Approaches to COPD Assessment and Treatment

Approaches to COPD Assessment and Treatment

Approaches to COPD Assessment and Treatment US-16960 12/17 Considerations in the Management of COPD Including GOLD Report Updates COPD=chronic obstructive pulmonary disease. US-16958 1/18 Welcome to This Promotional Program Sponsored by AstraZeneca The purpose of this presentation is for disease state education and is not meant to imply efficacy or safety of any AstraZeneca or Competitor products. 3 Objectives Review key updates in the GOLD 2017 Report with additions from GOLD 2018 Understand the role of spirometry and recognize the importance of full symptom evaluation in patients with COPD Acknowledge the need for individualized management approaches including those outlined in the GOLD Report Appreciate the importance of appropriate device selection for individual patients GOLD=Global Initiative for Chronic Obstructive Lung Disease. 4 GOLD Report: Individualization of COPD Management Looking Beyond FEV1 The 2017 GOLD Report provided its first major revision since the 2011 Report Revised definition of COPD

Focus on individualization of treatment Updates to pathophysiology Recognizes the importance of symptoms and the role of lung tissue and airway abnormalities in COPD development Highlights disease variability Refinement of ABCD tool Separates the spirometric grades from symptom evaluation and history of exacerbations Revised treatment guidance Reassesses treatment recommendations for pharmacologic and non-pharmacologic therapies Not all updates to GOLD 2017 are included in this list. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. http://goldcopd.org/. Accessed January 4, 2018 5 GOLD Report: Updated Definition of COPD 2011 COPD is a common preventable and treatable disease, characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or

gases1 2017 and 2018 COPD is a common preventable and treatable disease, characterized by persistent respiratory symptoms and airflow limitation that is due to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles and gases2,3 2017 definition included the impact of respiratory symptoms and the role of lung tissue and airway abnormalities in the development of COPD. The same definition appears in the 2018 update.2,3 1. Yusen R. Am J Resp Crit Care Med. 2013;188:4-5. 2. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017. http://goldcopd.org/. Accessed January 4, 2017. 3. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2018. http://goldcopd.org/. Accessed January 4, 2018. 6 Role of Spirometry in Diagnosis and Monitoring Spirometry Airflow Limitation Post-bronchodilator FEV1/FVC <0.70* GOLD Recommends Active Case Finding: ie, performing spirometry in patients with symptoms and/or risk factors, but not screening spirometry Spirometry confirms the diagnosis of COPD. It is used to assess airflow limitation

Observed disconnect between FEV1 and symptoms Classification of Severity of Airflow Limitation in COPD (Based on Post-Bronchodilator FEV 1) In patients with FEV1/FVC <0.70 GOLD 1: Mild FEV1 80% predicted GOLD 2: Moderate 50% FEV1 <80% predicted GOLD 3: Severe 30% FEV1 <50% predicted GOLD 4: Very Severe FEV1 <30% predicted *Required for the diagnosis of COPD. For FEV1 between 0.6 and 0.8, repeat spirometry should be conducted on a separate occasion to confirm diagnosis. FEV1=forced expiratory volume in 1 second; FVC=forced vital capacity. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2018. http://goldcopd.org/. Accessed January 4, 2018. 7 FEV1 Does Not Always Define Activity Level or Degree of Dyspnea In a study of patients with COPD and matched controls, FEV 1 did not correlate A B with dyspnea score or walking distance in patients with COPD A negative correlation was observed between dyspnea score and walking C distance

A C B Dyspnea-12 Score r = 0.12 P = 0.45 Shuttle Walk Test (m) Shuttle Walk Test (m) r = 0.12 P = 0.45 r = 0.57 P < 0.0001 Herigstad M, et al. Chest. 2015;148:953-961. 8 GOLD Report: The Refined ABCD Assessment Tool Looking Beyond FEV1 The Refined ABCD Assessment Tool SPIROMETRICALLY CONFIRMED DIAGNOSIS Postbronchodilator FEV1/FVC <0.7 ASSESSMENT OF AIRFLOW LIMITATION FEV1 (% predicted) GOLD 1

80 GOLD 2 5079 GOLD 3 3049 GOLD 4 <30 Moderate/severe exacerbation history ASSESSMENT OF SYMPTOMS/ RISK OF EXACERBATIONS 2 or 1 leading to hospital admission C D 0 or 1 (not leading to hospital admission) A B

mMRC 01 CAT <10 mMRC 2 CAT 10 Symptoms Copyright 2018 Global Initiative for Chronic Obstructive Lung Disease, reproduced with permission. mMRC=modified Medical Research Council (Questionnaire); CAT=COPD Assessment Test. 9 Full Symptom Evaluation in COPD Is Critical Symptom Evaluation Is Critical for Diagnosis and Management There is only a weak correlation between FEV1, symptoms, and impairment in a patients health status Full symptom assessment is critical Common Symptoms of COPD Dyspnea Cough Sputum production Wheezing Chest tightness Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2018. http://goldcopd.org/. Accessed January 4, 2018. 10

GOLD Report: Individualized Treatment Approaches C D A B GOLD Report has preferred treatment pathways for patients in each of the ABCD GOLD groups GOLD Report recognizes that patients are diverse, and there can be a need for individualization of treatment options The GOLD treatment algorithm allows for flexibility in treatment choices to accommodate individualized needs and preferences Inhaled Bronchodilators are a key component in the management of stable COPD LAMA/LABA is a preferred first-line option for many patients Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2018. http://goldcopd.org/. Accessed January 4, 2018. ICS/LABA remains a treatment option for many patients 11 The GOLD Report Highlights the Importance of Device Selection for Individualization of the Management of COPD More than two-thirds of patients make at least 1 device error There may be a relationship between poor inhaler use and symptom control

Right patient Right device Individualization Randomized, controlled trials have not identified superiority of 1 device/formulation Physicians should gain a working knowledge of inhalation devices The choice of inhaler device should be matched to the patient Patient training is essential Inhaler technique should be assessed regularly to help ensure correct device use Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2018. http://goldcopd.org/. Accessed January 4, 2018. 12 A Proposed Inhaler Decision Tree* Adult Adult Patient Patient Conscious Conscious inhalation inhalation possible possible Sufficient Sufficient inspiratory inspiratory flow flow Conscious Conscious inhalation inhalation NOT NOT possible possible Insufficient

Insufficient inspiratory inspiratory flow flow Coordination + Coordination Coordination + Coordination pMDI spacer pMDI + spacer pMDI spacer pMDI + spacer pMDI + spacer DPI DPI BA aerosol BA aerosol Nebulizer BA aerosol BA aerosol SMI SMI SMI

SMI A B Nebulizer C D E Reprinted from Respiratory Medicine, vol. 107, eds Dekhuijzen PNR, Vincken W, Virchow JC, Roche N, Agusti A, Lavorini F, van Aaldere WM, Price D, Prescription of inhalers in asthma and COPD: Towards a rational, rapid and effective approach, pp. 1817-1821, copyright 2013, with permission from Elsevier. *Treatments are not presented in order of preference. BA=breath actuated; DPI=dry powder inhaler; pMDI=pressurized metered dose inhaler; SMI=soft mist inhaler. Dekhuijzen PN, et al. Respir Med. 2013;107:1817-1821. Note: This content is from non-GOLD sources. 13 Summary The GOLD Report acknowledges the need for individualization of assessment and management approaches in COPD Symptom severity and exacerbation history are recommended to guide treatment approach Full evaluation of symptoms is important in patients with COPD Device choice can be a critical part of management in patients with COPD 14 Comments to AstraZeneca AstraZeneca is committed to conducting business with the highest standards of integrity and professionalism. If you have comments that could improve the

delivery of our promotional educational programs, please contact AstraZeneca at 1-800-236-9933. 2018 AstraZeneca. All rights reserved. US-16958 1/18 15 Managing Patients With COPD: Individualizing Treatment COPD=chronic obstructive pulmonary disease. US-16961 1/18 Welcome to this promotional program sponsored by AstraZeneca Please note that this entire presentation is a promotional presentation sponsored directly by AstraZeneca. There are no continuing medical education (CME) credits associated with the activity. Options for the Treatment of Patients With COPD Predominant Presentation: Bronchoconstriction Predominant Presentation: Bronchoconstriction and inflammation Hypothetical patients 18 BEVESPI AEROSPHERE (glycopyrrolate 9 mcg/ formoterol fumarate 4.8 mcg) Inhalation Aerosol Please see the full Prescribing Information, including Boxed WARNING and Medication Guide, available at this presentation. 19

BEVESPI AEROSPHERE for the Maintenance Treatment of COPD Indication BEVESPI AEROSPHERE is indicated for the long-term maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema BEVESPI AEROSPHERE is not indicated for the relief of acute bronchospasm, or for the treatment of asthma Boxed WARNING: Longacting beta2adrenergic agonists (LABAs), such as formoterol fumarate, one of the active ingredients in BEVESPI AEROSPHERE, increase the risk of asthmarelated death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of all LABAs, including formoterol fumarate The safety and efficacy of BEVESPI AEROSPHERE in patients with asthma have not been established. BEVESPI AEROSPHERE is not indicated for the treatment of asthma Please see the full Prescribing Information, including Boxed WARNING and Medication Guide, for BEVESPI AEROSPHERE, available at this presentation. 20 BEVESPI AEROSPHERE May Be Considered For a Patient With COPD With the Following Characteristics Predominant presentation is bronchoconstriction Short of breath; may be due to hyperinflation Increasing rescue use No ICS required Historically may have been treated with a LAMA Hypothetical patient Hypothetical patient ICS=inhaled corticosteroids; LAMA=inhaled long-acting muscarinic antagonist. 21

BEVESPI AEROSPHERE MAXIMIZE BRONCHODILATION* Improved lung function including predose FEV1 and peak FEV1 at 24 weeks1,2 In a separate study vs placebo, improvement in peak inspiratory capacity at Day 293 INTELLIGENT FORMULATION1 Intelligent formulation for a pMDI using patented AEROSPHERE Delivery Technology1 In a separate functional respiratory imaging study, an increase in specific-airway volume vs placebo was demonstrated 4 Adverse reactions with BEVESPI AEROSPHERE with a 2% incidence and more common than placebo were urinary tract infections and cough1 BEVESPI AEROSPHERE is NOT a rescue medication and does NOT replace fastacting inhalers to treat acute symptoms1 *Improvements in lung function relative to its individual components and placebo in two 24-week pivotal trials (n=3699). Peak inspiratory capacity after the evening dose on Day 29. BEVESPI AEROSPHERE is a pMDI containing the LAMA glycopyrrolate and LABA formoterol fumarate along with phospholipid porous particles that form the co-suspension with the micronized drug crystals. Geometric least squares mean specific image-based airway volume at Day 15 (n=19). FEV1=forced expiratory volume in 1 second; pMDI=pressurized metered dose inhaler. 1. BEVESPI AEROSPHERE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017. 2. Martinez FJ, et al. Chest. 2017;151:340-357. 3. Reisner C, et al. Resp Res. 2017;18:157. 4. Data on File, REF-14480. AstraZeneca Pharmaceuticals LP. 22

BEVESPI AEROSPHERE Is Formulated With AEROSPHERE Delivery Technology1 Intelligent formulation for a pMDI* using patented, phospholipid-based AEROSPHERE DELIVERY TECHNOLOGY1 Reaches LARGE AND SMALL airways2 Pressurized metered dose inhaler (pMDI) Phospholipid particles with drug crystals *BEVESPI is a pMDI containing the LAMA glycopyrrolate and LABA formoterol fumarate, along with phospholipid porous particles that form the co-suspension with the micronized drug crystals. As defined by mass median aerodynamic diameter (MMAD), changes in inspiratory capacity, and changes in specific image-based airway resistance for BEVESPI AEROSPHERE. 1. BEVESPI AEROSPHERE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017. 2. Data on File, REF-14480. AstraZeneca Pharmaceuticals LP. 23 PINNACLE-1 and PINNACLE-2, Phase III Confirmatory Trials: Study Design1,2 24-week, double-blind treatment period BEVESPI 18/9.6 mcg pMDI BID PINNACLE-1: n=526; PINNACLE-2: n=510 GP 18 mcg pMDI BID PINNACLE-1: n=451; PINNACLE-2: n=439 Screening FF 9.6 mcg pMDI BID PINNACLE-1: n=449; PINNACLE-2: n=437

Placebo pMDI BID PINNACLE-1: n=219; PINNACLE-2: n=223 28 Day to 1 Day Visit 1 Visit 2 & 3 Follow-up 14 days or invite into 28week safety extension study PINNACLE-3 Active Control QD* (PINNACLE-1; n=451) Visits: Day 1, Weeks 2, 4, 8, 12, 16, 20 and 24 Randomization Trials conducted in patients with moderate-to-verysevere COPD BID=twice daily; FF=formoterol fumarate; GP=glycopyrrolate; pMDI=pressurized metered dose inhaler. Randomization PINNACLE-1 N=2103; PINNACLE-2 N=1615 *Administered as open label. 1. BEVESPI AEROSPHERE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017. 2. Martinez FJ, et al. Chest. 2017;151:340-357. 24 Improvement in Lung Function: Almost a 300 mL Increase in Peak FEV1 for BEVESPI vs Placebo1,2 Statistically significant improvement in morning predose FEV1 and peak FEV1 at Week 24 were also demonstrated in PINNACLE-2 2 BEVESPI AEROSPHERE is not indicated for the relief of acute bronchospasm Secondary endpoint: Mean change from baseline in peak FEV1 within 2 hours postdose at Week 24 (ITT)1,2

PINNACLE-1 BEVESPI pMDI 18/9.6 mcg 500 FF pMDI 9.6 mcg 450 Mean change from baseline in peak FEV1 (mL) Primary endpoint: 150 mL increase from baseline in predose FEV1 at Week 24 vs placebo (P<0.0001) in PINNACLE-1. There was also an increase from baseline in predose FEV1 at Week 24 for BEVESPI AEROSPHERE vs glycopyrrolate 18 mcg (59 mL) and formoterol fumarate 9.6 mcg (64 mL) (both P<0.0001)1,2 GP pMDI 18 mcg Placebo pMDI 400 350 300 291 mL 250 200 Increase in peak FEV1 for BEVESPI vs placebo P<0.0001 150 100

50 0 0 2 4 8 12 20 24 Weeks All study treatments administered BID. n-values for PINNACLE-1 were BEVESPI: 428; placebo: 160; GP: 343; FF: 367. BID=twice daily; FEV1=forced expiratory volume in 1 second; FF=formoterol fumarate; GP=glycopyrrolate; ITT=intention to treat; pMDI=pressurized metered dose inhaler. 1. BEVESPI AEROSPHERE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017. 2. Martinez FJ, et al. Chest. 2017;151:340-357. 25 Adverse Reactions PINNACLE-1 and PINNACLE-2 (Adverse reactions with BEVESPI AEROSPHERE with a 2% incidence and more common than with placebo) BEVESPI pMDI 18/9.6 mcg N=1036 GP pMDI 18 mcg N=890 FF pMDI 9.6 mcg

N=890 Placebo pMDI N=443 Respiratory, thoracic, and mediastinal disorders Cough, % 4.0 3.0 2.7 2.7 2.6 1.8 1.5 2.3 Infections and infestation Urinary tract infection, % All treatments were administered twice daily. PINNACLE-3 was a 28-week, long-term safety extension trial The adverse reactions reported in the long-term safety trial were consistent with those observed in the 24-week, placebo-controlled trials, PINNACLE-1 and PINNACLE-2 FF=formoterol fumarate; GP=glycopyrrolate; pMDI=pressurized metered dose inhaler. BEVESPI AEROSPHERE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017. 26

Inspiratory Capacity (IC) and FEV1 Can Serve Different Purposes in the Assessment of COPD FEV1 IC FEV1 measures the volume of air that can be forcibly breathed out in the first second1 IC is the maximum amount of air that can be taken in after a normal breath3 FEV1 does not always correlate with activity level or degree of dyspnea2 In COPD, residual air trapped in the lungs after expiration reduces patients IC3,4 1. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2018. http://goldcopd.org/. Accessed January 4, 2018. 2. Herigstad M et al. Chest. 2015;148(4):953-961. 3. Seeley R. Respiratory System. In: Seeley R, Stephens T, Tate P, eds. Anatomy & Physiology. 6th ed. New York, NY: McGraw-Hill; 2003:813-859. 4. O'Donnell DE et al. COPD Res Pract. 2015:1:4. 27 Phase IIIb 24-Hour Lung Function Studies1,2 Objective: To evaluate the 24-hour lung function profile in patients with moderate-to-very-severe COPD Randomization Screening 2-period, 2-treatment crossover, BID dosing (Study A, n=35) 28-day treatment period 1 BEVESPI BID 28-day

treatment period 1 Placebo BID 721 day washout 28-day treatment period 2 BEVESPI BID 28-day treatment period 2 Placebo BID Follow-up A second study (3-period, 3-treatment crossover, BID dosing) was conducted (Study B, n=75) BEVESPI AEROSPHERE is NOT indicated for the relief of acute bronchospasm and does NOT replace fast-acting inhalers to treat acute symptoms Spirometry was performed at the beginning of each 4-week treatment period, and 24-hour pulmonary function tests were performed at the end of each treatment period. BID=twice daily; COPD=chronic obstructive pulmonary disease. 1. Data on File, REF-4976. AstraZeneca Pharmaceuticals LP. 2. Reisner C, et al. Resp Res. 2017;18:157. 28 Primary endpoint : 2 Change from baseline (95% CI) in FEV 1 AUC0-24 on Day 29 (mITT)2 Mean increase in FEV1 AUC0-24 for BEVESPI AEROSPHERE vs placebo on Day 29 was 249 mL in Study A (P<0.0001) 2 Consistent results were demonstrated in the second trial (Study B), with a 265 mL improvement vs placebo (n=65) 2 Secondary endpoint2: The difference in LSM peak change from baseline in IC after evening dose between BEVESPI and placebo on Day 29 was

0.381 L in Study A (P<0.0001)2 Consistent results were noted in the second trial (Study B) with a 0.312 L improvement (BEVESPI n=62, placebo n=63) 2 L S M P e a k C h a n g e F r o m B a s e lin e , L Improvement in Lung Function: Inspiratory Capacity in Two Phase IIIb Studies1,2 Study A Secondary endpoint: Peak change from baseline (95% CI) in inspiratory capacity (IC) on Day 29 following evening dose (mITT)1,2 Difference .381 L P<0.0001 0.9 0.7 0.7 Placebo (n=30); 0.7 0.5 0.3 BEVESPI AEROSPHERE is NOT indicated for the relief of acute bronchospasm and does NOT replace fast-acting inhalers to treat acute symptoms BEVESPI (n=34); 0.7 .486 0.1 .105

-0.1 BEVESPI (n=34) Placebo (n=30) BEVESPI and Placebo were administered as 2 inhalations BID CI=confidence interval; IC=inspiratory capacity; L=liters; LSM=least-squares mean; mITT=modified intention to treat. 1. Data on File, REF-4976, AstraZeneca Pharmaceuticals LP. 2. Reisner C, et al. Resp Res. 2017;18:157. 29 Phase IIIb Functional Respiratory Imaging Study Primary Objective: To evaluate the effects of BEVESPI vs placebo on specific image-based airway volumes and resistance in patients with moderate-to-severe COPD 2-period, 2-treatment crossover, BID dosing (n=19) Visit 1 Screening 721 Day Run-In Atrovent HFA 14-day treatment period 1 BEVESPI 18/9.6 mcg BID Visit 2 Randomization Day 1 treatment period (TP) 14-day treatment period 1 Placebo BID

14-day treatment period 2 BEVESPI 18/9.6 mcg BID 521 Day Washout Atrovent HFA Visit 3 Day 15 TP 1 710 day follow-up Phone call 14-day treatment period 2 Placebo BID Visit 4 Day 1 TP 2 Visit 5 Day 15 TP 2 BEVESPI AEROSPHERE is NOT indicated for the relief of acute bronchospasm and does NOT replace fast-acting inhalers to treat acute symptoms Spirometry and HRCT were performed at the beginning of each treatment period. BID=twice daily; COPD=chronic obstructive pulmonary disease; HRCT=high resolution computed tomography. Data on File, REF-14480. AstraZeneca Pharmaceuticals LP. 30 Functional Respiratory Imaging: BEVESPI Increased Airway Volume Throughout Airways Measured Computer-generated composite representative of patient results demonstrating change from baseline in specific imagebased airway volume (siVaw) at Day 15

Data on File, REF-14480. AstraZeneca Pharmaceuticals LP. Achieved Achieved a a 75% 75% increase increase in in specific specific airway volume (siVaw) with airway volume (siVaw) with BEVESPI BEVESPI vs vs placebo placebo Geometric Least Squares (LS) mean siVaw at Day 15 was 1.79 mL/L and 1.02 mL/L for BEVESPI and placebo, respectively (n=19) (P<0.0001) (LS mean ratio between treatments: 1.75) Co-primary endpoint: Specific image-based airway resistance (siRaw) demonstrated a decrease in airway resistance for BEVESPI vs placebo of approximately 71% at Day 15. Overall LS mean ratio between treatments in siRaw was 0.29 (P<0.0001) There were no major differences between BEVESPI and placebo in the incidence of adverse events

31 Important Safety Information, Including Boxed WARNING* WARNING: Longacting beta2adrenergic agonists (LABAs), such as formoterol fumarate, one of the active ingredients in BEVESPI AEROSPHERE, increase the risk of asthmarelated death. A placebocontrolled trial with another LABA (salmeterol) showed an increase in asthmarelated deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of all LABAs, including formoterol fumarate. The safety and efficacy of BEVESPI AEROSPHERE in patients with asthma have not been established. BEVESPI AEROSPHERE is not indicated for the treatment of asthma. CONTRAINDICATIONS: All LABAs are contraindicated in patients with asthma without use of a longterm asthma control medication. BEVESPI is contraindicated in patients with hypersensitivity to glycopyrrolate, formoterol fumarate, or to any component of the product. WARNINGS AND PRECAUTIONS If paradoxical bronchospasm occurs, discontinue BEVESPI immediately and institute alternative therapy If immediate hypersensitivity reactions occur, in particular, angioedema, urticaria, or skin rash, discontinue BEVESPI at once and consider alternative treatment BEVESPI can produce a clinically significant cardiovascular effect in some patients, as measured by increases in pulse rate, blood pressure, or symptoms. If such effects occur, BEVESPI may need to be discontinued Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines Be alert to hypokalemia and hyperglycemia Worsening of narrow-angle glaucoma or urinary retention may occur. Use with caution in patients with narrow-angle glaucoma, prostatic hyperplasia, or bladder-neck obstruction, and instruct patients to contact a physician immediately if symptoms occur BEVESPI should not be initiated in patients with acutely deteriorating

chronic obstructive pulmonary disease (COPD), which may be a lifethreatening condition BEVESPI should not be used for the relief of acute symptoms (ie, as rescue therapy for the treatment of acute episodes of bronchospasm). Acute symptoms should be treated with an inhaled short-acting beta 2 agonist BEVESPI should not be used more often or at higher doses than recommended, or with other LABAs, as an overdose may resultfor BEVESPI AEROSPHERE, including Boxed *Please see the full Prescribing Information WARNING and Medication Guide, available at this presentation. BEVESPI AEROSPHERE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017. 32 Important Safety Information, Including Boxed WARNING* (Continued) ADVERSE REACTIONS: The most common adverse reactions with BEVESPI (2% and more common than placebo) were: cough, 4.0% (2.7%), and urinary tract infection, 2.6% (2.3%). DRUG INTERACTIONS Use caution if administering additional adrenergic drugs because the sympathetic effects of formoterol may be potentiated Concomitant treatment with xanthine derivatives, steroids, or diuretics may potentiate any hypokalemic effect of formoterol Use with caution in patients taking nonpotassiumsparing diuretics, as the ECG changes and/or hypokalemia may worsen with concomitant beta2agonists The action of adrenergic agonists on the cardiovascular system may be potentiated by monoamine oxidase inhibitors, tricyclic antidepressants, or other drugs known to prolong the QTc interval. Therefore, BEVESPI should be used with extreme caution in patients being treated with these

agents Use betablockers with caution as they not only block the therapeutic effects of betaagonists, but may produce severe bronchospasm in patients with COPD Avoid coadministration of BEVESPI with other anticholinergic containing drugs as this may lead to an increase in anticholinergic adverse effects INDICATION: BEVESPI AEROSPHERE is a combination of glycopyrrolate, an anticholinergic, and formoterol fumarate, a long-acting beta2-adrenergic agonist (LABA), indicated for the long-term, maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. LIMITATION OF USE: Not indicated for the relief of acute bronchospasm or for the treatment of asthma. *Please see the full Prescribing Information for BEVESPI AEROSPHERE, including Boxed WARNING and Medication Guide, available at this presentation. BEVESPI AEROSPHERE [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017. 33 SYMBICORT (budesonide/formoterol fumarate dihydrate) 34 Indication, Dosage, and Important Safety Information for Patients With COPD 160/4.5 g, 2 inhalations twice daily* SYMBICORT 160/4.5 is indicated for the maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD) including chronic bronchitis and/or emphysema. SYMBICORT 160/4.5 is also indicated to reduce exacerbations of COPD. SYMBICORT 160/4.5 is the only strength indicated for the treatment of COPD SYMBICORT is NOT indicated for relief of acute bronchospasm

Use of long-acting beta2-adrenergic agonists (LABA) as monotherapy (without inhaled corticosteroids [ICS]) for asthma is associated with an increased risk of asthma-related death. These findings are considered a class effect of LABA. When LABA are used in fixed dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared to ICS alone *Administered in the morning and in the evening. Please see full Prescribing Information, including Patient Information, available at this presentation. SYMBICORT [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; December 2017. 35 SYMBICORT May Be Considered for a Patient With COPD With the Following Characteristics Predominant presentation is bronchoconstriction and inflammation A patient with COPD who Needs an ICS May have asthma-like features and a history of exacerbations1-3 Hypothetical patient 1. Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2018. http://goldcopd.org. Accessed January 4, 2018. 2. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. www.ginasthma.org. Updated 2017. Accessed January 18, 2018. 3. Data on File, REF-5531, AstraZeneca Pharmaceuticals LP. 36 SYMBICORT 160/4.5 Inhalation Aerosol Majority of patients FEV1* improvement occurred at 5 minutes in COPD1-3 SPEED CONTROL

Reduced COPD exacerbations vs formoterol alone3,4 Reduced COPD symptom scores vs formoterol alone5 SYMBICORT is NOT a rescue medication and does NOT replace fast-acting inhalers to treat acute symptoms. The most common adverse reactions 3% reported in COPD lung function clinical trials included nasopharyngitis, oral candidiasis, bronchitis, sinusitis, and upper respiratory tract infection. The safety findings from the two exacerbation clinical trials were consistent with the lung function studies. *1-hour postdose FEV1. Serial spirometry subset of SUN study patients taking SYMBICORT 160/4.5. In the SUN study, COPD symptom scores were assessed with The Breathlessness, Cough, and Sputum Scale (BCSS). BCSS was measured in diary cards every day before the evening dose. BCSS measurement was a secondary endpoint, with the primary comparison being SYMBICORT vs placebo. 5 1. Data on File, 1084400, AstraZeneca Pharmaceuticals LP. 2. Rennard SI, et al. Drugs. 2009;69(5):549-565. 3. SYMBICORT [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; December 2017. 4. Data on File, REF-16658, AstraZeneca Pharmaceuticals LP. 5. Data on File, 1814606, AstraZeneca Pharmaceuticals LP. 37 SYMBICORT 160/4.5 for the maintenance treatment of COPD SUN Phase III Study Design in Patients With COPD1 Two Pivotal Efficacy and Safety (n=494) SYMBICORT pMDI Run-in R A N D O M I Z

A T I O N Phase III Lung Function Studies in Moderate-to-Very-Severe COPD 160/4.5 g 2 Inhalations BID SYMBICORT pMDI (n=494) 80/4.5 g 2 Inhalations BID Follow-up Formoterol DPI (n=495) SUN Study*1: 12 months, N=1964: SYMBICORT pMDI 160/4.5 g and SYMBICORT pMDI 80/4.5 g vs formoterol DPI and placebo 4.5 g 2 Inhalations BID (n=481) Placebo 2 Inhalations BID Double-blind Visit 1 Month -0.5

Primary efficacy endpoints for both studies were change from baseline to the average over the randomized treatment period in predose FEV1 and in 1-hour postdose FEV1 2 3 4 5 6 7 8 FU 0 1 2 4 6 9 12 13 SHINE Study*2: 6 months, N=1704: SYMBICORT pMDI 160/4.5 g and SYMBICORT pMDI 80/4.5 g vs its

monocomponents and placebo SYMBICORT 160/4.5 g x 2 inhalations twice daily (BID) is the only approved dose for patients with COPD *All treatments were administered as 2 inhalations BID. Monocomponents refer to administration of budesonide monotherapy, formoterol monotherapy, and budesonide + formoterol administered in separate devices, all administered as 2 inhalations BID. DPI=dry powder inhaler; pMDI=pressurized metered dose inhaler. Figure adapted with kind permission from Springer Science+Business Media: Drugs, Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease, 69, 2009, p.551, Rennard SI, et al, figure 1. 1. Rennard SI, et al. Drugs. 2009;69(5):549-565. 2. Tashkin DP, et al. Drugs. 2008;68(14):1975-2000. 38 SYMBICORT 160/4.5 for the maintenance treatment of COPD Better BreathingFast1,2 Percent of 1-Hour Improvement in FEV1 Occurring at 5 Minutes Over the 12-Month Study1 (serial spirometry subset) Mean Percent Change From Baseline in FEV1 30 25 SUN: A 12-month efficacy and safety study 83 84 % 20 %

67 % 15 Majority of total 1-hour improvement occurred at 10 5 MINUTES 5 0 Baseline* Day of Randomization Improvement at 5 minutes daily 6 Months Improvement at 1 hour End of Treatment SYMBICORT 160/4.5 significantly improved 1-hour postdose FEV1 at 1 month and end of treatment compared to placebo, and improved predose FEV1 averaged over the course of the study compared to placebo and formoterol, co-primary endpoints2

SYMBICORT 160/4.5 g 2 inhalations twice serial spirometry subset (n=121) SYMBICORT is NOT a rescue medication and does NOT replace fast-acting inhalers to treat *Baseline is defined as the predose FEV value on the day of randomization. acute symptoms Month 12, last observation carried forward. 1 FEV1=forced expiratory volume in 1 second. 1. Data on File, 1084400, AstraZeneca Pharmaceuticals LP. 2. Rennard SI, et al. Drugs. 2009;69(5):549-565. 39 SYMBICORT 160/4.5 for the maintenance treatment of COPD SYMBICORT Reduced COPD Symptom Scores Absolute Mean Change in BCSS Symptom Score Over 12 Months 0.0 SYMBICORT 160/4.5 g 2 inhalations twice daily (n=489) Absolute Mean Change Baseline* -0.38 Formoterol 4.5 g 2 inhalations twice daily (n=489)

Placebo (n=467) -0.63 -0.85 SYMBICORT reduction vs formoterol (P=0.027) SUN: A 12-month efficacy and safety study The overall BCSS measurement was a secondary endpoint with the primary comparison being SYMBICORT vs placebo (P<0.001 for the treatment average over 12 months) 35% *Baseline is defined as the mean of all values obtained during the last 10 days of the run-in period. Mean BCSS baseline values were 5.35 for SYMBICORT 160/4.5, 5.39 for formoterol 4.5, and 5.34 for placebo. P values based on treatment comparison of absolute mean change from baseline for SYMBICORT vs formoterol. BCSS=Breathlessness, Cough, and Sputum Scale. This is a validated 3-item questionnaire designed to assess the patients respiratory symptoms. The BCSS was recorded in diary cards every day before the evening dose. Patients were asked to evaluate each symptom/item on a Likert-type scale ranging from 0 to 4, with higher scores indicating a more severe manifestation of the symptom. A total symptom score is expressed as the sum of 3 item scores, with a range from 0 to 12. Data on File, 1814606, AstraZeneca Pharmaceuticals LP. 40 SYMBICORT 160/4.5 for reducing COPD exacerbations Study 4 Phase IIIb Exacerbation Study Design in Patients with COPD1,2 Two efficacy and safety studies evaluated the effect of SYMBICORT 160/4.5 g compared to formoterol 4.5 g on g compared to formoterol 4.5 g compared to formoterol 4.5 g on g on COPD exacerbations in patients with COPD1

Run-in ICS only Study 4 (12-Month) N=811 2 weeks Visit 1 Month -1 R A N D O M I Z A T I O N SYMBICORT pMDI 160/4.5 g 2 Inhalations BID (n=407) Follow-up Formoterol DPI 4.5 g 2 Inhalations BID (n=404) Telephone call 2 weeks post-last study treatment 2 3 4

5 6 7 8 9 -0.5 0 1 2 4 6 9 12 Study 31: 6-month study; N=1219 The study randomized 606 subjects to SYMBICORT 160/4.5 x 2 inhalations BID and 613 to formoterol 4.5 g x 2 inhalations BID DPI=dry powder inhaler; pMDI=pressurized metered dose inhaler; BID=twice daily dosing. 1. SYMBICORT [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; December 2017. 2. Sharafkhaneh A, et al. Respir Med. 2012;106:257-268. 41 SYMBICORT 160/4.5 for reducing COPD exacerbations SYMBICORT Reduced COPD Exacerbations1 A n n u a l R a t e E s t im a t e Study 4: 12-month study

1.05 *P<.0001 vs formoterol2 (Estimate RR=0.65; 95% CI: 0.53, 0.80) Reduction in Exacerbation Rate 35% 1.2 0.68* 1 0.8 0.6 0.4 0.2 0 Formoterol 4.5 g (n=403) SYMBICORT 160/4.5 g (n=404) In a 12-month exacerbation clinical trial (Study 4), SYMBICORT 160/4.5 significantly reduced the annual rate of moderate/severe COPD exacerbations vs formoterol1,2 In Study 4, COPD exacerbations were defined as worsening of COPD that required treatment with a course of

oral steroids, hospitalization, or both Study 3: 6-month study In a second exacerbation clinical trial of 6-month duration (Study 3), SYMBICORT 160/4.5 significantly reduced the annual rate of moderate/severe COPD exacerbations by 26% vs formoterol (Estimate RR=0.74; 95% CI: 0.61, 0.91; P=.004)1,2 Annual rate estimate was 0.94 for SYMBICORT 160/4.5 g (n=606) vs 1.27 for formoterol 4.5 g (n=613) In Study 3, COPD exacerbations were defined as worsening of 2 major symptoms (dyspnea, sputum volume, sputum color/purulence) or worsening of any 1 major symptom together with 1 of the minor symptoms (sore throat, colds [nasal discharge and/or nasal congestion], fever without other cause, increased cough or increased wheeze) for 2 consecutive days. COPD exacerbation severity was classified as moderate if symptoms required systemic corticosteroid (3 days) and/or antibiotic treatment, and severe if symptoms required hospitalization Administered as 2 inhalations twice daily. RR=rate ratio. 1. SYMBICORT [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; December 2017. 2. Data on File, REF-16658. AstraZeneca Pharmaceuticals LP. 42 Adverse Reactions in COPD Clinical Trials1,2 Adverse reactions occurring in the lung function clinical studies at an incidence of 3% and more commonly than placebo in the SYMBICORT group SYMBICORT 160/4.5 g (n=771) Budesonide 160 g (n=275) Formoterol 4.5 g (n=779) Placebo (n=781) Adverse Event %

% % % Nasopharyngitis 7.3 3.3 5.8 4.9 Oral candidiasis 6.0 4.4 1.2 1.8 Bronchitis 5.4 4.7 4.5 3.5 Sinusitis 3.5 1.5

3.1 1.8 Viral upper respiratory tract infection 3.5 1.8 3.6 2.7 255.2 157.1 240.3 223.7 Treatment* Average duration of exposure (days) In the pooled safety data from the lung function studies (SUN and SHINE), pneumonia did not occur with greater incidence in the SYMBICORT 160/4.5 g group, compared g group, compared with placebo (2.3% vs 3.3%, respectively)1,2 The safety findings from the two exacerbation clinical trials were consistent with the lung function studies2

Represents pooled data from the lung function studies (SUN and SHINE) at a dose of 2 inhalations BID. Since the SUN study did not include a budesonide arm, there are fewer patients in this treatment group. *All treatments were administered as 2 inhalations twice daily. 1. Data on File, 1803306, AstraZeneca Pharmaceuticals LP. 2. SYMBICORT [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; December 2017. 43 Important Safety Information Use of long-acting beta2-adrenergic agonists (LABA) as monotherapy (without inhaled corticosteroids [ICS]) for asthma is associated with an increased risk of asthma-related death. These findings are considered a class effect of LABA. When LABA are used in fixed dose combination with ICS, data from large clinical trials do not show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared to ICS alone SYMBICORT is NOT a rescue medication and does NOT replace fast-acting inhalers to treat acute symptoms SYMBICORT should not be initiated in patients during rapidly deteriorating episodes of asthma or COPD Patients who are receiving SYMBICORT should not use additional formoterol or other LABA for any reason Localized infections of the mouth and pharynx with Candida albicans has occurred in patients treated with SYMBICORT. Patients should rinse the mouth after inhalation of SYMBICORT Lower respiratory tract infections, including pneumonia, have been reported following the administration of ICS Due to possible immunosuppression, potential worsening of infections could occur. A more serious or even fatal course of chickenpox or measles can occur in susceptible patients It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression may occur, particularly at higher doses. Particular care is needed for patients who are transferred from systemically active corticosteroids to ICS. Deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available ICS

Caution should be exercised when considering administration of SYMBICORT in patients on long-term ketoconazole and other known potent CYP3A4 inhibitors As with other inhaled medications, paradoxical bronchospasm may occur with SYMBICORT Immediate hypersensitivity reactions may occur, as demonstrated by cases of urticaria, angioedema, rash, and bronchospasm Excessive beta-adrenergic stimulation has been associated with central nervous system and cardiovascular effects. SYMBICORT should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension Please see full Prescribing Information, including Patient Information, available at this presentation. SYMBICORT [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; December 2017. 44 Important Safety Information (Continued) SYMBICORT should be administered with caution to Long-term use of ICS may result in a decrease in bone patients being treated with MAO inhibitors or tricyclic mineral density (BMD). Since patients with COPD often antidepressants, or within 2 weeks of discontinuation of have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating such agents SYMBICORT and periodically thereafter Beta-blockers may not only block the pulmonary effect Glaucoma, increased intraocular pressure, and of beta-agonists, such as formoterol, but may produce cataracts have been reported following the severe bronchospasm in patients with asthma administration of ICS, including budesonide, a ECG changes and/or hypokalemia associated with component of SYMBICORT. Close monitoring is

nonpotassium-sparing diuretics may worsen with warranted in patients with a change in vision or history concomitant beta-agonists. Use caution with the of increased intraocular pressure, glaucoma, or coadministration of SYMBICORT cataracts In rare cases, patients on ICS may present with INDICATIONS systemic eosinophilic conditions SYMBICORT 160/4.5 is indicated for the maintenance SYMBICORT should be used with caution in patients treatment of airflow obstruction in patients with chronic with convulsive disorders, thyrotoxicosis, diabetes obstructive pulmonary disease (COPD), including chronic mellitus, ketoacidosis, and in patients who are bronchitis and/or emphysema, and to reduce COPD unusually responsive to sympathomimetic amines exacerbations. Beta-adrenergic agonist medications may produce SYMBICORT is NOT indicated for the relief of acute hypokalemia and hyperglycemia in some patients bronchospasm. The most common adverse reactions 3% reported in COPD clinical trials included nasopharyngitis, oral candidiasis, bronchitis, sinusitis, and upper respiratory tract infection Please see full Prescribing Information, including Patient Information, available at this presentation. SYMBICORT [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; December 2017. 45 Comments to AstraZeneca AstraZeneca is committed to conducting business with the highest standards of integrity and professionalism. If you have comments that could improve the delivery of our promotional educational programs, please contact AstraZeneca at 1-800-236-9933.

2018 AstraZeneca. All rights reserved. US-16961 1/18

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