symbicort faqs- copd.pdf

8/18/2019 SYMBICORT FAQs- COPD.pdf

1/25

SYMBICORT FAQs- COPD

June 9, 2015

Objection Handler

FOR INTERNAL USE/ TRAINING PURPOSES ONLY.DO NOT DISTRIBUTE FURTHER.


2/25

COPD

PATHOS 6 was carried out in Sweden because this is a country with a high-qualitystorage system for electronic medical files. The data of the study were collected fromelectronic data records of primary health care centers and linked with the mandatorySwedish national registers. The data linkage was done by relying on the socialinsurance numbers of the patients. These data are thus well suited for retrospective,observational registry, "Real World Evidence" study. Researchers monitored thepatients’ treatment to get solid and unique information. This helped researchers findout the correlation between COPD treatment strategies with clinical outcomes suchas 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 notapplicable to only Sweden but are applicable to all places around the world.Therefore, the effect of the therapy used in PATHOS for treating clinicalexacerbations is relevant not only to the health care system in Sweden but to allother health care systems.

Q: Why is PATHOS carried out in Sweden? Are results ofthis study relevant only to the healthcare system inSweden?


3/25

Q: The population characteristics of PATHOS differ fromthe population of COPD living in Asia. Does thisdifference in population distribution affect the research

results?PATHOS 6 is a Real World Evidence study, so an obvious value of this study is that itmay reflect the reality demographic distribution of COPD patients in Sweden. Due tothe culture’s influence, most European countries have higher proportion of femaleCOPD patients than male. This is different from the demographic distribution ofCOPD in Asia. However, while analyzing patients groups based on age, sex,treatment duration, etc., the authors found that these factors did not influence thestudy results. In other words, both groups of patients, male and female, showedsimilar results to those of the general population. Therefore, the results from thePATHOS study are consistent with the population in other countries and are notaffected by demographic characteristics.


4/25

Q: PATHOS is not a Randomized Controlled Trial.Therefore, Budesonide/Formoterol may show highereffectiveness because it is used on less severe COPDpatients. Is it possible that physicians in the studyperceived Fluticasone/Salmeterol to be a better fit fortreating more severe COPD patients?

PATHOS 6 study analyzed a database of 9893 patients using ICS/LABA (7,155patients using Budesonide /Formoterol and 2738 patients usingFluticasone/Salmeterol). The patients in both groups were "matched" (paired up) atthe beginning of the study to ensure that two groups had similar characteristics.After matching, the study had 2734 pairs of Seretide-Symbicort patients with similarcharacteristics. The "matching" analysis (pairing) minimized the confoundingfactors of non- random assignment of patients to treatments.


5/25

Q: How does one know that all factors causing variation to the results ofthe study have been removed by the method of “score -matching”? Can the31 variables chosen for score-matching ensure that the severity of COPD isequivalent 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 PATHOS 6 study must satisfy 2 criteria (1) can becollected from the medical records, and (2) were found to be important parameters that can affect the studyresults. PATHOS study used 31 different variables. The important parameters that affected the exacerbationrisk were recorded in Sweden while monitoring the patients and thus, may be used for matching. These 31variables 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 intwo 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 ofCOPD patients using two different types of ICS / LABA

These two results used the same research method, the same matching method, the same variables anddatabase. However, the authors only used part of the database when published on each journal according tothe requirements of respective Evaluation and Approval Council of each journal. This is why the numbers ofvariables differ in 2 reputable journals. A total of 26 variables were mentioned in these journals. However, inthis study, the authors used 31 pairs of variables for matching and analysis (However, a few variables werenot mentioned in the full text).


6/25

Q: The table analyzing the characteristics of patients atthe start of the study records only around 20% of thepatients possessing FEV1 data. Does this affect the result

of the study?Although the use of spirometers at primary healthcare centers in Sweden hasgrown tremendously in the past decade and is increasingly popular, there is noroutine 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 twogroups of patients using Symbicort vs. Fluticasone/Salmeterol with similarpropensity scores, implying similar burden of COPD. When the authors analyzedonly the group of patients with FEV1 data who were matched between the twogroups, they saw similar results when compared to the general population of 5468patients (including patient groups with and without FEV1 data). Whether or notFEV1 data was included, results of the PATHOS 6 study would still be unchanged.Therefore, the lack of information on FEV1 does not affect the published results ofthis study.


7/25

Q: In the study, the physicians in charge were primary carephysicians and not respiratory specialist physicians. Does thisaffect the result of the study?

The process of gathering information in the PATHOS 6 study was carried outas follows:

Starting with the data from 76 primary healthcare centers, the authors found21361 patients with COPD. They then retrieved all the information of thesepatients through social insurance books of the Department of Health andSocial Welfare Department, including details of treatment, diagnosticparameters, drugs use, cause hospitalization, mortality, ... At the same time,they linked the patient’s data with those of major hospitals (in the casewhere patients were transferred to a different hospital) . All data collectedwas sent to the research center of the University of Uppsala-Sweden to beprocessed. Therefore, the study results of PATHOS not only assessed theeffectiveness of treatment in one group of primary care physicians butduring the 11 years tracking COPD patients through their history oftreatment, starting from the primary care centers.


8/25

Q: Were diagnoses of patients with pneumonia in the studysupported by pulmonary x-ray?

Not only PATHOS but all previous RCTs on COPD classified pneumonia asan adverse event. Therefore, the diagnosis of pneumonia can be based onclinical 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 fordiagnosing pneumonia.


9/25

Q: How do you explain the difference between ICS dose used in thestudy and ICS recommened dose?

The results of the study show that in real-life therapy, the two ICS/LABAdrugs are used at doses different than recommended doses. However, theaverage dose of Budesonide found in the research survey was 568µg/dayand 783 µg/day for Fluticasone. This showed that 80-90% of patients in the 2groups followed the recommended dose.


10/25

Q: PATHOS study showed that Symbicort group used on average568 µg Budesonide/day and Fluticasone/Salmeterol group used onaverage 783 µg Fluticasone/day. Is this difference the cause of ahigher rate of pneumonia in the Fluticasone/Salmeterol group?

PATHOS 6 is a Real World Evidence study, which recorded real-life medicalpractices in the community regarding treatment doses and clinicaloutcomes, including factors causing increase/decrease of doses dependingon the patient's condition and clinical examination of doctors. According tothe product’s prescribing information, the recommended dose ofBudesonide in Symbicort is 640 µg/day and of Fluticasone inFluticasone/Salmeterol is 1000 µg/day. Thus, the doses used in PATHOSwere relatively consistent with the prescribing information of these 2products.

On the other hand, with the aforementioned doses, the efficacy in reducingexacerbation risk of Symbicort was 26% higher than that ofFluticasone/Salmeterol. This confirmed the advantage of using Symbicort intreating COPD because its ICS was used at a lower dose yet its therapeuticefficacy was better with higher safety.


11/25

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

Randomized clinical trial is often the “gold standard” in which the effectiveness and safetyof drugs are shown. However, these studies are often designed with strict control and thusthey are limited and protected from the impact of actual treatment variables. Thus, theycannot answer problems related to actual health care processes in everyday life. Thelimitations of randomized clinical trials include: removal of previous therapies, shortfollow-up time, small study population, quitting of patients, excluding patients with

associated diseases, conditions for adherence too strict, unrealistic and incapable ofdetecting rare adverse events (


12/25

Q: PATHOS study showed the difference between the two groupsBudesonide/Formoterol and Fluticasone/Salmeterol in theireffectiveness on controlling exacerbation and safety in treatingpneumonia. How do you explain this difference?

Explanation fo r the d i fferences in p neumo nia :

The problem of pneumonia in COPD patients when using ICS/LABA has existed sincelong. Before PATHOS, there were at least 5 randomized clinical trials (RCTs) showingFluticasone/Salmeterol increased the risk of pneumonia compared to placebo-groupand other bronchodilators. 6

According to the authors of PATHOS, the difference of pneumonia risk in COPDpatients using ICS/LABA containing budesonide or fluticasone may be related to thepharmacological properties of these two ICS. When inhaled, corticosteroids will stay athigh concentrations in the lungs and increase the risk of pneumonia due to itsimmunosuppressive properties. Immunosuppressive potency of Fluticasone is about10 times higher than that of Budesonide, which in ex vivo inhibits alveolarmacrophages from activating the intrinsic immune system against invading bacteria 7.This may be one reason to explain the higher risk of pneumonia in the group ofFluticasone/Salmeterol compared to the group of Budesonide/Formoterol. In addition,differences in pharmacodynamic properties and pharmacological activities related tosolubility properties (water-based or oil-based) can lead to differences in the risk ofpneumonia between Budesonide and Fluticasone 8. In patients with severe COPD,Fluticasone molecule with relatively high oil make-up will last longer in the mucousmembrane and alveolar epithelial cells compared with Budesonide 9. This can causestronger and longer local immunosuppression after using Fluticasone compared withBudesonide, increasing local bacterial growth and leading to pneumonia.


13/25

Explanat ion for th e d i fferences in the ra te of exacerbat ion:

The authors of PATHOS 6 hypothesized an explanation for the differencesin the rate of exacerbation between the two groupsBudesonide/Formoterol and Fluticasone/Salmeterol. According to thishypothesis, there is a significant amount of bacteria in the lowerrespiratory tract in patients with well-controlled COPD. The bacteria maycontribute to stimulating airway inflammation, leading to the start of anexacerbation.

On the other hand, we know that the immunosuppressive potency ofFluticasone is about 10 times higher than that of Budesonide . Therefore,Fluticasone may facilitate favourable conditions for bacteria in the lowerrespiratory tract of patients to develop stronger, affecting the rate ofexacerbation.


14/25

SYMBICORT

A partial agonist can activate the respective receptors but cannot promotethe maximum effect like a full agonist even after saturation of receptors(according to Trần ThịThu Hằng, Pharmacokinetics, 2006). In other words, afull agonist leads to a tight and clear relationship between the dose and theresponse whereas a partial agonist does not.

Q: Fluticasone shows higher ICS potency whichcan help moderate-severe asthma patients to

achieve asthma control faster.Higher potency does not equate to high efficacy. Potency is how much drugconcentration to produce an action. But when looking into clinical studies,indicated dosage shows better efficacy with Symbicort.

Q: Formoterol is a full agonist while Salmeterolis a partial agonist. What is the difference?


15/25

ULTIBRO FAQs


16/25

SPARK study - Ultibro


17/25

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

STRENGTH

WEAKNESS

• 1 st in Class for LABA/LAMA

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

• Significantly reduced the rate of moderate to severeexacerbations versus glycopyrronium by 12%

• 75% of patients used ICS as standard therapy

• Both glycopyrronium and indacaterol are not best inclass for LAMA and LABA

• No differences in “severe exacerbation”


18/25

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

Key Take Away

• SPARK trial, Ultibro significantlyreduced the rate of severe or verysevere COPD exacerbations compared toglycopyrronium 50 mcg

• Ultibro significantly reduced the rate of allCOPD exacerbations compared to open-

label tiotropium 18 mcg andglycopyrronium

• Ultibro also demonstrated significantimprovements in lung function andhealth-related quality of life

• Statistical significance was observed forthe primary endpoint with inhaled

corticosteroid use which should beinterpreted with caution since most patientsused ICS

• Ultibro indicated in limited group of patientswith emphysema-predominant COPD andlow exacerbation risk only

If I were a Symbicort Rep…

• Based on GOLD revised 2014, combination ofICS/LABA is recommended first choice which ismore effective in improving lung function andreduce exacerbations in gold C&D COPDpatients

• Symbicort is ICS/LABA combination which

strongly provide reduction of exacerbationssignificantly in moderate to very severe COPDpatients

PATHOS : Symbicort significantly reduced 26%all cause exacerbations (NNT is 3.4) and the29% reduction in hospital admissions (NNT =16 ) in moderate to severe COPD patients

CLIMB : Symbicort + tiotropium as triple therapydecreased the rate of severe exacerbations by62% and decreased the number ofhospitalizations/emergency room visits by 65%compared with tiotropium alone

• Symbicort indication cover both asthma andCOPD


19/25

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

Strategic drivers for Symbicort vs. Seretide

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

1. Define and defend key patient groups through clear positioning

3. Invest in evidence generation and share of voice

2. Position LAMA/LABAs in a relevant patient type

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

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

Use the launch of the LAMA/LABA class to re-establish Symbicort as a vital treatmentoption for inflammatory / exacerbating COPD patients and all asthma patients through clear

positioning and strong communication of the evidence


20/25

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


21/25

Breezhaler DPI, Once Daily LABA/LAMA, 30 capsules perblister pack

Ultibro SWOT(50mcg Glycopyrronium + 110mcg Indacaterol)

l b ( l d l)


22/25

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

40 Author | 00 Month Year Set area descriptor | Sub level 1

Strengths Weaknesses

• 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 improvementin Lung Function and QOL (INGNITE trials : SPARK,SHINE and ILLUMINATE)• Perceived by HCPs to provide better efficacy with betterside-effects than ICS/LABA and at no added cost topatients• Very convenient dosing for patients (Once daily dosing)

• Inconvenient storage and

handling (needs to be kept below25 degrees Centigrade andcapsules must only be removedimmediately from the blistersbefore actual use)

• Both Glycopyrronium andIndacaterol are not best in classLAMA or LABA

Opportunities Threats

• New data and evidence supporting that the withdrawalof ICS in COPD patients offers no difference versusmaintaining patients on LAMA/LABA (Wisdom trial)• Further support in using LAMA/LABA in international andlocal guidelines (GOLD 2015 reccomends LAMA/LABA asalternate 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, APSR, Loc. Societies, Clinical Trials)

• New LAMA/LABA launchesexpected within 6 mos. to 1 year ofUltibro launch (limited window ofexclusivity)

• Introduction of new LAMA/LABAfixed dose combinations withNOVEL delivery devices, including

pMDI


23/25

PPO for Ultibro

Barrier 1 Barrier 2 Barrier 3

Physicians still believethat PMDi is easier to usefor their patients withCOPD

There are some HCPs thatstill adhere to ClinicalPractice Guidelines (CPGs),and LAMA/LABA is only analternate treatment for COPD(Level B-C evidence)

New LAMA/LABAlaunches will dilute brandequity

Who: Specialists managing COPDWhat: Establish Ultibro as the first choice treatment for all COPD patientsWhere: Treatment Initiation and Intensification


Educate HCPs onthe role ofLAMA/LABA andUltibro in managingbroad COPD patienttypes

Partner with localsocieties to includeUltibro in CPGs

Facilitate and ownCOPD patienteducation. Teachpatients aboutCOPD and theirtreatment, and howto use Ultibro


24/25

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, 725 – 736

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 969110. Nannini LJ, the Cochrane Library, 2012, Issue 9

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

http://www.thelancet.com/journals/lancet/issue/vol374no9691/PIIS0140-6736(09)X6089-7http://www.ncbi.nlm.nih.gov/pubmed?term=Nannini%20LJ[Author]&cauthor=true&cauthor_uid=22972099http://www.ncbi.nlm.nih.gov/pubmed?term=Nannini%20LJ[Author]&cauthor=true&cauthor_uid=22972099http://www.thelancet.com/journals/lancet/issue/vol374no9691/PIIS0140-6736(09)X6089-7


25/25


Confidentiality NoticeThis file is private and may contain confidential and proprietary information. If you have received this file in error, please notify us and remove itfrom your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of thecontents of this file is not permitted and may be unlawful. AstraZeneca PLC, 2 Kingdom Street, London, W2 6BD, UK, T: +44(0)20 7604 8000, F:+44 (0)20 7604 8151, www.astrazeneca.com

symbicort faqs- copd.pdf

Documents