Nebulised interferon beta-1a (SNG001) in the treatment of viral exacerbations of COPD

Abstract

Background: Respiratory viral infections are major drivers of chronic obstructive pulmonary disease (COPD) exacerbations. Interferon-β is naturally produced in response to viral infection, limiting replication. This exploratory study aimed to demonstrate proof-of-mechanism, and evaluate the efficacy and safety of inhaled recombinant interferon-β1a (SNG001) in COPD. Part 1 assessed the effects of SNG001 on induced sputum antiviral interferon-stimulated gene expression, sputum differential cell count, and respiratory function. Part 2 compared SNG001 and placebo on clinical efficacy, sputum and serum biomarkers, and viral clearance.

Methods: In Part 1, patients (N = 13) with stable COPD were randomised 4:1 to SNG001 or placebo once-daily for three days. In Part 2, patients (N = 109) with worsening symptoms and a positive respiratory viral test were randomised 1:1 to SNG001 or placebo once-daily for 14 days in two Groups: A (no moderate exacerbation); B (moderate COPD exacerbation [i.e., acute worsening of respiratory symptoms treated with antibiotics and/or oral corticosteroids]).

Results: In Part 1, SNG001 upregulated sputum interferon gene expression. In Part 2, there were minimal SNG001-placebo differences in the efficacy endpoints; however, whereas gene expression was initially upregulated by viral infection, then declined on placebo, levels were maintained with SNG001. Furthermore, the proportion of patients with detectable rhinovirus (the most common virus) on Day 7 was lower with SNG001. In Group B, serum C-reactive protein and the proportion of patients with purulent sputum increased with placebo (suggesting bacterial infection), but not with SNG001. The overall adverse event incidence was similar with both treatments.

Conclusions: Overall, SNG001 was well-tolerated in patients with COPD, and upregulated lung antiviral defences to accelerate viral clearance. These findings warrant further investigation in a larger study.

Trial registration: EU clinical trials register (2017-003679-75), 6 October 2017.

Keywords: Biomarkers; Chronic obstructive pulmonary disease; Interferons; Symptom flare up.

Fig. 1

Patient flow through the two parts of the study Group A: Patients with cold-like symptoms and/or a deterioration in COPD symptoms, but without a moderate COPD exacerbation. Group B: Patients with a moderate COPD exacerbation with or without cold symptoms. FEV₁, forced expiratory volume in 1 s; COPD, chronic obstructive pulmonary disease

Fig. 2

Part 1: Antiviral interferon-stimulated sputum gene expression following administration of SNG001 Data are geometric mean fold change from baseline and 95% confidence intervals. Data available from 6 and 5 patients on Days 2 and 4, respectively, for Mx1, CXCL10, and GBP1, and for 5 and 4 patients, respectively, for OAS1 and IFIT2. Baseline mean (minimum, maximum) values were 3.96 (2.33, 5.28), 2.68 (2.05, 2.99), 1.77 (0.42, 2.90), − 0.20 (–0.87, 0.75) and − 0.24 (–0.57, − 0.05) for Mx1, OAS1, CXCL10, IFIT2 and GBP1, respectively. Values were not calculated for placebo, given data were available for ≤ 3 patients. Mx1, MX dynamin-like GTPase-1; OAS1, 2’-5’-oligoadenylate synthetase; CXCL10, C-X-C motif chemokine ligand-10; IFIT2, interferon-induced protein with tetratricopeptide repeats-2; GBP1, guanylate-binding protein 1

Fig. 3

Part 2: BCSS total score change from baseline in (A) Group A (cold-like symptoms and/or deterioration in COPD symptoms) and (B) Group B (moderate COPD exacerbation) Data are least squares mean and 95% confidence intervals. BCSS, Breathlessness, Cough and Sputum Scale. N values are the intention-to-treat population

Fig. 4

Part 2: Home-assessed PEF change from baseline in (A) Group A (cold-like symptoms and/or deterioration in COPD symptoms) and (B) Group B (moderate COPD exacerbation) *p < 0.05 SNG001 vs. placebo. Data are least squares mean and 95% confidence interval. Mean (SD) baseline values were 254.8 (96.84), 239.6 (93.21), 212.5 (60.42) and 230.0 (105.71) L/min in placebo Group A, SNG001 Group A, placebo Group B, and SNG001 Group B, respectively. N values are the intention-to-treat population. PEF, peak expiratory flow

Fig. 5

Part 2: (A) Summary of baseline positive respiratory virus test results in the overall population; (B) Proportion of patients with detectable viral load for rhinovirus at baseline who had detectable rhinovirus viral load at each visit (ITT population) Panel A: Note that patients could test positive for more than one respiratory virus. Panel B: N values are the number of patients with detectable viral load for rhinovirus at baseline

Fig. 6

Part 2: Sputum cell interferon-stimulated gene expression in Group A (cold-like symptoms and/or deterioration in COPD symptoms) and Group B (moderate COPD exacerbation) The data plotted are normalised to housekeeping (reference) genes. As reference genes are expressed at a higher level than the interferon-stimulated genes of interest, higher gene expression is indicated by lower values (i.e., in direction of grey arrow). *p < 0.05 SNG001 vs placebo. Data are least squares mean and 95% confidence intervals. Data available at baseline (i.e., pre-dose on Day 1) from 18 and 19 patients receiving placebo and SNG001, respectively, in Group A, and 9 and 7 patients, respectively, in Group B (except for placebo Group B for CXCL10 [N = 8]). Mx1, Mx dynamin like GTPase 1; OAS1, 2’-5’-oligoadenylate synthetase; CXCL10, C-X-C motif chemokine ligand 10

Fig. 7

Part 2: (A) Mean and (B) categorical analyses of serum CRP in Group B (moderate COPD exacerbation) *p < 0.05 SNG001 vs. placebo (there were no statistically significant differences between treatments in the categorical analysis). Panel A: Data are least squares mean and 95% confidence intervals, with data available at baseline (i.e., pre-dose on Day 1) from 13 and 16 patients receiving placebo and SNG001, respectively. CRP, C-reactive protein

Fig. 8

Part 2: Proportion of patients with purulent sputum in Group B (moderate COPD exacerbation) *p < 0.05 SNG001 vs. placebo. Sputum was graded on a colour scale from 1 to 5 where 1 indicated that antibiotics would not be usually required and 5 indicated that antibiotics may be required, with Grades of 3 to 5 reflecting ‘purulent’ sputum. Percentages are calculated as the number of patients with purulent sputum (n) divided by the number with non-missing data (N)