IFN-β1a 的潜在亚组。
