Inhaled Interferon: A Novel Treatment for Virus-induced Asthma?

Virus infections play a critical role in both the inception and exacerbation of asthma (1). Over 80% of asthma exacerbations in children and more than half of asthma exacerbations in adults are associated with virus infections, most commonly rhinovirus (RV) (2). Conventional therapies are only partially effective in the prevention of asthma exacerbations, and strategies directed toward the virus itself and/or antiviral immune responses are currently unavailable to clinicians and their patients. In this issue of the Journal, Djukanovic and colleagues (pp. 145–154) report the results of a phase 2 clinical trial examining the efficacy of inhaled interferon (IFN)-β (SNG-001) for the prevention and treatment of asthma symptoms associated with upper respiratory virus infections in adults with asthma (3).

The foundation of this bench-to-bedside story are data published nearly a decade ago identifying impaired airway epithelial cell type I (β) and type III (λ) IFN production in response to ex vivo RV infection in patients with moderate to severe atopic asthma compared with nonatopic control subjects (4, 5). This antiviral defect was associated with enhanced RV replication and impaired apoptosis. Furthermore, exogenous IFN-β restored the antiviral response. After performing initial dose-escalation and safety studies, Djukanovic and colleagues began this phase 2 clinical trial, aiming to translate these ex vivo findings into a novel therapeutic for patients with virus-induced asthma.

The investigators used texting technology to carefully track the onset of cold symptoms in study participants to begin therapy as soon as possible after the onset of a cold. Once meeting clinical criteria for a cold, the participants were then instructed to come to the clinical center within 24 hours to begin daily IFN-β versus placebo nebulization for 14 days. Study participants had a range of asthma severity, but all had persistent disease (British Thoracic Society [BTS] Guideline Steps 2–5) and histories of virus-induced asthma exacerbations in the prior 2 years. The primary outcome of the trial, change in ACQ-6 score from baseline to Day 8, was not significantly different between the IFN-β– and placebo-treated groups. IFN-β treatment led to a significant, but modest, improvement in peak flow compared with the placebo group.

Interestingly, in prespecified subgroup analyses, IFN-β effectively prevented virus-induced asthma symptoms, as assessed by the ACQ-6, in patients with more severe disease (BTS Steps 4–5). Greater improvements in peak flows were observed in this subgroup as well. The authors therefore conclude that future studies of IFN-β should target this population of patients with more severe asthma. However, it may be important to not simply select on the basis of disease severity, as selection by disease severity alone will identify a heterogeneous population of patients with asthma (6). Prior studies of biological therapies such as omalizumab and mepolizumab have identified the importance of targeting biological therapies to patients in whom underlying disease characteristics are targeted by the therapy (7, 8). Moving forward, it will be critical to identify patients most likely to achieve benefit from IFN-β therapy. For example, total IgE levels are inversely associated with RV-induced mononuclear cell IFN production, and allergen sensitization and exposure lead to significant impairment of IFN production (9, 10). Thus, one can hypothesize that targeting patients with type 2 predominant airway inflammation with moderate to severe disease will benefit most from IFN-β. This was not addressed in the current trial.

The authors suggest that enhanced innate immunity and improved viral clearance are the mechanisms responsible for the positive effects of IFN-β in this trial; however, it is unlikely that this tells the entire story. Prior studies have been unable to link viral load to severity of RV infections (11, 12). In addition to its antiviral effects, IFN-β has immune-modulating effects such as constraining type 2 inflammatory responses to RV infections (13), which play an important role in asthma exacerbations, and could contribute to the mechanisms of action of this intervention.

The potential deleterious effects of IFN-β seen in the patients with mild asthma are of interest as well. While peak flows were unaffected, IFN-β–treated participants with mild asthma (BTS Step 2) had increased symptoms from baseline to Day 8, although not significantly increased compared with placebo. The significance and mechanism of this observation are unknown. However, it has been reported that patients with mild asthma have normal epithelial cell IFN production (14–16). It is possible that the addition of exogenous IFN-β in these individuals could lead to greater inflammation and thus worsening symptoms. In future clinical trials with IFN-β, baseline assessment of IFN production may be of interest to address this question.

Djukanovic and colleagues report on a well-conducted clinical trial, but there are a number of limitations to consider. The ultimate target of IFN-β therapy is the prevention of severe virus-induced exacerbations, and these events were uncommon within this study. The authors acknowledge that larger, sufficiently powered studies are needed to assess the efficacy of IFN-β in exacerbation prevention. In addition, more comprehensive characterization of the study participants could have provided further insight into predictors of response to therapy.

As the development of IFN-β therapy continues, it will be of great interest to bring this strategy to the pediatric population, a group that has the greatest burden of virus-induced asthma exacerbations. Further, studies comparing the efficacy of IFN-β to other “yellow zone” strategies for exacerbation prevention, such as dynamic dosing with inhaled corticosteroid (ICS)/long-acting β-agonist or ICS/short-acting β-agonist combinations and 4× ICS dosing, will be very important.

In conclusion, this phase 2 trial of IFN-β nebulization therapy at the onset of cold symptoms in adult patients with asthma provides the proof of concept that an antiviral immune modulatory approach may be effective for the prevention of virus-induced asthma exacerbations. This therapy may be most effective in more severe asthma, and moving forward it is critical to design clinical trials to identify patients most likely to benefit from this novel intervention.