SYMBICORT FAQs- COPD

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June 9, 2015

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COPD
Q: Why is PATHOS carried out in Sweden? Are results of
this study relevant only to the healthcare system in
Sweden?
PATHOS6 was carried out in Sweden because this is a country with a high-quality
storage system for electronic medical files. The data of the study were collected from
electronic data records of primary health care centers and linked with the mandatory
Swedish national registers. The data linkage was done by relying on the social
insurance numbers of the patients. These data are thus well suited for retrospective,
observational registry, "Real World Evidence" study. Researchers monitored the
patients treatment to get solid and unique information. This helped researchers find
out the correlation between COPD treatment strategies with clinical outcomes such
as hospital admissions, emergency visits, antibiotics and oral steroids usage.
The results from PATHOS are not only relevant to the health care system in Sweden.
COPD treatment strategies and the use of ICS/LABA in COPD treatment are not
applicable to only Sweden but are applicable to all places around the world.
Therefore, the effect of the therapy used in PATHOS for treating clinical
exacerbations is relevant not only to the health care system in Sweden but to all
other health care systems.

Q: The population characteristics of PATHOS differ from

the population of COPD living in Asia. Does this
difference in population distribution affect the research
results?
PATHOS6 is a Real World Evidence study, so an obvious value of this study is that it
may reflect the reality demographic distribution of COPD patients in Sweden. Due to
the cultures influence, most European countries have higher proportion of female
COPD patients than male. This is different from the demographic distribution of
COPD in Asia. However, while analyzing patients groups based on age, sex,
treatment duration, etc., the authors found that these factors did not influence the
study results. In other words, both groups of patients, male and female, showed
similar results to those of the general population. Therefore, the results from the
PATHOS study are consistent with the population in other countries and are not
affected by demographic characteristics.

Q: PATHOS is not a Randomized Controlled Trial.

Therefore, Budesonide/Formoterol may show higher
effectiveness because it is used on less severe COPD
patients. Is it possible that physicians in the study
perceived Fluticasone/Salmeterol to be a better fit for
treating more severe COPD patients?
PATHOS6 study analyzed a database of 9893 patients using ICS/LABA (7,155
patients using Budesonide /Formoterol and 2738 patients using
Fluticasone/Salmeterol). The patients in both groups were "matched" (paired up) at
the beginning of the study to ensure that two groups had similar characteristics.
After matching, the study had 2734 pairs of Seretide-Symbicort patients with similar
characteristics. The "matching" analysis (pairing) minimized the confounding
factors of non- random assignment of patients to treatments.

Q: How does one know that all factors causing variation to the results of
the study have been removed by the method of score-matching? Can the
31 variables chosen for score-matching ensure that the severity of COPD is
equivalent between the two groups? Did this study provide information
about the GOLD classification of COPD patients?
The parameters used to "match" (pair up) patients in the PATHOS6 study must satisfy 2 criteria (1) can be
collected from the medical records, and (2) were found to be important parameters that can affect the study
results. PATHOS study used 31 different variables. The important parameters that affected the exacerbation
risk were recorded in Sweden while monitoring the patients and thus, may be used for matching. These 31
variables reflected most of the COPD burden faced by patients in the study.
The "matching" analysis minimized the confounding factors which can affect the results of the study.
The PATHOS study was published in 2 journals:
(1) Internal Medicine Journal acknowledged the comparable results between the exacerbation rate in
two groups of COPD patients using two different types of ICS/LABA
(2) BMJ acknowledged the comparable results between the incidence of pneumonia in two groups of
COPD patients using two different types of ICS / LABA
These two results used the same research method, the same matching method, the same variables and
database. However, the authors only used part of the database when published on each journal according to
the requirements of respective Evaluation and Approval Council of each journal. This is why the numbers of
variables differ in 2 reputable journals. A total of 26 variables were mentioned in these journals. However, in
this study, the authors used 31 pairs of variables for matching and analysis (However, a few variables were
not mentioned in the full text).

Q: The table analyzing the characteristics of patients at

the start of the study records only around 20% of the
patients possessing FEV1 data. Does this affect the result
of the study?
Although the use of spirometers at primary healthcare centers in Sweden has
grown tremendously in the past decade and is increasingly popular, there is no
routine procedure for storing electronic data of respiratory function of each patient.
The data were stored in different places for different centers under different forms
in the medical record systems, be it personal computer or paper records. Therefore,
it was not possible to retrieve electronic data of FEV1 for all patients.
The matching method used in the study was a 1:1 matching in order to create two
groups of patients using Symbicort vs. Fluticasone/Salmeterol with similar
propensity scores, implying similar burden of COPD. When the authors analyzed
only the group of patients with FEV1 data who were matched between the two
groups, they saw similar results when compared to the general population of 5468
patients (including patient groups with and without FEV1 data). Whether or not
FEV1 data was included, results of the PATHOS6 study would still be unchanged.
Therefore, the lack of information on FEV1 does not affect the published results of
this study.

Q: In the study, the physicians in charge were primary care

physicians and not respiratory specialist physicians. Does this
affect the result of the study?
The process of gathering information in the PATHOS6 study was carried out
as follows:
Starting with the data from 76 primary healthcare centers, the authors found
21361 patients with COPD. They then retrieved all the information of these
patients through social insurance books of the Department of Health and
Social Welfare Department, including details of treatment, diagnostic
parameters, drugs use, cause hospitalization, mortality, ... At the same time,
they linked the patients data with those of major hospitals (in the case
where patients were transferred to a different hospital) . All data collected
was sent to the research center of the University of Uppsala-Sweden to be
processed. Therefore, the study results of PATHOS not only assessed the
effectiveness of treatment in one group of primary care physicians but
during the 11 years tracking COPD patients through their history of
treatment, starting from the primary care centers.

Q: Were diagnoses of patients with pneumonia in the study

supported by pulmonary x-ray?
Not only PATHOS but all previous RCTs on COPD classified pneumonia as
an adverse event. Therefore, the diagnosis of pneumonia can be based on
clinical examination of a doctor or on pulmonary x-ray. In PATHOS study,
more than 67% of pneumonia cases were diagnosed from the hospital with
X-ray method, which is one of the routine diagnostic procedures for
diagnosing pneumonia.

Q: How do you explain the difference between ICS dose used in the
study and ICS recommened dose?
The results of the study show that in real-life therapy, the two ICS/LABA
drugs are used at doses different than recommended doses. However, the
average dose of Budesonide found in the research survey was 568g/day
and 783 g/day for Fluticasone. This showed that 80-90% of patients in the 2
groups followed the recommended dose.

Q: PATHOS study showed that Symbicort group used on average

568 g Budesonide/day and Fluticasone/Salmeterol group used on
average 783 g Fluticasone/day. Is this difference the cause of a
higher rate of pneumonia in the Fluticasone/Salmeterol group?
PATHOS6 is a Real World Evidence study, which recorded real-life medical
practices in the community regarding treatment doses and clinical
outcomes, including factors causing increase/decrease of doses depending
on the patient's condition and clinical examination of doctors. According to
the products prescribing information, the recommended dose of
Budesonide in Symbicort is 640 g/day and of Fluticasone in
Fluticasone/Salmeterol is 1000 g/day. Thus, the doses used in PATHOS
were relatively consistent with the prescribing information of these 2
products.
On the other hand, with the aforementioned doses, the efficacy in reducing
exacerbation risk of Symbicort was 26% higher than that of
Fluticasone/Salmeterol. This confirmed the advantage of using Symbicort in
treating COPD because its ICS was used at a lower dose yet its therapeutic
efficacy was better with higher safety.

Q: What are the differences between Real World Evidence (RWE) and
Randomized Controlled Trial (RCT)?

Randomized clinical trial is often the gold standard in which the effectiveness and safety
of drugs are shown. However, these studies are often designed with strict control and thus
they are limited and protected from the impact of actual treatment variables. Thus, they
cannot answer problems related to actual health care processes in everyday life. The
limitations of randomized clinical trials include: removal of previous therapies, short
follow-up time, small study population, quitting of patients, excluding patients with
associated diseases, conditions for adherence too strict, unrealistic and incapable of
detecting rare adverse events (<1%) or of drug interactions due to restriction applied on
patients to not use multiple drugs simultaneously.
"Real World Evidence" studies can bring about benefits of costs and reflect the reality of
daily therapy that randomized trials cannot. These studies will provide better information
about the use of drugs in everyday treatment, real-life situations, etc.
Please note that we are not proposing that RWEs can replace RCTs; RCTs are considered to be
the Gold Standard however data represented through RWEs may be more closer to the real world
practice.

Q: PATHOS study showed the difference between the two groups

Budesonide/Formoterol and Fluticasone/Salmeterol in their
effectiveness on controlling exacerbation and safety in treating
pneumonia. How do you explain this difference?
Explanation for the differences in pneumonia:
The problem of pneumonia in COPD patients when using ICS/LABA has existed since
long. Before PATHOS, there were at least 5 randomized clinical trials (RCTs) showing
Fluticasone/Salmeterol increased the risk of pneumonia compared to placebo-group
and other bronchodilators.6
According to the authors of PATHOS, the difference of pneumonia risk in COPD
patients using ICS/LABA containing budesonide or fluticasone may be related to the
pharmacological properties of these two ICS. When inhaled, corticosteroids will stay at
high concentrations in the lungs and increase the risk of pneumonia due to its
immunosuppressive properties. Immunosuppressive potency of Fluticasone is about
10 times higher than that of Budesonide, which in ex vivo inhibits alveolar
macrophages from activating the intrinsic immune system against invading bacteria7.
This may be one reason to explain the higher risk of pneumonia in the group of
Fluticasone/Salmeterol compared to the group of Budesonide/Formoterol. In addition,
differences in pharmacodynamic properties and pharmacological activities related to
solubility properties (water-based or oil-based) can lead to differences in the risk of
pneumonia between Budesonide and Fluticasone8. In patients with severe COPD,
Fluticasone molecule with relatively high oil make-up will last longer in the mucous
membrane and alveolar epithelial cells compared with Budesonide9. This can cause
stronger and longer local immunosuppression after using Fluticasone compared with
Budesonide, increasing local bacterial growth and leading to pneumonia.

Explanation for the differences in the rate of exacerbation:

The authors of PATHOS6 hypothesized an explanation for the differences
in the rate of exacerbation between the two groups
Budesonide/Formoterol and Fluticasone/Salmeterol. According to this
hypothesis, there is a significant amount of bacteria in the lower
respiratory tract in patients with well-controlled COPD. The bacteria may
contribute to stimulating airway inflammation, leading to the start of an
exacerbation.
On the other hand, we know that the immunosuppressive potency of
Fluticasone is about 10 times higher than that of Budesonide. Therefore,
Fluticasone may facilitate favourable conditions for bacteria in the lower
respiratory tract of patients to develop stronger, affecting the rate of
exacerbation.

SYMBICORT
Q: Formoterol is a full agonist while Salmeterol
is a partial agonist. What is the difference?
A partial agonist can activate the respective receptors but cannot promote
the maximum effect like a full agonist even after saturation of receptors
(according to Trn Th Thu Hng, Pharmacokinetics, 2006). In other words, a
full agonist leads to a tight and clear relationship between the dose and the
response whereas a partial agonist does not.

Q: Fluticasone shows higher ICS potency which

can help moderate-severe asthma patients to
achieve asthma control faster.
Higher potency does not equate to high efficacy. Potency is how much drug
concentration to produce an action. But when looking into clinical studies,
indicated dosage shows better efficacy with Symbicort.

ULTIBRO FAQs

SPARK study - Ultibro

Ultibro (glycopyrronium/indacaterol)
SPARK TRIAL : To evaluate the effect of dual, long acting inhaled
bronchodilator treatment on exacerbations in patients with severe & very severe
COPD

1st in Class for LABA/LAMA

STRENGTH

Well-designed study with 64 weeks ( long-term study )

Significantly reduced the rate of moderate to severe
exacerbations versus glycopyrronium by 12%

75% of patients used ICS as standard therapy

WEAKNESS

Both glycopyrronium and indacaterol are not best in

class for LAMA and LABA
No differences in severe exacerbation

Ultibro (glycopyrronium/indacaterol)
SPARK TRIAL : To evaluate the effect of dual, long acting inhaled bronchodilator treatment on
exacerbations in patients with severe & very severe COPD

If I were a Symbicort Rep

Key Take Away

SPARK trial, Ultibro significantly
reduced the rate of severe or very
severe COPD exacerbations compared to
glycopyrronium 50 mcg
Ultibro significantly reduced the rate of all
COPD exacerbations compared to openlabel tiotropium 18 mcg and
glycopyrronium
Ultibro also demonstrated significant
improvements in lung function and
health-related quality of life
Statistical significance was observed for
the primary endpoint with inhaled
corticosteroid use which should be
interpreted with caution since most patients
used ICS
Ultibro indicated in limited group of patients
with emphysema-predominant COPD and
low exacerbation risk only

Based on GOLD revised 2014, combination of

ICS/LABA is recommended first choice which is
more effective in improving lung function and
reduce exacerbations in gold C&D COPD
patients
Symbicort is ICS/LABA combination which
strongly provide reduction of exacerbations
significantly in moderate to very severe COPD
patients
PATHOS : Symbicort significantly reduced 26%
all cause exacerbations (NNT is 3.4) and the
29% reduction in hospital admissions (NNT =
16) in moderate to severe COPD patients
CLIMB: Symbicort + tiotropium as triple therapy
decreased the rate of severe exacerbations by
62% and decreased the number of
hospitalizations/emergency room visits by 65%
compared with tiotropium alone
Symbicort indication cover both asthma and
COPD

Strategic drivers for Symbicort vs. Seretide

Use the launch of the LAMA/LABA class to re-establish Symbicort as a vital treatment
option for inflammatory / exacerbating COPD patients and all asthma patients through clear
positioning and strong communication of the evidence
1. Define and defend key patient groups through clear positioning

Clearly position the role and importance of Symbicort vs. LAMA/LABA in

three key target patient groups:
- At risk of exacerbation / those with an inflammatory component
- Those with mixed disease / uncertain diagnosis (COPD and asthma)
- Patients in need of triple therapy (often very severe patients)

2. Position LAMA/LABAs in a relevant patient type

Create the perception that patients with emphysema and without inflammation who are
experiencing breathlessness on mono-bronchodilation will gain significant additional
benefit from LAMA/LABAs without an ICS

3. Invest in evidence generation and share of voice

Consider the potential for a clinical trial to show that switching to Symbicort delivers better
outcomes than switching to LABA / LAMA

Confidential information for internal AZ use only. Any potential promotional messaging/product
claims are subject to regulatory review and approval and local promotional practices and policies.

Ultibro (glycopyrronium/indacaterol)
SPARK TRIAL : Statistical significance was observed for the primary endpoint
with inhaled corticosteroid use

Ultibro SWOT
(50mcg Glycopyrronium + 110mcg Indacaterol)
Breezhaler DPI, Once Daily LABA/LAMA, 30 capsules per
blister pack

Ultibro (50mcg Glycopyrronium + 110mcg Indacaterol)

Breezhaler DPI, Once Daily LABA/LAMA, 30 capsules per blister pack
Strengths

Exclusivity and innovative: First fixed-dose LAMA/LABA

combination
The only LAMA/LABA with exacerbation data at launch
(SPARK trial)
In clinical trials, it demonstrates significant improvement
in Lung Function and QOL (INGNITE trials : SPARK,
SHINE and ILLUMINATE)
Perceived by HCPs to provide better efficacy with better
side-effects than ICS/LABA and at no added cost to
patients
Very convenient dosing for patients (Once daily dosing)
Opportunities

New data and evidence supporting that the withdrawal

of ICS in COPD patients offers no difference versus
maintaining patients on LAMA/LABA (Wisdom trial)
Further support in using LAMA/LABA in international and
local guidelines (GOLD 2015 reccomends LAMA/LABA as
alternate treatment for GOLD B,C,and D)
Pneumonia seen by HCPs as a class effect of ICS
LAMA/LABA is well talked about as treatment for COPD
patients
(ATS,
ERS,
40 Author
| 00 Month
Year APSR, Loc. Societies, Clinical Trials)

Weaknesses

Inconvenient storage and

handling (needs to be kept below
25 degrees Centigrade and
capsules must only be removed
immediately from the blisters
before actual use)
Both Glycopyrronium and
Indacaterol are not best in class
LAMA or LABA
Threats

New LAMA/LABA launches

expected within 6 mos. to 1 year of

Ultibro launch (limited window of
exclusivity)
Introduction of new LAMA/LABA
fixed dose combinations with
NOVEL delivery devices, including
pMDI Set area descriptor | Sub level 1

PPO for Ultibro

Who: Specialists managing COPD
What: Establish Ultibro as the first choice treatment for all COPD patients
Where: Treatment Initiation and Intensification

Barrier 1
Physicians still believe
that PMDi is easier to use
for their patients with
COPD

Educate HCPs on
the role of
LAMA/LABA and
Ultibro in managing
broad COPD patient
types
41

Author | 00 Month Year

Barrier 2

Barrier 3

There are some HCPs that

New LAMA/LABA
still adhere to Clinical
launches will dilute brand
Practice Guidelines (CPGs),
equity
and LAMA/LABA is only an
alternate treatment for COPD
(Level B-C evidence)

Partner with local

societies to include
Ultibro in CPGs

Set area descriptor | Sub level 1

Facilitate and own

COPD patient
education. Teach
patients about
COPD and their
treatment, and how
to use Ultibro

References:

1. INSPIRE Study- Wedzicha J., et al, Am J Crit Care Med 2008; 177:19-26
2. GINA 2014
3. COMPASS Study- Kuna P., et al, Int J Clin Pract, May 2007, 61, 5, 725736

4. AHEAD- Bosquet J., et al, J Resp Med, .2007.07.014

5. COSMOS- Vogelmeier C., et al, Eur Resp J, 2005 Vol 26 no. 5
6. PATHOS study 2013
7. Thorax 2006, 61:164-168
8. Respiratory Med (2008) 102, 1099-1108
9. Sin et al, The Lancet, Volume 374, Issue 9691
10. Nannini LJ, the Cochrane Library, 2012, Issue 9

11. SPARK Study- Wedzicha J., et al, Lancet Respir Med 2013; 1:199-209

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Author | 00 Month Year

Set area descriptor | Sub level 1