Asthma New Horizons 10/24/2017. Dr Michael Ho. Asthma in the World common disease with increasing prevalence. Agenda

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1 1/24/217 Dr Michael Ho Asthma New Horizons Consultant Respiratory & Sleep Physician Dandenong Respiratory Group Director of South Eastern Private Sleep Centre Disclosures Honorariums from Boehringer Ingelheim and GSK 1 Agenda Part 1 Part 2 Asthma: Perennial problem of diagnosis and assessment of asthma control Generalised asthma management: Stepwise approach with new inhalers (Breo and Spiriva) Asthma in the World common disease with increasing prevalence An estimated 3 million people worldwide have asthma 1 This number is expected to grow by more than 1 million by Part 3 Personalised asthma management: New endotypes/phenotypes with new pharmacological options Summary Adapted from WHO, Australia has a high asthma prevalence compared to international standards 1 in 9 Australians have asthma 2,3 1. World Health Organization. Global surveillance, prevention and control of chronic respiratory diseases: a comprehensive approach, 27. Available from Accessed June Australian Centre for Asthma Monitoring 211. Asthma in Australia 211: with a focus chapter on chronic obstructive pulmonary disease. Asthma series no. 4. Cat. no. ACM 22. Canberra: AIHW. Available from accessed June Australian Institute of Health and welfare (AIHW). Asthma. Last updated Dec 216. Available from accessed June 217. Asthma in Australia what s changed? 24/5 1 Approximately 2 million people with asthma Asthma caused 37,461 hospitalisations 211/12 2 Approximately 2.3 million people with asthma Asthma caused 38,681 hospitalisations 217 New treatment guidelines 3 New treatment options The goal of asthma management To achieve overall asthma control Overall asthma control Achieve Current control Reduce Future risk Mortality from asthma 4 Defined by Defined by Symptoms Reliever use Instability/ worsening Exacerbations Activity Lung function Loss of lung function Adverse effects of medication AIHW. About asthma. Accessed August National Asthma Council Australia. Australian Asthma Handbook Quick Reference Guide, AIHW. Mortality from asthma and COPD in Australia. Adapted from Bateman ED et al. J Allergy Clin Immunol 21; 125:

2 Flow (L/sec) 1/24/217 Asthma control requires treating underlying pathophysiology Symptoms and exacerbations represent only the tip of the iceberg Validated ways of assessing asthma control but all have limitations Spirometry Peak expiratory flow Royal College of Physicians 3 Questions Asthma Control Questionnaire Asthma Control Test Airway responsiveness Exhaled nitric oxide Eosinophil differential count in induced sputum Primary Care Asthma Control Screening tool GINA symptom control tool Tools that reflect the multidimensional aspects of asthma control and that are quick and easy to use are needed in busy everyday clinical practice Lung function tests are important for assessing asthma control: 1 But in clinical practice, use of lung function testing is often low, especially in primary care settings 2 In a large-scale survey of 29 countries, only one in three patients had had a lung function test during the past year 2 Schematic representation of underlying inflammation and AHR resulting in symptoms and exacerbations of asthma, with the latter representing the tip of the iceberg. Adapted from Currie et al 24 GINA Global Initiative for Asthma. 1. GINA. Global strategy for asthma management and prevention Available from: [Accessed January 217]; 2. Rabe KF, et al. J Allergy Clin Immunol. 24;114: Spirometric diagnosis of COPD and ASTHMA Asthma Fully reversible Airflow Obstruction COPD COPD IS DEFINED AS: 1 post-bd FEV 1 <8% of the predicted normal value, and post-bd FEV 1/FVC ratio <.7 ASTHMA AIRFLOW OBSTRUCTION IS USUALLY FULLY REVERSIBLE WITH BRONCHODILATOR 1 Post-bronchodilator (BD) Pre-bronchodilator (BD) COPD FEV 1 is not fully or substantially reversible with bronchodilator 1 ASTHMA FEV 1 is usually fully reversible with bronchodilator 1 SPIROMETRIC SEVERITY OF COPD 1 Mild Moderate Severe FEV 1 ~6 8% predicted FEV 1 ~4 59% predicted FEV 1 <4% predicted If FEV 1 response is >4 ml, or fully reversible, treat as asthma An FEV 1 response <4 ml but 2mL or 12% is suggestive of asthma, but can also occur frequently with COPD PRE-BD FEV 1 3. L (92% predicted) FVC 4.51 L (114% predicted) FEV 1/FVC.67 indicates obstruction POST-BD FEV L (113% predicted) FVC 4.85 L (122% predicted) FEV 1/FVC.76 no airflow limitation As classified by Australian COPD-X guidelines. BD, bronchodilator. Volume (L) Adapted from Paraskeva ml (23%) change in FEV 1 with bronchodilator Fully reversible Consistent with suboptimally controlled asthma Reference: 1. Yang I et al, on behalf of Lung Foundation Australia. The COPD-X Plan: Australian and New Zealand Guidelines for the management of Chronic Obstructive Pulmonary Disease. Version 2.49, March Reference: 1. Paraskeva M et al. Aust Fam Physician 211; 44(4): GINA assessment of asthma control REALISE study: Poor asthma control is common Asthma control according to GINA criteria among 8, patients from 11 European countries 2% 45% Controlled Partially controlled Uncontrolled 35% Reproduced from the Global Initiative for Asthma (GINA) Pocket Guide for Asthma Management and Prevention. Global Strategy for Asthma Management and Prevention 216, Available from Accessed June 217. Online survey, n=8 patients from 11 European countries with asthma and 2 prescriptions in the past 12 months Price D et al. NPJ Prim Care Respir Med 214; 24:

3 1/24/217 REALISE study: Yet most patients perceive their asthma as well controlled Patient viewpoint GINA-defined control for these patients Patients overestimate their level of control - Under-perceivers Self-assessed asthma control in adults in the last 4 weeks by symptom frequency index. 9% perceived Asthma their perceived asthma controlled as controlled (n = 7243) (n=7243) % were not Not concerned about about asthma their asthma (n = 5992) (n=5992) Asthma perceived as not serious (n = 6682) 83% perceived their asthma as not serious (n=6682) Respondents (%) Uncontrolled Partially controlled Controlled Online survey, n=8 patients with asthma and 2 prescriptions in the past 12 months Adapted from Price D et al. NPJ Prim Care Respir Med 214; 24: 149. Participants were asked, Overall, how well would you say your asthma has been controlled in the last 4 weeks? Adapted from Marks et al 27 What is the impact of poor asthma control? ED visits and hospitalisations Adherence with ICS/LABA treatment is low Impact of poor asthma control in UK patients treated with ICS+LABA (n=71) Activity impairment Work impairment Hospitalised in past 6 months Visited ED in past 6 months % 2% 4% 6% Not well-controlled (n=452) Respondents (%) Well-controlled (n=249) Activity and work impairment Greater use of healthcare resources Impaired health-related quality of life (P<.1) Asthma patients fill their ICS/LABA script an average of only 4.5 times per year Regular ICS use reduce admissions by 8%; reduce deaths by 21% for every extra ICS canister used P<.1 ; P=.22; P=.16. Total patients = 71 Results based on data from UK National Health and Wellness Surveys ICS=inhaled corticosteroids, LABA=long-acting β 2-agonist, ED=accident and emergency department Not well-controlled asthma defined as Asthma Control Test Score <2 Adapted from Pavord ID et al. NPJ Prim Care Respir Med 217; 27: 17. Based on 1% sample set of PBS data on adherence rates for asthma patients prescribed budesonide/eformoterol or fluticasone propionate/salmeterol during a 12 month period (April 213 to March 214). 1. Prospection Data (1% sample of PBS dispensed prescriptions) 213 April 214 March Understanding the reasons for poor asthma control Reasons for uncontrolled Asthma Wrong diagnosis 1,2 Poor inhaler tech 1,2 Poor adherence to ICS preventer 1,2 Smoking 1,2 Comorbid conditions (e.g. allergic rhinitis) 1,2 Exposure to trigger factors 1,2 ABPA Allergic rhino-sinusitis Aspirin/NSAID sensitivity Beta-blocker eyedrops Churg-Strauss syndrome GORD Obesity-related Occupational asthma Anaemia Anxiety Bronchiectasis CCF/ IHD COPD Hyperventilation syndrome Pulmonary embolism Vocal cord dyskinesia Undertreatment 3 1. Haughney J et al Resp Med 28; 12: National Asthma Council Australia. Australian Asthma Handbook, Version 1.2. National Asthma Council Australia, Melbourne, 216. Available from: Accessed June Reddel HK et al. Med J Aus 215; 22:

4 % improvement 1/24/217 We Can Always Do Better The control-based asthma management cycle GINA Guidelines recommend a continuous cycle: Assess, Adjust treatment and Review response 1 Symptoms Exacerbations Side-effects Patient satisfaction Lung function Diagnosis Symptom control & risk factors (including lung function) Inhaler technique & adherence Patient preference Asthma medications Non-pharmacological strategies Treat modifiable risk factors 19 Reproduced from the Global Initiative for Asthma (GINA) Pocket Guide for Asthma Management and Prevention. Global Strategy for Asthma Management and Prevention 216, Available from Accessed June 217. GINA Stepwise approach to control asthma symptoms and reduce risk In Australia, Tiotropium Respimat is indicated only for adult patients, as an add-on to ICS ( 8 μg budesonide/day or equivalent) and LABA 1 STEP 5 ICS is the corner-stone treatment for airway inflammation, remodelling and hyperresponsiveness STEP 1 STEP 2 PREFERRED CONTROLLER CHOICE Low dose ICS Other Consider low Leukotriene receptor antagonists (LTRA) controller dose ICS Low dose theophylline options STEP 4 Not for children <12 years STEP 3 Refer for For children 6-11 years, add-on the preferred Step 3 treatment e.g. treatment is medium dose tiotropium, Med/high ICS anti-ige, ICS/LABA anti-il5 # For patients prescribed Low dose BDP/formoterol or BUD/ ICS/LABA formoterol maintenance and reliever therapy Tiotropium by mist inhaler Med/high dose ICS Add tiotropium Add low is an add-on treatment for Low dose ICS+LTRA High dose ICS + dose OCS patients 12 years with a (or + theoph) LTRA history of exacerbations (or + theoph) RELIEVER As-needed short-acting beta 2-agonist (SABA) As-needed SABA or low dose ICS/formoterol # GINA 217, Box 3-5 (1/8) 217 Global Initiative for Asthma, all rights reserved. Use is by express license from the owner Reproduced from the Global Initiative for Asthma (GINA) Pocket Guide for Asthma Management and Prevention. Global Strategy for Asthma Management and Prevention Global Initiative for Asthma (GINA) all rights reserved. Use is by express license from the owner. Available from Accessed June SPIRIVA Respimat Approved Product Information, 13 September 216. Australian guideline recommendations for a stepwise approach Time course of gaining asthma control No night symptoms 1 FEV 1 am PEF No SABA use AHR! Before considering stepping up, check symptoms are due to asthma, inhaler technique is correct, and adherence is adequate (Histamine) Consider stepping up if good control is not achieved When asthma is stable and well controlled for 2 3 months, consider stepping down (e.g. reducing inhaled corticosteroid dose, or stopping longacting beta 2 agonist if inhaled corticosteroid dose is already low Days Weeks Months Years National Asthma Council Australia. Australian Asthma Handbook, Version 1.2. National Asthma Council Australia, Melbourne, 216. Available from: Accessed June 2, Woolcock AJ Clin Exp Allergy Rev 21; 1:

5 1/24/217 What if the patient s asthma remains uncontrolled despite adherence to maximal therapy What next? Key considerations in achieving asthma control Asthma remains uncontrolled despite: Adherence checked Inhaler technique checked Co-morbidities and contributing factors addressed Optimised on maximal therapy REFER Each patient is different Each patient s asthma is different TASK FORCE REPORT ERS/ATS GUIDELINES ON SEVERE ASTHMA SEVERE ASTHMA Asthma that requires treatment with high-dose inhaled corticosteroids plus a second controller medication and/or systemic corticosteroids to prevent it from becoming uncontrolled or that remains uncontrolled despite this therapy ATS, American Thoracic Society; ERS, European Respiratory Society 1. Chung KF et al. Eur Respir J. 214;43: BREO Ellipta inhaler - Indication Breo Ellipta is indicated in the regular treatment of moderate to severe asthma in patients ( 12 years of age) who require a medium to high dose of inhaled corticosteroid (ICS) combined with a long-acting 2 agonist (LABA). 1 What can we do about it? New medical therapies for stepping up in Primary Care 1. Breo Ellipta Approved Product Information (Version 3.) Fluticasone furoate exhibits greater occupancy of ligand binding domain of the GR than fluticasone propionate Duration of GR binding: fluticasone furoate vs fluticasone propionate In-vitro data does not necessarily predict clinical effect Fluticasone furoate Fluticasone propionate Fluticasone furoate 17-α furoate ester of FF occupies the 17-α pocket of the GR to a greater extent than FP 1,2 Fluticasone propionate 4 hours 3 hours FF, fluticasone furoate; FP, fluticasone propionate; GR, glucocorticoid receptor Study design: yellow fluorescent protein-conjugated GR was overexpressed in BEAS2B cells, and GR nuclear translocation was detected under microscopy over 3 hours. FF, fluticasone furoate; FP, fluticasone propionate; GR, glucocorticoid receptor; ICS, inhaled corticosteroid 1. Biggadike K et al. Ann Allergy Asthma Immunol. 27;98(Suppl 1):A91 2; 2. Biggadike K et al. J Med Chem. 28;51: Adapted from Rossios C et al. Eur J Pharmacol. 211;67:

6 Probability of severe asthma exacerbation (%), 95% CI Mean change from baseline in -24h FEV 1 (L) Mean change from baseline in - 24 h FEV 1 (L) Geometric weighted mean (95% CI) serum cortisol levels (nmol/l) 1/24/217 Duration of bronchodilation: vilanterol vs salmeterol 1 In-vitro data does not necessarily predict clinical effect Control Vilanterol (1 nm) Salmeterol (1 nm) Breo Ellipta: Effect on lung function 1,2 Mean change from baseline in serial ( to 24h) FEV 1 (primary endpoint).6 Baseline.4.2 Carbachol.3 µm FF/VI 1/25 mcg (n=18). Placebo (n=95) % bronchial closure P<.1 at 22 hours Study design: the duration of action of VI and SAL were investigated in human precision-cut lung slices following carbachol-induced bronchoconstriction. FF, fluticasone furoate; LABA, long-acting β-agonist; SAL, salmeterol; VI, vilanterol 1. Adapted from Slack RJ et al. J Pharmacol Exp Ther. 213;344: Time since dose (h) Statistically significant differences were observed for FF/VI (32mL) and FF (186mL) vs placebo (p<.1 and p=.3, respectively). Difference between FF/VI and FF (116mL) was not statistically significant (p=.6) (co-primary endpoint). Twelve-week randomised, double-blind control study (n=69) Adapted from Bleecker ER et al. J Allergy Clin Immunol Prac 214: 5: Breo Ellipta Product Information Once-daily ICS/LABA vs once-daily ICS monotherapy (primary endpoint: Time to first severe asthma exacerbation) 1 How does the efficacy of Breo Ellipta (once daily) compare with existing ICS/LABA (twice daily)? Adjusted means for to 24 h serial weighted mean FEV 1 at Week Week Cox proportional hazards model. Randomised, double-blind, parallel group study of variable study duration ( weeks) comparing FF/VI (1/25 mcg) OD and FF (1 mcg) OD in patients ( 12 years old) with uncontrolled asthma (n=219). 1 Designed to be event driven (i.e. to finish after 33 events). 1 FF, fluticasone furoate; OD, once-daily; VI, vilanterol. Probability of event at week 52 FF 15.9% FF/VI 12.8% 2% risk reduction (P=.36) Additional endpoint Rate of severe asthma exacerbations/patient/year FF versus FF/VI,.19 versus.14 Reduction of 25% (P=.14) FF 1 µg OD FF/VI 1/25 µg OD 1. Bateman ED et al. Thorax 214: 69: FF/VI (Breo) 1/25mcg OD FP/SAL (Seretide) 25/5mcg BD No significant difference in 24-hour serial wmfev 1 between Breo Ellipta (341 ml) vs Seretide (377 ml) p=.162 (primary endpoint was not met) 24-week randomised, double-blind, double-dummy study comparing FF/VI (1/25 mcg) Ellipta OD and FP/SAL (25/5 mcg) Accuhaler BD in patients ( 12 years old) with persistent asthma uncontrolled on a medium dose of inhaled corticosteroid (n=86). 1 BD, twice-daily; CI, confidence interval; FEV 1, forced expiratory volume in one second; FF, fluticasone furoate; FP, fluticasone propionate; LS, least squares; OD, once-daily; SAL, salmeterol; VI, vilanterol. 1. Adapted from Woodcock A et al. Chest 214; 144: Adverse event profile of Breo Ellipta (once daily) compare with an existing ICS/LABA (twice daily)? The effect of FF/VI on HPA axis function Event Breo Ellipta 1/25mcg OD pm (n=43) Nasopharyngitis 46 (11) 46 (11) Headache 34 (8) 41 (1) URTI 26 (6) 16 (4) Cough 15 (4) 13 (3) Back pain 11 (3) 11 (3) Oropharyngeal pain 11 (3) 9 (2) Sinusitis 12 (3) 7 (2) Pyrexia 13 (3) 5 (1) Productive cough 11 (3) 5 (1) Treatment-related AEs (any) 19 (5) 15 (4) Seretide Acc 25/5mcg BID (n=43) Day 1 (baseline) Day 42 Time (hours) Time (hours) FF/VI 1/25 µg OD FF/VI 2/25 µg OD Prednisolone 1 mg OD Placebo No significant cortisol suppression at Day 42 with FF/VI 1/25, FF/VI 2/25 µg or placebo; however, serum cortisol levels were notably lower in the prednisolone group at Day FF, fluticasone furoate; HPA, hypothalamic-pituitary-adrenal; OD, once daily; VI, vilanterol AE, adverse event; BID, twice-daily; OD, once-daily; URTI, upper respiratory tract infection. 1. Adapted from Woodcock A et al. Chest 214: 144: Adapted from Allen A et al. Clin Respir J. 213;7:

7 1/24/217 Over half of patients prefer once-daily medication reinforcing the importance of taking the time to understand patient preference1 Once-daily administration associated with higher mean adherence to treatment compared to twice-daily1 UK retrospective observational study (n = 3,731) Twelve week open-label study (n=1,233) Patients level of agreement with a statement indicating preference for once-daily therapy in asthma and COPD Patients (%) Strongly agree Agree Not sure Disagree Strongly disagree Patient s level of agreement noted above was not subject to statistical analysis. Statistical analysis conducted to identify patient characteristics associated with preference to once daily medicine in COPD and asthma (primary endpoint). Patients were asked to choose one of five possible responses (strongly agree, agree, not sure, disagree, strongly disagree) with regard to the following statement of preference for once-daily medication: I would prefer to take my inhaler once a day 1. Adapted from Price D et al. Prim Care Respir J 213; 22(2): ICS used in this study was mometasone furoate (not currently registered for asthma in Australia). 1. Adapted from Price D et al. BMC Pulm Med 21; 1:1. BREO Ellipta inhaler device1 Stepping up to Breo Ellipta from ICS/LABA (uncontrolled asthma on maintenance-only regimen) Existing therapy twice daily ICS/LABA Two 3 dose foil blister strips for combination products Recommended dose Seretide Accuhaler (fluticasone propionate/salmeterol) 1/5mcg twice daily Symbicort Turbuhaler (budesonide/eformoterol) 2/6mcg 1 inhalation twice daily Breo Ellipta 1/25mcg One inhalation once daily Breo Ellipta 1/25mcg One inhalation once daily Inhaled images for illustrative use only. Not actual size and not to scale Seretide, Accuhaler, Breo, Ellipta are registered trade mark of GSK, Symbicort and Turbuhaler are registered trade mark of AstraZeneca 1. Breo Ellipta Approved Product Information. SPIRIVA Respimat : PBS listed for adult asthma patients as add-on therapy to ICS/LABA ( 8 µg of budesonide per day or equivalent) Peak FEV1( 3h) response at week 24 when added to ICS/LABA Add-on to at least ICS+LABA PBS criteria and prescribing instructions: Add-on treatment option for adult patients ( 18 years) already on medium-high dose LABA/ICS ( 8 µg of budesonide per day or equivalent) Patient must have had at least one severe exacerbation in the previous 12 months requiring a course of systemic (e.g. oral) corticosteroids, which has been documented Adherence and inhaler technique with the ICS/LABA preventer should be formally assessed and documented prior to adding tiotropium Respimat Trial 1 FEV1 (ml) change from baseline Mean adherence to treatment. Adherence was calculated as administered doses divided by scheduled doses x 1, as measured by dose counter and patient self-report. Error bars represent standard error and mean. P <.1. Trial mL 45 4 (95% CI 2, 152; p<.5) mL (95% CI 91, 217; p<.1) Time post-dosing (h) Time post-dosing (h) Tiotropium Respimat + ICS/LABA (n=217) Placebo Respimat + ICS/LABA (n=211) P<.5; P<.1 Error bars represent standard errors Adapted from Kerstjens HAM et al. NEJM Accessed March 217 FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting β2-agonist. Kerstjens HAM et al. NEJM 212; 367:

8 FEV 1 (ml) change from baseline 1/24/ hour FEV 1 response at week 24 when added to ICS/LABA Time to first severe asthma exacerbation after 48 weeks pooled Add-on to at least ICS+LABA Trial 1 Trial 2 Trough response 5 vs placebo: +83 ml 4 (95% CI 27, 149; p=.1) Trough response vs placebo: +111 ml (95% CI 53, 169; p<.1) Add-on to at least ICS+LABA 21% relative risk reduction (HR.79; 95% CI.62, 1.; p=.3) Number needed to treat: Dosing 7: 1: AM Time post-dosing (h) Dosing 7: 1: AM Time post-dosing (h) Tiotropium Respimat + ICS/LABA (n=84 [trial 1], n=77 [trial 2]) Placebo Respimat + ICS/LABA (n=83 [trial 1], n=89 [trial 2]) P<.5; P<.1 Error bars represent standard errors Adapted from Kerstjens HAM et al. NEJM 212 (Supplementary appendix) Graphs represent a subgroup of patients who underwent 24 hour spirometry (n=333) Trough response represents full study population (n=912) FEV 1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting β 2-agonist. Kerstjens HAM et al. NEJM 212; 367: (supplementary appendix). Adapted from Kerstjens et al. 212 Severe asthma exacerbation defined as a deterioration of asthma necessitating initiation or at least a doubling of systemic glucocorticoids for 3 days HR, hazard ratio; ICS, inhaled corticosteroid; LABA, longacting β 2-agonist; OR, odds ratio. Kerstjens HAM et al. NEJM 212; 367: Adverse events: Overall summary Tiotropium Respimat n (%) Placebo Respimat n (%) Number of patients 456 (1.) 456 (1.) Total with any adverse event 335 (73.5) 366 (8.3) Drug-related adverse event as defined by Investigator 26 (5.7) 21 (4.6) Serious adverse event 37 (8.1) 4 (8.8) No deaths occurred. Adverse events reported by >2% of randomised patients in pooled groups Tiotropium Respimat n (%) Placebo Respimat n (%) Patients with any adverse event 335 (73.5) 366 (8.3) Asthma 182 (39.9) 232 (5.9) Nasopharyngitis 51 (11.2) 56 (12.3) Peak expiratory flow rate decreased 93 (2.4) 122 (26.8) Headache 29 (6.4) 33 (7.2) Bronchitis 25 (5.5) 2 (4.4) Sinusitis 16 (3.5) 22 (4.8) Upper respiratory tract infection 21 (4.6) 16 (3.5) Influenza 2 (4.4) 14 (3.1) Cough 13 (2.9) 13 (2.9) Rhinitis allergic 13 (2.9) 3 (.7) Pneumonia 12 (2.6) 7 (1.5) Back pain 11 (2.4) 12 (2.6) Arthralgia 1 (2.2) 9 (2.) Dysphonia 1 (2.2) 8 (1.8) Oropharyngeal pain 9 (2.) 11 (2.4) Diarrhoea 8 (1.8) 1 (2.2) Respiratory tract infection 7 (1.5) 11 (2.4) Hypertension 6 (1.3) 1 (2.2) Insomnia 2 (.4) 1 (2.2) AE, adverse event; SAE, serious adverse event; ICS, inhaled corticosteroid; LABA, long-acting β 2-agonist. Kerstjens HAM et al. NEJM 212; 367: Adapted from Kerstjens et al Dry mouth reported in 3 (.7%) placebo Respimat and 8 (1.8%) tiotropium Respimat patients; P<.5. Events are described according to preferred term classifications in the Medical Dictionary for Drug Regulatory Affairs, version 14.. Kerstjens HAM et al. NEJM 212; 367: Spiriva/Tiotropium Respimat in asthma: contraindications Spiriva/Tiotropium Respimat in asthma: precautions Contraindications 1 Do not use tiotropium Respimat in patients with hypersensitivity to tiotropium bromide, atropine or its derivatives (e.g. ipratropium or oxitropium) or to any other excipients in tiotropium Respimat benzalkonium chloride, disodium edetate and hydrochloric acid 1 Patients must continue to use their preventer (ICS therapy) while using tiotropium Respimat Tiotropium Respimat should not be used for the treatment of acute episodes of bronchospasm (i.e. as rescue therapy) or for the relief of acute symptoms 1 Immediate hypersensitivity reactions may occur after administration of tiotropium 1 Use with caution in patients with narrow-angle glaucoma, prostatic hyperplasia and bladderneck obstruction, as with other anticholinergic drugs 1 1. SPIRIVA Respimat Approved Product Information, 13 September SPIRIVA Respimat Approved Product Information, 13 September

9 1/24/217 How does LABA/ICS ( 8 µg budesonide per day) compare with other brands for adults with asthma? RESPIMAT SOFT MIST INHALER : DRUG DELIVERY TO THE LUNGS Lung deposition scintigraphy study in asthma patients comparing Respimat, Turbuhaler and CFC-pMDI 1,2 RESPIMAT Soft Mist Inhaler 51.6% Lung deposition CFC-pMDI 8.9% lung deposition (p<.1) Turbuhaler DPI (flow rate 6 L/min) 28.5% lung deposition (p<.1) Tiotropium Respimat is an add-on treatment to ICS ( 8 µg of budesonide daily) and LABA 7 Adapted from 1. National Asthma Council Australia. Australian Asthma Handbook, Version 1.2. National Asthma Council Australia, Melbourne, 216. Website. Available from: 2. Symbicort Turbuhaler Product Information (March 217). 3. Symbicort Rapihaler Product Information (March 217). 4. Seretide Accuhaler Product Information (September 216). 5. Seretide MDI Product Information (September 216). 6. Breo Ellipta Product Information (March 217). 7. SPIRIVA Respimat Approved Product Information, 13 September 216. Adapted from Pitcairn et al. 25 and Anderson 26. 1,2 vs Respimat. Lung deposition (% of metered dose ex-valve, mean) measured by gamma scintigraphy. Test drug budesonide (Respimat and Turbuhaler ) or beclomethasone (pmdi). Asthma patients (n=14). CFC, chlorofluorocarbon; pmdi, pressurised metered-dose inhaler; DPI, dry powder inhaler. References: 1. Anderson P. Int J COPD 26; 1: Pitcairn G et al. J Aerosol Med 25; 18: ARE THERE DIFFERENCES BETWEEN INHALER CLASSES? pmdis DPIs Soft Mist TM Inhaler DEVICE CHOICE Active device 1 Aerosol cloud of high velocity and short duration 2 Requires significant coordination 2 Breath-actuated (passive) devices 2 Delivered dose and particle size dependent on inspiratory flow 2,3 Requires a forceful inhalation 2,3 Minimum coordination required 2 Active device 4 Slow-moving aerosol cloud vs pmdis 5 Requires a slow inhalation 2 Improved coordination vs pmdis References: 1. Laube B et al. Eur Respir J 211; 37: Newman S. Eur Respir Rev 25; 14: 96, Newman S and Busse W. Resp Med 22; 96: Dalby R et al. Int J Pharm 24; 283: Hochrainer D et al. J Aerosol Med 25; 18: Hodder R et al. Int J Chron Obstruct Pulmon Dis 29; 4: ASSESSING INHALER TECHNIQUE 1 Up to 94% of asthma and COPD patients incorrectly use their inhaler device 2,3 check adherence and inhaler technique ideally at each visit 4 The EFFICACY of INHALED therapies is DEPENDENT on the EFFICIENT drug DELIVERY to the LUNGS 1,2 Key factors affecting lung deposition include: Patient demonstrates inhaler technique 2 Demonstrate correct technique highlighting steps that need correction 3 Patient re-demonstrates inhaler technique repeat until all steps performed correctly A low aerosol velocity to reduce oropharyngeal deposition 5,6 Long aerosol cloud duration may facilitate coordination of actuation with inhalation 5,6 A high fine particle fraction particles 5.8 µm in diameter are ideal to travel into the lungs 6 Patient factors can the patient use the device correctly? 1 References: 1. Newman SP. Eur Respir Rev 25; 14: Vincken W et al. Prim Care Respir J 21; 19: Hochrainer D, et al. J Aerosol Med 25;18: Scichilone N et al. Pulm Pharmacol Ther 215; 31: Ganderton D. J Aerosol Med 1999; 12(suppl 1): S3 S8. 6. Dalby RN et al. Med Devices (Auckl) 211; 4: References: 1. National Asthma Council. Australian Asthma Handbook, Lavorini F et al. Respir Med 28; 12: Melani AS et al. Respir Med 211; 15: Abramson M et al. COPD-X concise guide for primary care. Brisbane: Lung Foundation Australia,

10 1/24/217 Inflammation in asthma Allergens Pollution, Microbes Airway epithelium Goblet cells What other new asthma treatments? New and novel therapies in Specialist Care Basophil IgE IL-33 IL-25 TSLP Mast cells IL-9 Dendritic cells Naive T cells IL-13 T H 2 IL-13 IL-33 IL-25 TSLP IL-33 ILC2 IL-17R Macrophages NKT IL-17A cells CXCL8 GM-CSF IL-17 Th17 cells IL-4,IL-13 IL-5 IL-5 IL-13 Eosinophils IL-13 Neutrophils B cells Smooth muscle cells Allergic eosinophilic asthma Nonallergic eosinophilic asthma Adapted from Brusselle G, et al Ann Am Thorac Soc. 214;11:S322-S328. Neutrophilic asthma Asthma phenotypes and personalised treatment approaches 1,2 Asthma phenotypes and personalised treatment approaches 1,2 Severe asthma with high IgE levels or high eosinophil count Phenotype-directed management options: Non-pharmacologic Phenotype-directed add-on treatment options: biologics Individualise according to phenotype 2 e.g. smoking cessation, weight loss Anti-IgE mab: Omalizumab 2,3 Administered by s/c injection every 2 4 weeks PBS listed for severe uncontrolled allergic asthma Must be treated by specialist physician Anti-IL-5 mab: Mepolizumab 2,4 Administered by s/c injection every 4 weeks PBS listed for severe uncontrolled eosinophilic asthma Must be treated by specialist physician 1. Wenzel S. Nature Med 212; 18: Guilleminault L et al. Eur Respir Rev 217; 26: 161. ICS: inhaled corticosteroids; IgE: immunoglobulin E; Anti-IL-5 mabs: anti interleukin-5 monoclonal antibody. 1. Wenzel S. Nature Med 212; 18: National Asthma Council Australia. Australian Asthma Handbook, Version 1.2. National Asthma Council Australia, Melbourne, 216. Available from: Accessed June Omalizumab Product Information. March Mepolizumab Product information. May 217. Effect of omalizumab on exacerbations in severe allergic asthma Omalizumab as add-on therapy in severe persistent asthma inadequately controlled despite best available therapy Effect of mepolizumab on exacerbations in severe eosinophilic asthma Adapted from Humbert et al. 25 Study design: 28-week, double-blind, randomised controlled study of omalizumab vs placebo in 419 patients aged years with severe persistent allergic asthma inadequately controlled despite high ICS/LABA (i.e. GINA 22 Step 4 treatment), reduced lung function, and a recent history of clinically significant exacerbations. Primary efficacy variable: clinically significant asthma exacerbation rate defined as a worsening of asthma symptoms requiring treatment with systemic corticosteroids, adjusted for baseline exacerbation history, primary intent-to-treat population. Secondary efficacy variable: PEF or FEV 1 <6% of personal best, requiring treatment with systemic corticosteroids. Adapted from Ortega et al. 214 Results at week 32, intent-to-treat (ITT) population. s.c. = subcutaneous Study design: Randomised double-blind dummy study in 576 patients with recurrent asthma exacerbations and evidence of eosinophilic inflammation despite high dose ICS. Patients were assigned to receive mepolizumab (75 mg intravenous dose or a 1 mg subcutaneous dose) or placebo every 4 weeks for 32 weeks. The primary outcome was the annualised rate of clinically significant exacerbations (defined as a worsening of asthma symptoms requiring treatment with systemic corticosteroids for 3 days, and/or ED visits, and/or hospitalisation). Humbert M et al. Allergy 25: 6: Ortega HG et al. NEJM 214; 371:

11 1/24/217 Other personalised therapies Thunderstorm ASTHMA Melbourne is the global capital Bronchial thermoplasty Allergen immunotherapy : sub-lingual vs sub-cut Macrolide antibiotics WHAT? - Rare potentially catastrophic allergic event whereby aeroallergens (rye and fungal spores) with thunderstorm activity cause acute bronchospasm in susceptible people WHY? - Wet spring allowed lush rye grass growth around Melbourne. Thunderstorm lift pollens into charged storm clouds, where the grains absorb moisture and rupture to disperse over 7 particles per grain; strong winds to funnel the pollens into Melbourne dome PERFECT STORM WHEN? - November 1984/ 1987/ 1989/ 23/ 21/ 211/ 216 in Melbourne. Also documented in UK, USA, Canada, Iran. On : 2 calls in 5hrs (21 bet 7pm-7.15pm or 1 call every 4.5 seconds), 85 ED visits and sadly NINE deaths Thunderstorm ASTHMA Plan and Prepare WHO? - Mean 3 s male. 9% hayfever, >5% undiagnosed asthma, >5% overseas-born. Among asthmatics: 1/3 on ICS, >5% without action plan. Tended to be allergic to rye grass (serum RAST or skin prick test). HOW? - Critical period between October and December New State Health Emergency Response that sets out responsibilities of various health & emergency services. Real- Time Emergency Dept Info Trending System (REDIT) for early recognition of emergency surges in ED, communicating & directing ambulance and health services. Local hospitals have disaster planning with adequate medical supplies, as well as ensure staff is aware how to manage their asthma. Medical clinics need to have a disaster plan with local pharmacies to have reasonable stock of bronchodilators, steroids and adrenaline. Potential patients reminded to be compliant on Preventive Inhalers or Anti-Histamines; ALWAYS carry Reliever Inhalers; stay indoors on very high to extreme pollen count days; aware of daily forecast pollen counts available ( remember rule of 4 in emergency (1 puff in spacer + 4 breaths, every 4 mins till help arrives); review asthma action plan. 64 Develop an Asthma Action Plan with your patient A written asthma action plan should include the following: the person s usual asthma and allergy medicines clear instructions on how to change medication (including when and how to start a course of oral corticosteroids) when and how to get medical care, including during an emergency National Asthma Council Australia. Australian Asthma Handbook, Version 1.2. National Asthma Council Australia, Melbourne, 216. Website. Available from: Accessed June 217. Reproduced from National Asthma Council Australia website. _action_plan_colour_a4.pdf NATIONAL GUIDELINES RECOMMEND A STEPWISE APPROACH TO COPD TREATMENT 1 ASTHMA vs. COPD: TREATMENT APPROACHES DIFFER MILD FEV 1 6 8% predicted few symptoms breathless on moderate exertion recurrent chest infections little or no effect on daily activities MODERATE FEV % predicted increasing dyspnoea breathless walking on level ground increasing limitation of daily activities cough and sputum production exacerbations requiring oral corticosteroids and/or antibiotics SEVERE FEV 1 <4% predicted dyspnoea on minimal exertion daily activities severely curtailed experiencing regular sputum production chronic cough exacerbations of increasing frequency and severity CHECK DEVICE USAGE TECHNIQUE AND ADHERENCE AT EACH VISIT Short-acting reliever medication: Short-acting ß 2-agonist (SABA) or short-acting muscarinic antagonist (SAMA) Symptom relief Exacerbation prevention - precautions apply (refer to reference 1) PBS-eligible symptomatic patients should be stabilised on a combination of LAMA and LABA. Not indicated for the initiation of bronchodilator therapy in COPD. 2,3 LAMA OR LABA OR LAMA/LABA Exacerbation prevention When FEV 1 <5% predicted AND LABA/ICS 2 exacerbations in 12 months Consider low-dose theophylline References: 1. Lung Foundation Australia. Stepwise management of stable COPD, February Symbicort Rapihaler approved Product Information (March 217). 3. Seretide Accuhaler approved Product Information (September 216)

12 1/24/217 GUIDELINE RECOMMENDATIONS FOR LONG-TERM ICS THERAPY IN COPD National COPD-X guidelines1-3 International GOLD strategy4 Moderate to severe COPD with frequent exacerbations COPD patients at high risk of exacerbations: When FEV1 <5% predicted - At least 2 exacerbations (or 1 hospitalised) in 12 months AND 2 exacerbations in 12 months Only as an add-on therapy to LAMA and/or LABA therapy SUMMARY - only as add-on therapy in those who continue to exacerbate despite LAMA/LABA therapy Long-acting bronchodilators are the cornerstone of COPD treatment 1-4 ICS ± LABA are the cornerstone of adult asthma treatment5 References: 1. Abramson M et al. COPD-X concise guide for primary care. Brisbane: Lung Foundation Australia, Yang I et al, on behalf of Lung Foundation Australia. The COPD-X Plan: Australian and New Zealand Guidelines for the management of Chronic Obstructive Pulmonary Disease. Version 2.49, March Lung Foundation Australia. Stepwise management of stable COPD, February Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for diagnosis, management, and prevention of COPD National Asthma Council. Australian Asthma Handbook. Quick reference guide, version 1.2, April GINA Stepwise approach to control asthma symptoms and reduce risk Summary : Asthma diagnosis & control In Australia, Tiotropium Respimat is indicated only for adult patients, as an add-on to ICS ( 8 μg budesonide/day or equivalent) and LABA1 Assess control and future risk Asthma in Australia is not a solved problem; there are still major unmet needs in asthma1 Patients with poorly controlled asthma have higher risk of exacerbations and hospitalisations 2 Assess symptom levels regularly using tools and specific questioning 3 STEP 5 STEP 4 Not for children <12 years STEP 2 STEP 1 STEP 3 Adjust treatment Non-pharmacological strategies first, e.g. optimising adherence and inhaler technique3,4 Pharmacological strategies, eg : step up and step down therapy Med/high ICS/LABA PREFERRED CONTROLLER CHOICE Low dose ICS Refer for add-on treatment e.g. tiotropium, anti-ige, anti-il5 Low dose ICS/LABA For children 6-11 years, the preferred Step 3 treatment is medium dose ICS #For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy Tiotropium Other controller options Review treatment response Ensure inhaler technique is checked at every visit 3 Review response to treatment and also consider step-down when stable3 Consider specialist referral if no adequate response to treatment3 1. Reddel al, Med J Aus 215;22: HKyettake away messages 2. Pavord ID et al. NPJ Prim Care Respir Med 217;27: National Asthma Council Australia. Australian Asthma Handbook, Version 1.2. National Asthma Council Australia, Melbourne, 216. Website. Available from: Accessed June 2, Global Initiative for Asthma (GINA) Pocket Guide for Asthma Management and Prevention. Global Strategy for Asthma Management and Prevention 216, Available from Accessed June 2, SPIRIVA Respimat Approved Product Information, 13 September 216. Summary : Breo Ellipta in Asthma - Only once daily ICS/LABA 1 Approved for adults and adolescents aged (12 years and over) for convenience and improved adherence Available as 2 doses for treatment of moderate-to-severe asthma RELIEVER Consider low dose ICS Leukotriene receptor antagonists (LTRA) Low dose theophylline As-needed short-acting beta2-agonist (SABA) GINA 217, Box 3-5 (1/8) Med/high dose ICS Add tiotropium Low dose ICS+LTRA High dose ICS + LTRA (or + theoph) (or + theoph) Add low dose OCS by mist inhaler is an add-on treatment for patients 12 years with a history of exacerbations As-needed SABA or low dose ICS/formoterol # 217 Global Initiative for Asthma, all rights reserved. Use is by express license from the owner Reproduced from the Global Initiative for Asthma (GINA) Pocket Guide for Asthma Management and Prevention. Global Strategy for Asthma Management and Prevention Global Initiative for Asthma (GINA) all rights reserved. Use is by express license from the owner. Available from Accessed June SPIRIVA Respimat Approved Product Information, 13 September 216. Summary : Tiotropium Respimat in Asthma Tiotropium Respimat as an add-on to those on medium-high dose ICS/LABA with > 1 severe exacerbation in last 12 months : (ICS 8 µg budesonide/day, or equivalent) improves lung function at peak and trough 1,2 reduces risk of severe exacerbations 1,2 increases the number of patients with improved asthma control 3 Safety profile comparable to placebo1,2 Effective independent of patient characteristics 3 1/25mcg 2/25mcg 1. SPIRIVA Respimat Approved Product Information, 13 September Kerstjens HAM et al. NEJM 212; 367: Kerstjens HAM et al. Resp Med 216; 117: Breo Ellipta Approved Product Information. 12

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