Prof. Florian Gantner. Vice President Respiratory Diseases Research Boehringer Ingelheim

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2 Prof. Florian Gantner Vice President Respiratory Diseases Research Boehringer Ingelheim

3 Research and Development in Practice: COPD

4 Chronic Obstructive Pulmonary Disease (COPD) Facts Main cause of COPD is inhalation of cigarette smoke More than 210 million people suffer from COPD More than 3 million people die of COPD each year (WHO) Breathlessness is the main problem for COPD patients Exacerbations may be life threatening For a decade, Spiriva (tiotropium) has been the only approved Long Acting Muscarinic Antagonist (LAMA)

5 Respiratory Research & Boehringer Ingelheim Preventing airways from closing Tiotropium/Spiriva Opening up airways Olodaterol (Long-Acting β2-agonist, LABA) Optimised bronchodilation by tiotropium + olodaterol combination Going beyond bronchodilation Disease modification, preventing inflammation, airway remodelling in COPD

6 History of inhaled anticholinergics Spiriva Atropine from Atropa belladonna atropine Atrovent short-acting anticholinergics ipratropium once-daily, long acting anticholinergic: tiotropium once-daily, LAMA + LABA combination datura stramonium 2000 B.C

7 Bronchodilator keeping the airways open Human bronchioli Precision Cut Lung Slice (PCLS) Carbachol 3x10-6 M bronchospasm occurs Carbachol nm tiotropium prevents the brochospasm

8 Rationale for dual bronchodilation Long acting Muscarinic Antagonists (LAMA): Preventing airways from closing tiotropium Long acting β2-agonists (LABA): Opening up airways olodaterol M 3 Muscarinic Receptors Smooth Muscle Cell β 2 Adrenergic Receptors contraction relaxation Muscarinic antagonist (LAMA) and β2-agonist (LABA) administered together results in greater smooth muscle cell relaxation and helps patient breathe better

9 The search for the ideal LABA as a partner to tiotropium Development goal To identify a once-daily β2-agonist as the ideal combination partner to tiotropium to offer optimum bronchodilation treatment when administered as a fixed-dose combination in the Respimat inhaler

10 Identify ideal partner to tiotropium to offer optimised dual bronchodilation 700,000 for β2-agonism 12,000 in focused library 205 selected; MedChem applied 20 for Respimat feasibility 4 profiled with tiotropium olodaterol TARGET SELECTION CRITERIA 24-hour duration of action Rapid onset of action At least as safe as existing standard of care twice-daily LABA Compatible with Respimat device

11 Olodaterol versus formoterol Bronchoprotection maintained even after 24 hours 80 bronchoprotection (%) time (h) NO Protection after 12 hours olodaterol formoterol Protection after 24 hours still maintained 24 h duration of action for olodaterol but not for formoterol

12 Olodaterol in combination with tiotropium (pre-clinical model) 100 Rapid onset tiotropium 0.1 µg/kg Prolonged bronchodilation olo 0.3 µg/kg + tio 0.1 µg/kg * bronchoprotection (%) T+O combination tiotropium mono time (min) Higher efficacy and rapid onset of action of tiotropium + olodaterol combination

13 Olodaterol in combination with tiotropium (clinical testing) 1.60 Lung function (FEV 1 ) Time (hours) Tiotropium + olodaterol (5 / 10 µg) Tiotropium + olodaterol (5 / 5 µg) Tiotropium + olodaterol (5 / 2 µg) Tiotropium (5 µg) T+O combinations tiotropium mono Maltais F et al. Poster P5557 presented at ERS 2010 a Mean values adjusted for baseline, treatment and centre

14 Proven efficacy of combination treatment Greater lung function improvement More responders Better patient compliance Better symptomatic outcomes (less dyspnoea, fewer exacerbations, better QoL, improved exercise endurance)

15 Walking the extra mile : going beyond bronchodilation What comes next? Beyond bronchodilation: BI develops new therapeutic principles Research addresses Airway inflammation Exacerbation prevention Lung tissue destruction Mucus production Fibrosis Patient benefits Reduction of symptoms Prevention of exacerbations Reduction of hospitalisations Prevention of lung function decline increased quality of life

16 Pathophysiology of COPD Active research activities at Boehringer Ingelheim Smooth muscle cell Bronchoconstriction tiotropium olodaterol Neutrophils 1 target T cells 2 targets Inflammation Macrophages 2 targets epithelial cells Airway remodelling, fibrosis, emphysema 4 targets

17 Respiratory Boehringer Ingelheim Insensitivity to steroids in COPD and severe asthma Resolution of inflammation Structural changes in the diseased lung (emphysema, fibrosis) Models of exacerbation and smooth muscle proliferation Value through Innovation