Portfolio news 2012
Synairgen plc - Positive Phase II asthma data
19 Apr 2012
Southampton, UK - 19 April 2012: Synairgen plc (LSE: SNG),
announces positive data from its Phase II clinical trial.
This pioneering trial investigated the potential for SNG001
(inhaled interferon beta) to protect asthmatics from
respiratory virus infections (principally the common cold)
that can spread to the lung, which are a major cause of
worsening asthma symptoms. It is estimated that viral
infection is associated with up to eight out of ten
asthma-related emergency department visits.
There are 5.4 million asthmatics in the UK (Asthma UK) and
25.7 million in the USA (Centers for Disease Control and
Prevention).
The study investigated SNG001 in a population of 134 adult
asthma patients, representing 'mild-moderate'
through to 'severe' asthmatics, who caught a cold.
Patients with 'difficult to treat' asthma, being
approximately half of the patients in the trial, benefitted
significantly from SNG001 treatment. This category of
patient is estimated to represent between 10% and 20% of
all adult asthma sufferers.
The key trial findings in this 'difficult to treat'
category were:
Clinically important and statistically significant
differences in favour of SNG001 as compared to placebo
across recognised measures of asthma symptom severity and
lung function including:
-
Prevention of worsening of asthma symptoms during the
critical first week of infection and treatment as
measured by the Asthma Control Questionnaire (sACQ)
(p=0.004)
-
65% reduction in the number of patients experiencing
moderate exacerbations during the treatment period
(p=0.01)
-
Reduced use of inhaled reliever bronchodilators on day
5 (p=0.02) and day 6 (p=0.01)
-
In the SNG001-treated patients there was a steady
improvement in morning peak expiratory flow whilst in
the placebo-treated patients there was an initial dip
during the first week followed by an improvement
(p=0.03)
-
SNG001 was well tolerated
Professor Stephen Holgate CBE, leading international asthma
specialist and founder of Synairgen, said: "This is a
really promising breakthrough for the future treatment of
asthma and one of the most exciting developments that I
have seen in years. This is the first clinical study which
appears to demonstrate that, by boosting the antiviral
defences of the lungs of asthmatics rather than trying to
inhibit rapidly evolving viruses, we can limit the adverse
effects of viral infection significantly to prevent
worsening of asthma symptoms in a high risk group of
patients.
This trial is an important milestone in the development of
our SNG001 programme from its origins in research supported
by the MRC, Asthma UK, the British Lung Foundation, the
National Institute of Health Research and the University of
Southampton, to today's exciting results in this
'real world' asthma study. Not only have we
established the potential of SNG001 as a novel treatment
for viral exacerbations in difficult to treat asthma but
also a crucial link between viral infection, asthma
symptoms and severity of disease.
These impressive findings across different endpoints,
together with the accumulating body of evidence we have
generated for other respiratory viruses such as influenza
(Swine and Bird flu) and respiratory syncytial virus (RSV),
strongly suggest that SNG001 has the potential to be used
as a powerful broad spectrum antiviral respiratory drug in
other lung diseases such as COPD and pandemic flu."
Leanne Metcalf, Assistant Director of Research at Asthma
UK, says: "This has the potential to be one of the
biggest breakthroughs in asthma treatments in the past 20
years. We are incredibly excited by the possibilities this
research could bring to reduce hospital admissions and
deaths as a result of asthma attacks. Over 80% of asthma
attacks are triggered by cold and flu viruses, and until
now we haven't had any effective treatments that can
stop this from happening. This clinical trial demonstrates
the potential of this anti-viral drug to prevent asthma
attacks for thousands of people with severe asthma. We are
incredibly proud to have played a part in the realisation
of this research programme which should benefit people with
asthma in a really significant way."
Richard Marsden, Chief Executive of Synairgen, said,
"This is a great result for the development of our
programme. To put SNG001's potential into
context, it is estimated that in the US alone there are
some 2 to 4 million difficult to treat (Step 4 and 5) adult
asthma sufferers who could benefit from this therapy.
Children, who get more colds than adults, represent an
additional asthma market opportunity. We believe that there
will be even greater potential in COPD. We continue to
analyse the wealth of data generated by this important
trial and to plan the next phase of its development,
ideally alongside an industry partner. "
For further information, please contact:
Synairgen
plc
Tel: + 44 (0) 23 8051 2800
Richard Marsden, Chief Executive Officer
John Ward, Finance Director
Asthma UK
Tel: + 44 (0) 20 7786 4949
FinnCap
Tel: + 44 (0) 20 7220 0500
Geoff Nash, Christopher Raggett (Corporate Finance)
Stephen Norcross, Simon Starr (Corporate Broking)
NewgateThreadneedle
Tel: + 44 (0) 20 7653 9850
Graham Herring
Josh Royston
Notes to Editors
1) About Synairgen
Synairgen is a respiratory drug development company founded
by Professors Stephen Holgate, Donna Davies and Ratko
Djukanovic at the University of Southampton, with a
particular focus on lung antiviral defence in asthma, COPD
and severe viral infections. Synairgen is listed on AIM
(LSE: SNG).
For more information about Synairgen please see www.synairgen.com.
2) SG005 Structure of trial and detailed
study findings
Structure of trial
The Phase II multi-centre, randomised, double-blind,
placebo-controlled study recruited a broad spectrum of
adult asthmatic patients, all of whom were taking inhaled
corticosteroids and had a history of deteriorating symptoms
when they contracted common respiratory viruses (primarily
the common cold). 147 patients were randomised to receive
either SNG001 or placebo for 14 days at the onset of cold
symptoms.
Detailed study findings
· 134 out of the 147 patients (91%) who
commenced treatment had confirmed colds as determined by
the Jackson Cold Score and formed the modified intention to
treat population (mITT). These patients are used for the
analysis of efficacy.
· A range of respiratory viruses were
identified in nasal lavage and sputum samples, of which
rhinoviruses represented 68% of detected viruses.
· Common cold symptoms tightly correlated
with worsening asthma symptoms.
· Patients with worse underlying asthma
(more intensively treated with routine asthma therapies)
before onset of cold symptoms were more adversely affected
by the cold than patients with less problematic asthma.
· Approximately half the patients in the
trial were categorised as falling within the highest two
steps of the asthma spectrum as defined by the British
Thoracic Society (BTS) and Global Initiative for Asthma
(GINA) Guidelines (Steps 4 and 5). This group is estimated
to represent some 10%-20% of the adult asthma population
and is the most expensive to treat.
o A clinically meaningful and statistically significant
favourable difference in asthma control, measured using the
shortened Asthma Control Questionnaire (sACQ) over the
first week of treatment (for which a change in individual
score of 0.5 or more is considered to be clinically
relevant):
§ from pre-treatment baseline levels (mean change in sACQ
score: placebo: 0.53, SNG001: -0.10, difference: -0.63,
p=0.004). This met the criteria for the primary endpoint.
§ from screening levels (mean change in sACQ score:
placebo: 0.90, SNG001: 0.22, difference: -0.67, p=0.003).
Furthermore, the proportion of patients having an increase
of more than 0.5 (p=0.012) from pre-treatment baseline was
reduced by two-thirds in SNG001-treated patients over the
first week of treatment.
o The proportion of patients having moderate exacerbations
was significantly lower in SNG001-treated patients
(placebo: 54%; SNG001: 19%) during the treatment phase
(p=0.01).
o In addition (and not included in the moderate
exacerbation data above), during treatment, 2 placebo
patients (one of whom was hospitalised for 5 days) took a
course of oral steroids and one other placebo patient had a
course of antibiotics (all for a deterioration in asthma
symptoms). No SNG001 patients required oral steroids,
hospitalisation or antibiotics during treatment.
o Inhaled reliever bronchodilator usage was significantly
less for the SNG001-treated patients on day 5 (p=0.017) and
day 6 (p=0.0096).
o Morning peak expiratory flow rate ('PEFR'), a
measure of lung function, was significantly lower in
placebo compared to SNG001-treated patients as measured by
area under the curve analysis of morning PEFR change from
Day 2 to the end of treatment (p=0.03). Day 2 was the first
timepoint at which morning PEFR was recorded during the
treatment period.
· The Company has also conducted
statistical analyses using the GINA step classifications.
Similar results were found for the difference in sACQ over
the first week of treatment in Step 4 and 5 GINA classified
patients (a more expansive group than the BTS
classification: placebo: n=42; SNG001: n=32) between
SNG001- and placebo-treated patients:
o from pre-treatment baseline levels (mean change in sACQ
score: placebo: 0.40, SNG001: 0.00, difference: -0.40,
p=0.048).
o from screening levels (mean change in sACQ score:
placebo: 0.78, SNG001: 0.32, difference: -0.46, p=0.028).
· Viral infection in both groups was
accompanied by an increase in a biomarker of anti-viral
activity. While this rapidly decayed in the placebo-treated
group, those receiving SNG001 had a persistent elevation in
the biomarker as long as the 14 day treatment was
administered, but rapidly decayed to screening levels after
treatment. Thus SNG001 was pharmacologically active
irrespective of asthma severity.
· SNG001 was well tolerated, in line with
the Phase I data.
Stepwise management of asthma in adults
· British Guideline on the Management of
Asthma (produced by The British Thoracic Society
('BTS') and Scottish Intercollegiate Guidelines
Network)1
o Step 1 (Mild intermittent asthma) - inhaled short-acting
beta-agonist
o Step 2 (Regular preventer therapy) - add inhaled steroid
200-800 mcg/day*
o Step 3 (Initial add-on therapy) - add inhaled long-acting
beta-agonist ('LABA'). If no response, stop LABA,
increase inhaled steroids to 800mcg/day* and trial other
therapies such as leukotriene receptor antagonist or SR
theophylline
o Step 4 (Persistent poor control). Consider trials of
:increasing inhaled steroid up to 2000 mcg/day*; addition
of fourth drug (eg leukotriene receptor antagonist, SR
theophylline, beta-agonist tablet)
o Step 5 (Continuous or frequent use of oral steroids). Use
daily steroid tablet. Maintain high dose inhaled steroid at
2000 mcg/day*
*BDP or equivalent
For the full guidelines refer to the British Thoracic
Society website (www.brit-thoracic.org.uk).
· Global Initiative for Asthma
('GINA') Treatment Steps2
o Step 1 - inhaled short-acting beta-agonist
('SABA')
o Step 2 - SABA plus either low dose inhaled steroid or
leukotriene modifier
o Step 3 - SABA plus one of:
§ low dose inhaled steroid + LABA
§ medium or high dose inhaled steroid
§ low dose inhaled steroid + leukotriene modifier
§ low dose inhaled steroid + SR theophylline
o Step 4 - To Step 3 treatment select one or more of:
§ Medium or high dose inhaled steroid + LABA
§ Leukotriene modifier
§ SR theophylline
o Step 5 - Step 4 treatment plus one of:
§ Oral steroid
§ Anti-IgE treatment
For the full guidelines refer to the GINA website (www.ginasthma.org).
3)
Background to Synairgen's interferon beta
('IFN-beta') programme for virus-induced asthma
exacerbations
Using in vitro human models, it was discovered that
epithelial cells (cells which line the airways) from
patients with asthma3 have significantly weaker antiviral
responses to the common cold virus than non-asthmatic
controls. The addition of low levels of IFN-beta into the
models restored antiviral responses (simulating aerosolised
IFN-beta therapy). This suggests that local delivery of
IFN-beta to the lungs could limit the spread of virus to
the lungs in patients with respiratory disease and the
consequent worsening of their symptoms.
Synairgen has entered into a supply and licence agreement
for a patent-protected formulation of IFN-beta from the
Rentschler Group in Germany.
SG004
SG004, a placebo-controlled Phase I study in controlled
asthmatics taking inhaled corticosteroids, used the
Company's exclusively in-licensed Rentschler
formulation of inhaled IFN-beta and was designed to
establish its safety at three different dose regimens over
a 14 day period. In addition, biomarker activity (see
below) was measured as an indicator of antiviral activity.
The trial was completed in September 2009 and showed that
inhaled IFN-beta was well tolerated, causing no adverse
effect on standard measures of lung function and
inflammation.
SG004 Biomarkers
Neopterin is a well-recognised biomarker of IFN-beta
activity. Having developed and validated a test for
measuring neopterin in airway secretions, analysis of the
SG004 samples showed statistically significant and dose
dependent increases in neopterin levels, indicating that
biologically active drug had been successfully delivered to
the lung. Furthermore, there were increases of
between 4-fold and 64-fold in the gene expression of three
antiviral proteins (MxA, 2-5-OAS and IP-10) in the lung
cells of the asthmatic volunteers 24 hours after inhaling
IFN-beta, indicating that inhaled IFN-beta stimulated a
broad antiviral response in the lung.
Patents granted
The patents for inhaled IFN-beta to treat rhinovirus
infections in asthma and COPD were granted in the USA in
2009, Europe in 2010 and Japan in 2011. The patents form
part of a patent portfolio owned by the University of
Southampton, which is exclusively licensed to Synairgen.
4) Asthma statistics
· 25.7 million Americans have asthma, of
which 18.7 million are adults (aged 18 and over) and 7.0
million are children4
· The economic cost to the USA of asthma
is projected to be $20.7 billion for 20105
· In 2006, asthma accounted for 1.7
million emergency department visits in the USA6
· Hospital care for asthma in the USA is
projected to be $5.5 billion for 20105
· The average duration of a
hospitalisation for an asthma exacerbation in the USA is
2.7 days at a cost of $9,0787
· 50% of the total cost of asthma is
apportioned to 10% of the asthmatic population with the
severest disease8
5) Rhinovirus (common cold
virus) and exacerbations (worsening of symptoms) of asthma
· Adults get an average of two to four
colds per year, mostly between September and May. Young
children suffer from an average of six to eight colds per
year9
· Rhinovirus infections are the major
cause of asthma exacerbations, accounting for 50% to 80% of
all such attacks in both children and adults10
References
1. Sourced from the British Guideline on the Management of
Asthma. A national clinical guideline. May 2008. Revised
January 2012 (www.brit-thoracic.org.uk)
2. Sourced from Global Initiative for Asthma - Global
Strategy for Asthma Management and Prevention. Updated 2011
(www.ginasthma.org)
3. P. Wark et al. Asthmatic bronchial epithelial cells have
a deficient innate immune response to infection with
rhinovirus. J Exp Med. 2005; 201: 937-947
4. Centers for Disease Control and Prevention website
(www.cdc.gov/nchs/fastats/asthma.htm)
5. National Heart, Lung and Blood Institute. Morbidity and
Mortality 2009 Chart Book on Cardiovascular, Lung and Blood
Diseases
6. American Lung Association. Trends in Asthma Morbidity
and Mortality. July 2011 (www.lung.org)
7. V. Krishnan et al. Mortality in patients hospitalized
for asthma exacerbations in the United States. Am J Respir
Crit Care Med 2006 174, 633-638
8. P.J. Barnes, B. Johnson, J.B. Klim. The Costs of Asthma.
Eur Respir J 1996 9, 636-642
9. American Lung Association: Facts About the Common Cold
(www.lung.org)
10. J.T. Kelly et al. Host immune responses to rhinovirus:
Mechanisms in asthma. J Allergy Clin Immunol 2008; 122:
671-682
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