Inhaled interferon β ('IFN-β') for the treatment or prevention of asthma exacerbations caused by the common cold

 

Clinical need

Despite taking inhaled corticosteroids, asthmatics are still susceptible to exacerbations (worsening of asthma symptoms, refer to Figure 1 below). Respiratory virus infection (e.g. the common cold) is a major trigger for exacerbations and is associated with up to eight out of ten asthma related emergency department visits. Currently there are limited satisfactory treatments available to address this significant unmet medical need which is associated with a significant element of healthcare spending on asthma.

undefined

Figure 1: Loss of asthma control whilst on “gold standard” inhaled corticosteroid therapy (adapted from Reddel et al, 19991)

IFN-β deficiency

Asthmatics do not get more respiratory viral infections (common colds) than non-asthmatics, but infections are more likely to worsen inflammation in the lungs and cause exacerbations. Professor Donna Davies (one of the three Synairgen academic founders) and colleagues at the University of Southampton and Imperial College London found that lung cells from asthmatic volunteers were more vulnerable to virus infection, and found that more virus was produced in asthmatic cell cultures than non-asthmatic cultures2. They found that lung cells from asthmatics produced lower amounts of the key antiviral defence protein known as interferon beta (IFN-β) during virus infections. This offered a potential explanation for why the lungs of asthmatics are more affected by respiratory virus infections.

Boosting the immune response

By simply adding a small amount of IFN-β to cultures of lung cells from asthmatics it was shown that antiviral responses were improved (refer to Figure 2). This suggested that direct delivery of IFN-β to the lungs of asthmatics during a respiratory virus infection could limit the spread of the virus to the lungs and also ultimately reduce the number of asthma exacerbations.

Figure 2:
undefined

Intellectual property (patents) was exclusively in-licensed to Synairgen from the University of Southampton to protect this development programme. The patent was granted in the USA (August 2009), Europe (May 2010) and Japan (July 2011).

Development programme summary

  • Synairgen completed a successful Phase I safety and biomarker clinical trial of inhaled IFN-β in moderate asthmatic subjects (SG004). Inhaled IFN-β was well tolerated and evaluation of antiviral biomarker activity in the lungs confirmed activation of antiviral defences even in the absence of a virus. In effect in this Phase I trial, we were able to ‘trick’ the lungs into thinking there was an active virus infection, causing antiviral defences to be ‘switched on’. This was also shown through measuring neopterin, a well-recognised marker of IFN-β antiviral activity, in sputum (phlegm). Additionally, increases in gene expression (the ‘blueprint’ of proteins) of three antiviral proteins (MxA, 2-5-OAS and IP-10) were observed, indicating that inhaled IFN-β stimulated a broad antiviral response in the lung.
  • Synairgen followed this trial with a Phase II clinical trial (SG005) in a range of asthmatic patients, with moderate to severe asthma.
    • Patients were recruited into the trial and waited until they developed the early signs of a naturally acquired respiratory virus infection. When these symptoms appeared patients were given either inhaled IFN-β or inhaled placebo daily for 14 days. Initial data for this 147 patient trial became available in April 2012.
    • (i) Results in the whole trial population. Although SG005 missed its primary endpoint (change in asthma symptoms assessed by an asthma control questionnaire; ACQ) for the whole population who had a confirmed cold, patients taking inhaled IFN-β had better lung function (morning peak expiratory flow) during the two week treatment period. There were also fewer severe exacerbations (requiring treatment with oral corticosteroids/antibiotics or hospitalisation, for worsening asthma symptoms) in patients taking inhaled IFN-β.
    • (ii) Results in “difficult to treat” trial population. Of interest, the majority of patients suffering severe exacerbations came from a ‘difficult to treat’ group of asthmatics (BTS Step 4). In this group there was a significant improvement in asthma symptoms and better lung function.
    • In addition to the positive clinical data, sputum samples showed that there were fewer biological markers of inflammation (e.g. IL-8) in the lungs of patients taking IFN-β compared to placebo, suggesting that the lung cells were able to mount a better defence against the viruses.
    • The results were published in the American Journal of Respiratory and Critical Care Medicine in 20143.
  • In June 2014 the inhaled IFN-β programme was licensed to AstraZeneca, who commenced a Phase II trial in severe asthma in July 2015.
  • In April 2017, AstraZeneca handed back the rights of the inhaled IFN-β programme to Synairgen. Synairgen is awaiting full data analysis before making a decision on the future of the programme.

Asthma statistics

  • There are approximately 26 million asthmatics in the USA4
  • The economic cost to the US is $20.7 billion per year5
  • Asthma accounts for 1.7 million emergency department visits per year in the US6
  • 50% of the total cost of the asthma is apportioned to 10% of the asthmatic population with the severest disease7

Information about common colds

  • Adults get an average of two to four colds per year, mostly between September and May8
  • Young children suffer from an average of six to eight colds per year8

References

  1. Reddel H, Ware S, Marks G, Salome C, Jenkins C, Woolcock A. Differences between asthma exacerbations and poor asthma control. Lancet. 1999; 353(9150):364-9.
  2. Wark PA, Johnston SL, Bucchieri F, Powell R, Puddicombe S, Laza-Stanca V, Davies DE. Asthmatic bronchial epithelial cells have a deficient innate immune response to infection with rhinovirus. J. Exp. Med. 2005; 201(6):937-47
  3. Djukanović R, Harrison T, Johnston SL, Gabbay F, Wark P, Thomson NC, Niven R, Singh D, Reddel HK, Davies DE, Marsden R, Boxall C, Dudley S, Plagnol V, Holgate ST, Monk P; INTERCIA Study Group. The effect of inhaled IFN-β on worsening of asthma symptoms caused by viral infections. A randomized trial.Am. J. Respir. Crit. Care. Med. 2014;190(2):145-54.
  4. Centers for Disease Control and Prevention website (www.cdc.gov/nchs/fastats/asthma.htm)
  5. Morbidity & Mortality: 2009 Chart book on cardiovascular, lung and blood diseases produced by National Heart, Lung and Blood Institute
  6. American Lung Association. Trends in Asthma Morbidity and Motrality. July 2011 (www.lung.org)
  7. P.J. Barnes, B. Johnson, J.B. Klim. The Costs of Asthma. Eur Respir J 1996 9, 636-642
  8. American Lung Association: Facts About the Common Cold (www.lung.org)