The Advanced Role of Tiotropium in Asthma Ana

The Advanced Role of Tiotropium in Asthma Ana

The Advanced Role of Tiotropium in Asthma Ana Rima GPM-SV-0006-ID Outline Role of tiotropium in asthma Efficacy as add-on to ICS/LABA Efficacy in subpopulations Safety Effectiveness in real life Stepwise management pharmacotherapy Diagnosis RE Symptoms RE V Side-effects MENT ADJUST TREAT IE W Exacerbations SS SE AS SP O N

SE Symptom control & risk factors (including lung function) Patient satisfaction Inhaler technique & adherence Patient preference Asthma medications Non-pharmacological strategies Treat modifiable risk factors Lung function STEP 5 STEP 4 PREFERRED CONTROLLER CHOICE STEP 1 STEP 2 Low dose ICS Other controller options Consider low dose ICS RELIEVER GINA 2017, Box 3-5 Leukotriene receptor antagonists (LTRA) Low dose theophylline* As-needed short-acting beta2-agonist (SABA) STEP 3 Low dose ICS/LABA** Med/high dose ICS Low dose ICS+LTRA

(or + theoph*) Med/high ICS/LABA Refer for add-on treatment e.g. Tiotropium* Omalizumab, mepolizumab * Add tiotropium* Add low High dose ICS dose OCS + LTRA (or + theoph*) As-needed SABA or low dose ICS/formoterol# *Not for children <12 years **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 by mist inhaler is an add-on treatment for patients 12 years with a history of exacerbations Choosing between controller options: individual patient decisions Decisions for individual patients Use shared decision-making with the patient/parent/carer to discuss: 1. Preferred treatment for symptom control and for risk reduction 2. Patient characteristics (phenotype) Does the patient have any known predictors of risk or response?

(eg, smoker, history of exacerbations, blood eosinophilia) 3. Patient preference What are the patients goals and concerns for their asthma? 4. Practical issues Inhaler technique: can the patient use the device correctly after training? Adherence: how often is the patient likely to take the medication? Cost: can the patient afford the medication? Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention, 2017. GINA 2014, Box 3-3 (2/2) Provided by H Reddel Global Initiative for Asthma Spectrum of actions of acetylcholine in the airway Kummer K, et al. Histochem Cell Biol. 2008 130:219234. Pharmacological modulation of airway smooth muscle cell Mechanism of action of anticholinergic bronchodilators Barnes P. Physiol Rev. 1992; 72(3): 699 729. Ach Acetylcholine Milestones in the development of anticholinergics Cazzola M, et al. Pharmacol Rev. 2012;64:450504. Tiotropium 5 g qd morning Placebo I Visit 0 I I Visit 1 Visit 2 (screening) (randomization) -4 0 I

I 4-week screening I I I I Visit 34 Visit 58 Visit 9 (end of treatment) Visit 10 48 48-week double-blind treatment period Three co-primary endpoints: FEV1 peak(03 h) after 24 weeks FEV1 trough after 24 weeks Time to first severe asthma exacerbation in pooled analysis after 48 weeks I 4-week followup 52 I All patients at least on ICS maintenance

therapy (budesonide or equivalent)+LABA 148 centres, 5 continents Kerstjens H, et al. N Engl J Med. 2012;367:11981207. FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting 2-agonist; qd, once daily. Patients on at least Inclusion criteria: poorly controlled asthma Asthma diagnosis: Asthma diagnosed <40 years, documented by BHR, PEF var, or SABA/OCS response 5-year history of asthma 1875 years Never-smoker or ex-smoker 1 year cessation and <10 pack-years Poorly controlled: Despite ICS+LABA and potential other controllers Mandatory: high-dose ICS+LABA Permitted: stable theophylline, leukotriene modifiers, omalizumab, oral steroids (5 mg/day) Symptomatic Mean ACQ 1.5 at screening and baseline visit Persistent obstruction Postbronchodilator FEV1 80% predicted; FEV1/FVC 70%

At least one severe asthma exacerbation in previous year treated with systemic steroids Kerstjens H, et al. N Engl J Med. 2012;367:11981207. Patients on at least Pooled demographics Total treated, N (%) Tiotropium 5 g 456 (100) Placebo 456 (100) Total 912 (100) 273 (59.9) 278 (61.0) 551 (60.4) White 376 (82.5) 383 (84.0) 759 (83.2) Black 22 (4.8) 25 (5.5) 47 (5.2) Asian 56 (12.3) 47 (10.3) 103 (11.3) Other 2 (0.4)

1 (0.2) 3 (0.3) 52.2 (12.5) 53.8 (12.2) 53.0 (12.4) Median age of onset 26 26 26 Median duration 28 28 28 Never smoked 340 (74.6) 352 (77.2) 692 (75.9) Ex-smoker 116 (25.4) 104 (22.8) 220 (24.1) 5.4 (2.8) 4.8 (2.7) 5.1 (2.7) Gender, n (%) Female Race, n (%)

Age, years Current age, mean (SD) Mean pack years (SD) Kerstjens H, et al. N Engl J Med. 2012;367:11981207. SD, standard deviation. Patients on at least Pooled disease characteristics Total treated, N (%) Tiotropium 5 g 456 (100) Placebo 456 (100) Total 912 (100) FEV1, L mean (prebronchodilator) 1.63 1.58 1.60 FEV1, % predicted (prebronchodilator) 54.9 54.8 54.8 FEV1, % predicted (postbronchodilator) 62.0 62.5 62.2 FEV1 bronchodilator rev, ml (mean)* 214 219

217 FVC, % predicted (postbronchodilator) 87.3 88.1 87.7 FEV1/FVC % (postbronchodilator) 59.4 59.0 59.2 <60% 179 (39.3) 183 (40.1) 362 (39.7) 60% to <80% 274 (60.0) 264 (57.9) 538 (59.0) 80% to <90% 3 (0.7) 9 (2.0) 12 (1.3) 62.7 61.3 62.0 FEV1 % predicted classes, n (%) (postbronchodilator) Weekly mean PEF (% predicted)**

*Performed 30 minutes after four puffs of 100 g salbutamol. **Last week prior to Visit 2. Kerstjens H, et al. N Engl J Med. 2012;367:11981207. FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; PEF, peak expiratory flow. Patients on at least Pooled medications at Visit 1 (screening) Treatment arms, N (%) Tiotropium 5 g Placebo Total Total treated 456 (100.0) 456 (100.0) 912 (100.0) ICS 452 (99.1) 449 (98.5) 901 (98.8) OCS 24 (5.3) 24 (5.3) 48 (5.3) Anticholinergics Long-acting Short-acting 45 (9.9) 13 (2.9) 34 (7.5) 45 (9.9) 11 (2.4) 33 (7.2)

90 (9.9) 24 (2.6) 67 (7.3) 442 (96.9) 444 (97.4) 886 (97.1) Antibiotics 22 (4.8) 36 (7.9) 58 (6.4) Mucolytics 13 (2.9) 7 (1.5) 20 (2.2) Theophyllines 75 (16.4) 77 (16.9) 152 (16.7) Anti-allergic agents, excluding corticosteroids 18 (3.9) 17 (3.7) 35 (3.8) Leukotriene modifiers 96 (21.1) 107 (23.5) 203 (22.3) Omalizumab

12 (2.6) 24 (5.3) 36 (3.9) LABA Kerstjens H, et al. N Engl J Med. 2012;367:11981207. ICS, inhaled corticosteroid; LABA, long-acting 2-agonist; OCS, oral corticosteroid. Patients on at least Significant lung function improvement in from placebo FEV1 peak(03 h) andAdjusted trough:Difference Trials 1 Baseline, mL mean change Adjusted mean 95% CI, (SE), mL of difference P-value and 2 mL (SE), mL Trial 1 FEV1 peak(03h) Tiotropium Respimat (n=217) Placebo Respimat (n=211) 1578 401 (25) 315 (26) 86 (34) 20, 152 <0.05 88 (31) 27, 149

<0.01 154 (32) 91, 217 <0.0001 111 (30) 53, 169 <0.001 FEV1 trough Tiotropium Respimat (n=217) Placebo Respimat (n=211) 1578 144 (24) 56 (25) Trial 2 FEV1 peak(03h) Tiotropium Respimat (n=205) Placebo Respimat (n=218) 1628 401 (25) 248 (24) FEV1 trough Tiotropium Respimat (n=204) Placebo Respimat (n=218) 1628 155 (23) 44 (22) Kerstjens H, et al. N Engl J Med. 2012;367:11981207. CI, confidence interval; FEV1, forced expiratory volume in 1 second; SE, standard error. Patients on at least Significant lung function improvement in FEV1 peak : Trials

1 and 2 (03 h) FEV peak at Week 24 500 1 FEV1 peak: Change from baseline (mL) 450 Add-on to ICS+LABA (03 h) 400 ** ** * 350 * 300 250 200 *** ** 15 0 100 Trial 1; mean difference 8634 mL (P=0.01) 50 Trial 2; mean difference 15432 mL (P<0.001) P<0.0001 unless shown otherwise: *P<0.05 **P<0.01

0 0 Tiotropium Respimat 5 g Trial 1 0.5 1.0 2.0 3.0 Tiotropium Respimat 5 g Trial 2 Placebo Respimat Trial 2 Time post-dosing (h) Placebo Respimat Trial 1 FEV1 response results from Kerstjens H, et al. N Engl J Med. 2012;367:11981207. Error bars represent standard errors. FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; LABA, long-acting 2-agonist. Patients on at least Third co-primary endpoint: severe asthma exacerbation Definition of severe asthma exacerbation: the need for initiation or doubling of systemic corticosteroid therapy for at least 3 days* Time to first severe exacerbation Per protocol: pooled analysis over 48 weeks *ATS/ERS Statement Asthma Control and Exacerbations: Standardizing Endpoints for Clinical Asthma Trials and Clinical Practice (Reddel H, et al, AJRCCM 2009) Kerstjens H, et al. N Engl J Med. 2012;367:11981207. ATS, American Thoracic Society; ERS, European Respiratory Society. Patients on at least Patients with 1 severe asthma exacerbation (%) Risk of severe asthma exacerbation for tiotropium versus placebo HR=0.79 (95% CI: 0.62, 1.00); risk reduction 21% (P=0.034) Number needed to treat to prevent one severe

exacerbation during the 48-week treatment period: 15 Tiotropium Respimat 5 g qd n=122 (26.9%); placebo Respimat qd n=149 (32.8%) Tiotropium Respimat 5 g qd: 282 days; placebo Respimat qd: 226 days (25th percentile) 50 40 30 20 Placebo Respimat qd Tiotropium Respimat 5 g qd 10 0 Increased the time to first exacerbation by an average of 56 days 0 25 50 Patients at risk: Placebo Respimat qd 454 435 412 Tiotropium Respimat 453 430 5 g qd 40 9 75 100 125 150 175 200 Days 225 250 275 300 325 38 8 401 37 9 38

9 332 319 290 282 272 348 339 31 9 298 36 7 37 8 35 6 36 3 33 9 35 3 Kerstjens H, et al. N Engl J Med. 2012;367:11981207. Full analysis set. Pooled data. Add-on to high-dose ICS+LABA. Severe exacerbation defined as asthma necessitating the initiation or doubling of systemic corticosteroid therapy for 3 days. CI, confidence interval; HR, hazard ratio; qd, once daily. 30 3 33 1 308 Patients on at least Episodes of asthma worsening Definition of asthma worsening: One or more asthma symptoms outside of the patients usual range of day-to-day asthma that lasted for 2 consecutive

days; and/or Decrease of patients best morning PEF of 30% from patients mean morning PEF for at least 2 consecutive days As documented by the investigator in the CRF Includes severe exacerbations loss of control Time to first episode of asthma worsening Pooled analysis over 48 weeks Kerstjens H, et al. N Engl J Med. 2012;367:11981207. CRF, case report form; PEF, peak expiratory flow. Patients on at least Patients with at least one episode of asthma worsening (%) Episodes of asthma worsening Add-on to ICS+LABA Risk reduction of 31% 100 90 80 70 P<0.0001 Placebo 60 Tiotropium 5 g 50 40 30 20 10 0 0 25 50 75

100 125 150 175 200 225 250 275 300 325 Days Kerstjens H, et al. N Engl J Med. 2012;367:11981207 (supplementary information). ICS, inhaled corticosteroid; LABA, long-acting 2-agonist. Patients on at least Time to first severe asthma exacerbation by overall TH2 status TH2-low and TH2-high subgroups defined at baseline: TH2-low: low total serum IgE, 430 Mg/L (equivalent to 179.2 IU/L), and low blood eosinophils, 0.610 9/L (equivalent to 600/ML) TH2-high: high total serum IgE, >430 Mg/L, and high blood eosinophils, >0.610 9/L The height/width of the boxes in the forest plots represents the number of events proportionate to the number of events in PrimoTinA-asthma. a In PrimoTinA-asthma, final P-value adjusted for interim analysis; bP-value adjusted for treatment-bysubgroup interaction. CI, confidence interval; HR, hazard ratio; TioR, tiotropium Respimat. Patients on at least Time to first severe asthma exacerbation by IgE and blood eosinophil status The height/width of the boxes in the forest plots represents the number of events proportionate to the number of events in PrimoTinA-asthma. a P-value adjusted for treatment-by-subgroup interaction. Patients on at least

Time to first asthma worsening by overall TH2 status The height/width of the boxes in the forest plots represents the number of events proportionate to the number of events in PrimoTinAasthma a In PrimoTinA-asthma, final P value adjusted for interim analysis; bP value adjusted for treatment-by-subgroup interaction Time to first asthma worsening by IgE and blood eosinophil status The height/width of the boxes in the forest plots represents the number of events proportionate to the number of events in PrimoTinAasthma a P value adjusted for treatment-by-subgroup interaction Tiotropium Respimat in Asthma clinical development program Screening Treatment: add-on therapy to medium-dose ICS Followup Tiotropium Respimat 5 g qda Tiotropium Respimat 2.5 g qda Visit 0 Week 1 2 Salmeterol HFA-MDI 50 g bidb Placebo Respimat qda 3 4 5 4 0 4 8 12 6

7 24 27 Randomization Co-primary endpoints included: ACQ-7 responder rate Other co-primary endpoints were peak FEV1(03h) and trough FEV1 responses (pooled data) Kerstjens H, et al. Lancet Respir Med. 2015;3:367376. a Plus placebo HFA-MDI bid; bPlus placebo Respimat. HFA-MDI, hydrofluoroalkane metered-dose inhaler. Patients on at least ICS Kerstjens H, et al. Lancet Respir Med. 2015;3:367376. Patients on at least ICS Overall summary of adverse events for all parallel-group trials Patients, % PrimoTinA-asthmaa MezzoTinA-asthmaa GraziaTinA-asthma TioR 5 g qd g qd (n=456) PboR qd (n=456) TioR 5 g qd g qd (n=517)b TioR 2.5 g qd g qd (n=519)b Sal 50 g qd g bid (n=541)c Pbo

(n=523)d TioR5 g qd g qd (n=155) TioR2.5 g qd g qd (n=154) PboR qd (n=155) Any AE 73.5 80.3 57.3 58.2 54.3 59.1 32.3 31.2 29.0 Drug-related AEse 5.7 4.6 7.4 6.9 5.2 5.4 1.3 1.3

1.3 AEs leading to discontinuation 1.8 3.1 1.7 1.2 1.8 2.5 0.6 1.3 0 Serious AEs 8.1 8.8 2.1 2.3 2.0 2.7 0.6 0 0.6 Immediately life-threatening 0.7 0 0.4

0.2 0.2 0 0 0 0.6 Disabling / incapacitating 0.4 0 0 0 0 0 0 0 0 Requiring hospitalization 7.7 8.6 1.5 2.3 1.8 2.5 0.6 0

0 Prolonging hospitalization 0.7 0.2 0 0.2 0.4 0.2 0 0 0.6 Other 0.7 0 0.4 0 0.2 0.2 0.6 0 0 Treated set. a Pooled data; bPlus placebo HFA-MDI bid; cPlus placebo Respimat qd; dPlacebo Respimat qd plus placebo HFA-MDI bid; eInvestigator-defined. Pbo, placebo; PboR, placebo Respimat; TioR, Tiotropium Respimat. Adverse events reported by 5% of patients Patients, % PrimoTinA-asthmaa

MezzoTinA-asthmaa GraziaTinA-asthma TioR 5 g qd g qd (n=456) PboR qd (n=456) TioR 5 g qd g qd (n=517)b TioR 2.5 g qd g qd (n=519)b Sal 50 g qd g bid (n=541)c Pbo (n=523)d TioR5 g qd g qd (n=155) TioR2.5 g qd g qd (n=154) PboR qd (n=155) Asthma worsening / exacerbation 39.9 50.9 21.5 15.8 19.4

22.0 11.0 15.6 12.9 Bronchitis 5.5 4.4 2.1 1.7 1.7 1.0 1.9 0 0.6 Decreased peak expiratory flow rate 20.4 26.8 11.4 9.4 8.7 15.1 3.9 5.8 3.9 Headache

6.4 7.2 1.5 3.5 1.1 2.7 1.9 0.6 0 Nasopharyngitis 11.2 12.3 7.9 9.4 7.6 9.2 0.6 1.3 3.2 Upper respiratory tract infection 4.6 3.5 3.7 5.2 7.6 7.8

4.5 1.3 4.5 No deaths in any trial Treated set. a Pooled data; bPlus placebo HFA-MDI bid; cPlus placebo Respimat qd; dPlacebo Respimat qd plus placebo HFA-MDI bid. Pbo, placebo; PboR, placebo Respimat; TioR, Tiotropium Respimat. Drug-related AEs A small number of AEs considered to be drug related were reported Asthma worsening/exacerbation and dry mouth were among the most frequently reported, in all trials: Patients, % PrimoTinA-asthmaa MezzoTinA-asthmaa GraziaTinA-asthma TioR 5 g qd g qd (n=456) PboR qd (n=456) TioR 5 g qd g qd (n=517)b TioR 2.5 g qd g qd (n=519)b Sal 50 g qd g bid (n=541)c

Pbo (n=523)d TioR5 g qd g qd (n=155) TioR2.5 g qd g qd (n=154) PboR qd (n=155) Asthma worsening / exacerbation, n (%) 7 (1.5) 7 (1.5) 2 (0.4) 2 (0.4) 0 4 (0.8) 0 1 (0.6) 0 Dry mouth, n (%) 6 (1.3) 2 (0.4) 5 (1.0) 2 (0.4) 1 (0.2) 2 (0.4) 0

0 1 (0.6) Treated set. a Pooled data; bPlus placebo HFA-MDI bid; cPlus placebo Respimat qd; dPlacebo Respimat qd plus placebo HFA-MDI bid. Efficacy Traditional clinical studies (RCT) Real life Effectiveness Price D. et al. Journal of Asthma and Allergy 2015:8 113 Medical records of adults with asthma (aged >18 years) prescribed tiotropium were obtained from the UK Optimum Patient Care Research Database for the period 20012013. Primary outcomes were compared in the year before (baseline) and the year after (outcome) addition of tiotropium: exacerbations (asthma-related hospital emergency department attendance or inpatient admission, or acute oral corticosteroid course) and acute respiratory events (exacerbation or antibiotic prescription). Secondary outcomes included lung function test results and short-acting 2 agonist use. Price D. et al. Journal of Asthma and Allergy 2015:8 113 Percentage of patients having at least one exacerbation decreased from 37% to 27% (P<0.001) and the percentage having at least one acute respiratory event decreased from 58% to 47% (P<0.001) Price D. et al. Journal of Asthma and Allergy 2015:8 113 Summary Once-daily tiotropium Respimat use in asthma complements the use of other existing asthma medications

Tiotropium provides an important therapeutic option for patients with symptomatic asthma despite ICS+LABA, without the need for phenotyping The addition of tiotropium to ICS/LABA in patients with symptomatic asthma resulted in: up to 154 mL improvemen t in lung function 31% 31% risk risk in reduction reduction asthma in asthma worsening worsening 21% risk reduction for severe asthma exacerbation Safety profile comparable to placebo Thank you

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