Once-daily tiotropium add-on to at least ICS improves control and reduces exacerbation risk in symptomatic asthma, independent of serum IgE or blood eosinophils Presented by Alberto de la Hoz4 on behalf of: Michael Thomas,1 J Christian Virchow,2 Mark Vandewalker,3 Michael Engel,4 Petra Moroni-Zentgraf,4 Reinhold Lühmann,5 Thomas Casale6 1Aldermoor Health Centre, University of Southampton, Southampton, UK; 2Department of Pneumology, Intensive Care Medicine, Zentrum für Innere Medizin, Klinik I, University Clinic Rostock, Rostock, Germany; 3Clinical Research of the Ozarks, Columbia, MO, USA; 4TA Respiratory Diseases, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany; 5Global Biometrics and Data Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany; 6Division of Allergy and Immunology, University of South Florida Morsani College of Medicine, Tampa, FL, USA

Disclosures Dr Alberto de la Hoz is an employee of the Global Medical Team at Boehringer Ingelheim

Introduction and aim Introduction Over 40% of patients with asthma have symptomatic or uncontrolled disease1–3 Elevated TH2 biomarkers are often found in patients whose disease remains symptomatic despite treatment with ICS ± LABA4 Tiotropium Respimat® reduces the risk of severe exacerbations and worsening and improves asthma symptom control5,6 These effects have also been observed in subgroups of patients with serum IgE ≤ or >430 µg/La or blood eosinophil counts ≤ or >0.6 × 109b in conventional subgroup analyses7,8 Aim To investigate whether the beneficial effects of tiotropium Respimat® add-on to ICS ± LABA on exacerbations and asthma control can be observed across the continuous range of IgE levels and eosinophil counts 1. Bateman et al. Am J Respir Crit Care Med 2004; 2. Partridge et al. Prim Care Respir J 2011; 3. Demoly et al. Eur Respir Rev 2009; 4. Price. Prim Care Respir J 2008; 5. Kerstjens et al. N Engl J Med 2012; 6. Kerstjens et al. Lancet Respir Med 2015; 7. Dahl et al. Allergy 2013; 8. Dahl et al. Thorax 2014 aEquivalent to 179.2 IU/L; bEquivalent to 600 µL ICS, inhaled corticosteroids; IgE, immunoglobulin E; LABA, long-acting β2-agonist; TH2, T helper 2

PrimoTinA-asthma® study design and end points Treatment: add-on therapy to ICS (≥800 μg budesonide or equivalent) + LABA Follow- up Screening Tiotropium Respimat® 5 µga Placebo Respimat® Visit 1 2 3 4 5 6 9 10 Week −4 4 12 24 36 48 52 Randomisation Co-primary end points: peak FEV1(0–3h) and trough FEV1 responses at Week 24; time to first severe exacerbation during 48 weeks (pooled) Secondary end points included: time to first episode of asthma worsening during 48 weeks (pooled) and ACQ-7 aTwo puffs of 2.5 µg once daily ACQ-7, seven-question Asthma Control Questionnaire; FEV1, forced expiratory volume in 1 second; peak FEV1(0−3h), peak FEV1 within 3 hours post-dose Kerstjens et al. N Engl J Med 2012

MezzoTinA-asthma® study design and endpoints Treatment: add-on therapy to ICS (400–800 μg budesonide or equivalent) Follow- up Screening Tiotropium Respimat® 2.5 µga Tiotropium Respimat® 5 µgb Salmeterol HFA-MDI 50 µg Placebo Respimat® Visit 1 2 3 4 5 6 7 Week −4 4 8 12 24 27 Randomisation Co-primary end points: peak FEV1(0–3h) and trough FEV1 responses, and ACQ-7 responder rate (pooled), at Week 24 Secondary end points included: time to first severe exacerbation and time to first episode of asthma worsening during 24 weeks (pooled) aTwo puffs of 1.25 µg; bTwo puffs of 2.5 µg Kerstjens et al. Lancet Respir Med 2015;

Methods Analyses Severe exacerbations: post hoc Cox regression analyses were performed: HRs and 95% CIs were calculated across continuous ranges of eosinophils (0.05–2.00×109/L) and IgE (2–2000 μg/L), adjusted for treatment and eosinophils or IgE, and treatment by eosinophils or IgE interaction ACQ-7 responder rates: Post hoc logistical regression analysis was performed, adjusting for ‘study’ and including the ‘treatment’ effect ORs and 95% CIs were calculated across continuous ranges of blood eosinophils (0.05–2.00×109/L) and total serum IgE (0–2000 μg/L) Adjusted for treatment and eosinophils or IgE, and treatment by eosinophil or IgE interaction Eosinophil counts and IgE levels were log-transformed for modelling Two pairs of twin studies from BI’s Tiotropium in Asthma (TinA) development programme are in scope: the PrimoTinA-asthma® studies in patients with severe asthma and the MezzoTinA-asthma® studies in patients with moderate asthma Classical subgroup analysis focuses on analysing the treatment effect for fixed patient groups based on categorisation of continuous baseline variables, eg IgE values (threshold 430 µg/L) and eosinophil counts (threshold 0.6 Giga/L). This was also done in the TinA programme However, choice of thresholds for subgroup analyses often remains a topic of debate. Introduction of several thresholds and subsequent analyses increase the problem of multiplicity in testing and, hence, the likelihood to observe false-positive results. Therefore, in this presentation we complement the classical subgroup analysis through exploratory regression modelling of the treatment effect across the whole spectrum of the baseline variables IgE and eosinophils For ACQ specifically a logistical regression model was used to estimate the odds ratios for the treatment effect tiotropium/placebo including 95% confidence intervals. Treatment by IgE-baseline-value interaction was included in the model. The same applies to the analysis of eosinophil counts This way it is possible assess the treatment effect of an efficacy variable (here: ACQ-7) over the whole range of baseline IgE and eosinophils CI, confidence interval; HR, hazard ratio; OR, odds ratio

Baseline demographics and disease characteristics MezzoTinA-asthma® (n=2100) PrimoTinA-asthma® (n=912) Background therapy ICS (400–800 µg budesonide or equivalent) ICS (≥800 µg budesonide or equivalent) + LABA Female, % 59.0 60.4 Age, years 43.1 ± 12.9 53.0 ± 12.4 Body mass index, kg/m2 26.8 ± 6.2 28.2 ± 6.0 Never smoked, % 83.6 75.9 Ex-smoker, % 16.4 24.1 Smoking history, pack-years 4.2 ± 2.8 5.1 ± 2.7 Duration of asthma, years 21.7 ± 14.3 30.3 ± 13.9 Age at asthma onset, years 21.4 ± 12.7 22.7 ± 12.9 FEV1 % predicted 75.1 ± 11.5 56.0 ± 13.1 ACQ-7 score 2.18 ± 0.49 2.63 ± 0.69 Treated set; pooled data. All values are mean ± standard deviation except for female gender and smoking status

PrimoTinA-asthma®: tiotropium Respimat® 5 µg reduces the risk of severe exacerbations across IgE and blood eosinophil ranges Risk of severe exacerbations in the overall study population: Tiotropium 5 µg vs placebo HR = 0.79 (95% CI: 0.62, 1.00; P=0.03)1 Blood eosinophils Total serum IgE Tiotropium 5 µg vs placebo HR 95% Cl 4 0.125 0.25 0.5 1 2 Favours placebo HR Favours tiotropium 0.125 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 250 500 750 1000 1250 1500 1750 2000 Eosinophils (×109/L) IgE (µg/L) Number of patients above threshold Placebo 441 296 305 130 151 57 77 25 40 13 24 7 4 11 10 359 380 236 173 194 137 156 96 121 81 97 68 80 57 69 42 61 263 Tiotropium 5 µg Post hoc Cox regression analysis 1. Kerstjens et al. N Engl J Med 2012

MezzoTinA-asthma®: tiotropium Respimat® 5 µg reduces the risk of severe exacerbations across IgE and blood eosinophil ranges Risk of severe exacerbations in the overall study population: Tiotropium 5 µg vs placebo HR = 0.72 (95% CI: 0.45, 1.14; P=0.16)1 Blood eosinophils Total serum IgE Tiotropium 5 µg vs placebo HR 95% Cl 4 0.125 0.25 0.5 1 2 Favours placebo HR Favours tiotropium 0.125 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 250 500 750 1000 1250 1500 1750 2000 Eosinophils (×109/L) IgE (µg/L) Number of patients above threshold Placebo 517 510 353 354 165 158 60 63 30 22 20 12 13 7 6 8 514 509 395 304 303 240 237 197 208 168 172 148 155 127 134 111 123 387 Tiotropium 5 µg Post hoc Cox regression analysis 1. Kerstjens et al. Lancet Respir Med 2015;

PrimoTinA-asthma®: tiotropium Respimat® 5 µg increases the ACQ-7 responder rate across IgE and blood eosinophil ranges ACQ-7 responder rate in the overall study population: Tiotropium 5 µg vs placebo: 53.9% vs 46.9% OR = 1.32 (95% CI: 1.01, 1.73; P=0.04) Blood eosinophils Total serum IgE Tiotropium 5 µg vs placebo OR 95% Cl 8 8 4 4 Favours tiotropium 2 2 OR 1 1 0.5 0.5 Favours placebo 0.25 0.25 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 250 500 750 1000 1250 1500 1750 2000 Eosinophils (×109/L) IgE (µg/L) Number of patients above threshold Placebo 441 296 305 130 151 57 77 25 40 13 24 7 4 11 10 359 380 236 173 194 137 156 96 121 81 97 68 80 57 69 42 61 263 Tiotropium 5 µg Post hoc logistical regression analysis

MezzoTinA-asthma®: tiotropium Respimat® 5 µg increases the ACQ-7 responder rate across IgE and blood eosinophil ranges ACQ-7 responder rate in the overall study population: Tiotropium 5 µg vs placebo: 64.3% vs 57.7% OR = 1.32 (95% CI: 1.02, 1.71; P=0.03)1 Blood eosinophils Total serum IgE Tiotropium 5 µg vs placebo OR 95% Cl 8 8 4 4 Favours tiotropium 2 2 OR 1 1 0.5 0.5 Favours placebo 0.25 0.25 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 250 500 750 1000 1250 1500 1750 2000 Eosinophils (×109/L) IgE (µg/L) Number of patients above threshold Placebo 517 353 165 60 30 22 12 7 6 514 395 304 240 197 168 148 127 111 Tiotropium 5 µg 510 354 158 63 30 20 13 12 8 509 387 303 237 208 172 155 134 123 Post hoc logistical regression analysis Kerstjens et al. Lancet Respir Med 2015;

Conclusions Once-daily tiotropium Respimat® add-on to ICS ± LABA in patients with moderate or severe symptomatic asthma: improves asthma symptom control reduces risk of severe exacerbations These two effects were largely independent of IgE levels or blood eosinophil counts These findings support the findings of previous subgroup analyses using binary cut-offs of serum IgE ≤ or >430 µg/L and blood eosinophils ≤ or >0.6×109/L Tiotropium Respimat® add-on therapy may therefore be beneficial in symptomatic patients independent of TH2 status, avoiding the need for phenotyping before treatment