Filming: 15th of Febuary 2016, London, UK

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Filming: 15th of Febuary 2016, London, UK Pooled Analysis of 3 Clinical Trials of Nintedanib in the Treatment of IPF Filming: 15th of Febuary 2016, London, UK Prof. Vincent Cottin Prof. Luca Richeldi

TOMORROW and INPULSIS® trials design TOMORROW: Randomized, placebo-controlled, 52-week dose-finding trial1 INPULSIS®: Two randomized, placebo-controlled, double-blind, 52-week, phase III trials with replicate design2 Nintedanib 50 mg qd (n=86) Nintedanib 150 mg bid (n=638) Nintedanib 50 mg bid (n=86) R 1:1:1:1:1 ratio Screening Nintedanib 100 mg bid (n=86) Screening Follow-up R 3:2 ratio Nintedanib 150 mg bid (n=85) Placebo (n=423) Placebo (n=85) Visit 1 2 3 4 5 6 7 8 9 Visit 1 2 3 4 5 6 7 8 9 Week 2 4 6 12 24 36 52 Week 2 4 6 12 24 36 52 56 1. Richeldi L, et al. NEJM 2011;365:1079–1087. 2. Richeldi L, et al. NEJM 2014;370:2071–2082. references

FVC Decline

Adjusted annual rate (SE) of decline in FVC (mL/year) Nintedanib significantly reduced the annual rate of decline* in FVC by approximately 50%1-4 INPULSIS®-11 INPULSIS®-21 TOMORROW2 Adjusted annual rate (SE) of decline in FVC (mL/year) Δ125.2 mL/year (95% CI: 77.7, 172.8) p<0.001 Δ93.7 mL/year (95% CI: 44.8, 142.7) p<0.001 Δ131.0 mL/year (95% CI: 27, 235) p=0.01 Nintedanib 150 mg bid Placebo *The annual rate of decline in FVC (mL/year) was calculated based on a linear regression model without imputation of missing values. All available FVC values from baseline to week 52 were used, including FVC measurements form the follow-up visit for patients who prematurely discontinued trial medication and did not complete study visits until week 52.1 1. Richeldi L, et al. NEJM 2014;370:2071–2082. 2. Richeldi L, et al. NEJM 2011;365:1079–1087. 3. OFEV® SmPC. Boehringer Ingelheim International GmbH. 2015. 4. OFEV® Prescribing Information. Boehringer Ingelheim Pharmaceuticals Inc. 2015. references

Pooled analysis: INPULSIS®-1, INPULSIS®-2, and TOMORROW1† Consistent treatment effect of nintedanib across analyses: Annual rate of decline* in FVC Pooled analysis: INPULSIS®-1, INPULSIS®-2, and TOMORROW1† n=723 n=508 Δ110.9 mL/year (95% CI: 78.5, 143.3) p<0.0001 Nintedanib 150 mg bid Placebo *The annual rate of decline in FVC (mL/year) was calculated based on a linear regression model without imputation of missing values. All available FVC values from baseline to week 52 were used, including FVC measurements form the follow-up visit for patients who prematurely discontinued trial medication and did not complete study visits until week 52.2 † Pooled analysis of data from three 52-week trials with nintedanib, INPULSIS®-1 INPULSIS®-2 and TOMORROW, including 1231 patients with IPF. Annual rate of decline in FVC was the predefined primary endpoint in the TOMORROW and INPULSIS® trials.1-3 1. Richeldi L, et. al. Respir Med 2016;113:74–79. 2. Richeldi L, et al. NEJM 2014;370:2071–2082. 3. Richeldi L, et al. NEJM 2011;365:1079–1087. references

Mean (SE) observed change from baseline in FVC (mL) Nintedanib significantly reduced the mean change from baseline* in FVC by approximately 50%1-3 INPULSIS®-11 INPULSIS®-21 TOMORROW2 Mean (SE) observed change from baseline in FVC (mL) Week Week Day 2 4 6 12 24 36 52 2 4 6 12 24 36 52 No. of patients Nintedanib No. of patients 303 301 298 292 284 274 250 Nintedanib 323 315 312 303 295 269 Day No. of patients Nintedanib Placebo 15 29 43 85 169 365 253 Placebo 202 198 200 194 192 187 165 Placebo 215 210 207 209 203 196 180 †109.9 mL (95% CI: 71.3, 148.6) p<0.0001 †109.8 mL (95% CI: 70.9, 148.6) p<0.0001 89 84 82 83 78 71 57 68 87 81 82 80 79 61 74 Nintedanib 150 mg bid Placebo *Absolute change in FVC from baseline was calculated using values at baseline and at 52 weeks.1 †Adjusted mean difference versus placebo at Week 52 based on mixed effects model for repeated measures. 1. Richeldi L, et al. NEJM 2014;370:2071–2082. 2. Richeldi L, et al. NEJM 2011;365:1079–1087. 3. OFEV® SmPC. Boehringer Ingelheim International GmbH. 2015. references

Consistent treatment effect of nintedanib across analyses: Mean change from baseline* in FVC Pooled analysis: INPULSIS®-1, INPULSIS®-2, and TOMORROW1 Absolute mean change from baseline in FVC % predicted at week 52 Δ3.2 % (95% CI: 2.5, 4.0) p<0.0001 Mean (SEM) observed change from baseline in FVC (mL) Week 2 4 6 12 24 36 52 No. of patients Nintedanib 709 699 695 685 664 639 580 Placebo 497 490 484 475 460 408 Nintedanib 150 mg bid Placebo *Absolute change in FVC from baseline was calculated using values at baseline and at 52 weeks.2 1. Richeldi L, et. al. Respir Med 2016;113:74–79. 2. Richeldi L, et al. NEJM 2014;370:2071–2082. references

Acute Exacerbations of IPF

Nintedanib demonstrated significant reductions in the risk of acute IPF exacerbations in the INPULSIS®-2 and TOMORROW trials1-3 Incidence of investigator-reported acute IPF exacerbations across trials1-3 INPULSIS®-1 INPULSIS®-2 TOMORROW Nintedanib (n=309) Placebo (n=204) (n=329) (n=219) (n=86) (n=87) 6.1% 5.4% 3.6% 9.6% 2.4% 15.7% HR=1.15 (95% CI=0.54, 2.42) p=0.67 HR=0.38 (95% CI=0.19, 0.77) p=0.005 HR=0.16 (95% CI=0.03, 0.70) p=0.02 Nintedanib 150 mg bid Placebo 1. Richeldi L, et al. NEJM 2011;365:1079–1087. 2. Richeldi L, et al. NEJM 2014;370:2071–2082. 3. OFEV® SmPC. Boehringer Ingelheim International GmbH. 2015. references

Nintedanib demonstrated significant reduction in the risk of acute IPF exacerbations in the pooled analysis of three trials Pooled analysis: INPULSIS®-1, INPULSIS®-2, and TOMORROW1† HR 0.53 (95% CI: 0.34, 0.83) p=0.0047 Nintedanib 150 mg bid (n=723) Placebo (n=508) Patients with ≥1 acute exacerbation 4.6% 8.7% Nintedanib 150 mg bid Placebo †Pooled analysis of data from three 52-week trials with nintedanib, INPULSIS®-1 INPULSIS®-2 and TOMORROW, including 1231 patients with IPF. Time to first investigator-reported acute exacerbation over 52 weeks was a predefined secondary endpoint in the TOMORROW and INPULSIS® trials.1-3 1. Richeldi L, et. al. Respir Med 2016;113:74–79. 2. Richeldi L, et al. NEJM 2014;370:2071–2082. 3. Richeldi L, et al. NEJM 2011;365:1079–1087. references

Survival

Deaths due to respiratory cause* On-treatment deaths** Nintedanib consistently demonstrated a favorable trend in all-cause mortality1-3 INPULSIS®-11,2 INPULSIS®-21,2 TOMORROW2 Nintedanib (n=309) Placebo (n=204) (n=329) (n=219) (n=85) All-cause mortality 4.2% 6.4% 6.7% 9.1% 8.1% 10.3% HR=0.63 (95% CI=0.29, 1.36) p=0.2880 HR=0.74 (95% CI=0.40, 1.35) p=0.2995 HR=0.73 (95% CI=0.27, 1.98) p=0.5383 Deaths due to respiratory cause* 3.6% 4.9% 4.6% 5.9% 2.3% 9,2% HR=0.66 (95% CI=0.28, 1.58) p=0.4677 HR=0.78 (95% CI=0.37, 1.63) 0.4738 HR= 0.23 (95% CI=0.05, 1.07) p=0.0600 On-treatment deaths** 2.6% 4.4% 7.8% – HR=0.68 (95% CI=0.26, 1.82) p=0.4869 HR=0.68 (95% CI=0.34, 1.35) p=0.2209 *Adjudicated by Adjudication Committee; **Deaths that occurred between randomization and 28 days after last trial drug intake. 1. OFEV® SmPC. Boehringer Ingelheim International GmbH. 2015. 2. Richeldi L, et al. Poster presented at ICLAF 2014. 3. Cottin V. Clin Invest. 2015;5(2):621-632. references

Nintedanib showed numerical risk reduction of 30% vs placebo for all-cause mortality in the analysis of pooled data from three trials1,2 Pooled analysis over 52 weeks: INPULSIS®-1, INPULSIS®-2, and TOMORROW1,2* Nintedanib 150 mg bid (n=723) Placebo (n=508) Patients who died, n (%) 42 (5.8) 42 (8.3) HR 0.70 (95% CI; 0.46, 1.08) p=0.0954 Nintedanib 150 mg bid Placebo *The effect of nintedanib on mortality in patients with IPF was analyzed using pooled data from the TOMORROW and INPULSIS® trials. All-cause, respiratory, and on-treatment mortality were secondary endpoints in the TOMORROW and INPULSIS® trials.2-5 1. Richeldi L, et al. Poster presented at ICLAF 2014. 2. Richeldi L, et. al. Respir Med 2016;113:74–79. 3. Richeldi L, et al. Presented at the annual congress of the German Respiratory Society 2015. 4. Richeldi L, et al. NEJM 2014;370:2071–2082. 5. Richeldi L, et al. NEJM 2011;365:1079–1087. references

Nintedanib showed numerical risk reduction of 38% vs placebo for respiratory mortality in the analysis of pooled data from three trials1,2 Pooled analysis over 52 weeks: INPULSIS®-1, INPULSIS®-2, and TOMORROW1,2* Nintedanib 150 mg bid (n=723) Placebo (n=508) Patients who died, n (%) 26 (3.6) 29 (5.7) HR 0.62 (95% CI; 0.37, 1.06) p=0.0779 Nintedanib 150 mg bid Placebo *The effect of nintedanib on mortality in patients with IPF was analyzed using pooled data from the TOMORROW and INPULSIS® trials. All-cause, respiratory, and on-treatment mortality were secondary endpoints in the TOMORROW and INPULSIS® trials.2.4 1. Richeldi L, et al. Poster presented at ICLAF 2014. 2. Richeldi L, et. al. Respir Med 2016;113:74–79. 3. Richeldi L, et al. NEJM 2014;370:2071–2082. 4. Richeldi L, et al. NEJM 2011;365:1079–1087. references

Nintedanib significantly reduced the risk of on-treatment mortality Nintedanib significantly reduced the risk of on-treatment mortality* by 43% vs placebo in the analysis of pooled data from three trials1,2 Pooled analysis over 52 weeks: INPULSIS®-1, INPULSIS®-2, and TOMORROW1,2† Nintedanib 150 mg bid (n=723) Placebo (n=508) Patients who died, n (%) 25 (3.5) 34 (6.7) HR 0.57 (95% CI: 0.34, 0.97) p=0.0274 Nintedanib 150 mg bid Placebo *On- treatment mortality included deaths that occurred between randomization and up to 28 days after last treatment.3 †The effect of nintedanib on mortality in patients with IPF was analyzed using pooled data from the TOMORROW and INPULSIS® trials. All-cause, respiratory, and on-treatment mortality were secondary endpoints in the TOMORROW and INPULSIS® trials. 2-4 1. Richeldi L, et al. Abstract presented at the Winter British Thoracic Society 2015. 2. Richeldi L, et. al. Respir Med 2016;113:74–79. 3. Richeldi L, et al. NEJM 2014;370:2071–2082. 4. Richeldi L, et al. NEJM 2011;365:1079–1087. references

Pooled Analysis of 3 Clinical Trials Conclusions

Conclusions Pooled analysis of INPULSIS® and TOMORROW trials Nintedanib showed a consistent treatment effect: the adjusted annual rate of decline in FVC was −112.4 mL/year with nintedanib and −223.3 mL/year with placebo. A significant reduction in the risk of acute IPF exacerbations in the pooled analysis of three trials was observed. Trends towards a reduction in the risk of all-cause (30%) and respiratory mortality (38%) and a significant reduction (43%) in the risk of on-treatment mortality were observed. 1. Richeldi L, et. al. Respir Med 2016;113:74–79.