INEXAS: A Phase 2 Randomized Trial of On-demand Inhaled Interferon Beta-1a in Severe Asthmatics

Abstract

Background: 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.

Objective: To evaluate the efficacy of on-demand inhaled IFN-β1a (AZD9412) to prevent severe asthma exacerbations following symptomatic URTI.

Methods: 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.

Results: 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 × 10⁹ /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.

Trial registration: ClinicalTrials.gov NCT02491684.

Keywords: IFN response; IL-18; asthma; eosinophils; exacerbation; interferon; viral URTI.

Figure 1

Study design

Figure 2

Patient disposition

Figure 3

Mean mPEF AUC change from treatment baseline (day 1). Error bars are SEM. Closed circles: AZD9412; open circles: placebo

Figure 4

A, Asthma symptom score mean, at screening and during days 1‐7 of treatment. B, Reliever medication use, mean number of puffs, at screening and during days 1‐7 of treatment. Solid line: AZD9412; dashed line: placebo. Shaded area indicates the pre‐treatment waiting phase (from screening to randomization). Pre‐rand = pre‐randomization

Figure 5

Pharmacodynamic effect of AZD9412 based on IFN‐response biomarkers. A, Mean serum CXCL10 concentrations throughout the study time course. Error bars are SEM. Closed circles: AZD9412; open circles: placebo. B, Median mRNA levels of sputum IFN‐stimulated genes throughout the treatment and follow‐up period. For each gene, mRNA levels are normalized to housekeeping genes (PUM1, ACTB and HPRT) and expressed as fold change over day 1 (V1). Solid line: AZD9412; dashed line: placebo. Shaded areas indicate the pre‐treatment waiting phase from screening to randomization (left area), and follow‐up period (right area)

Figure 6

A, Mean mPEF AUC change (day 1‐7) in patients sub‐divided on blood eosinophil counts at screening. Patient numbers in low, mid and high subgroups were 9, 32 and 12 for AZD9412 and 19, 27 and 12 for placebo. B, Mean mPEF AUC change (day 1‐7) in patients sub‐divided on mean IL‐18 relative change from screening to treatment baseline. Patient numbers in low, mid and high subgroups were n = 14, 29 and 13 for AZD9412, and n = 14, 30 and 13 for placebo. A‐B, All = main ITT population. Error bars are 95% confidence intervals. C, Scatterplot of blood eosinophil counts versus EDN (log₁₀‐scale) based on all patients with both EDN and eosinophil count data at screening (n = 47, excluding one patient whose blood eosinophil count = 0 and 3 patients with missing eosinophil count data). Correlation between EDN and blood eosinophil counts (log₁₀‐scale) is 0.78 (Pearson's correlation coefficient)