Interpreting INPULSIS® results Speaker: Luca Richeldi

Interpreting INPULSIS® results Speaker: Luca Richeldi
Professor of Respiratory Medicine Chair of Interstitial Lung Disease University of Southampton, United Kingdom

Disclosures Scientific Advisory Board
InterMune, Boehringer Ingelheim, Fibrogen, GlaxoSmithKline, Sanofi- Aventis, Anthera, Genentech, Medimmune, Takeda, UCB, Promedior Research Grants InterMune, Italian Ministry of Health, National Drug Agency (It), National Research Council (It) Trial Principal Investigator Boehringer Ingelheim, InterMune, Gilead, Roche, Takeda, UCB Speaker’s Fees InterMune, Boehringer Ingelheim, Cipla The TOMORROW and INPULSIS® trials were funded by Boehringer Ingelheim

Importance of the INPULSIS® trials
Prof Richeldi, how would you describe the overall importance of the INPULSIS® trials?

TOMORROW: Study design
Nintedanib 50 mg qd (n=87) Day 1 92 sites in 25 countries (non-US) Study medication was administered for 52 weeks R A N D O M I Z T Review by DMC Nintedanib 50 mg bid (n=86) Screening Before Day-4 Review by DMC Nintedanib 100 mg bid (n=86) Patients were randomized to one of four nintedanib doses (50 mg qd, 50 mg bid, 100 mg bid, 150 mg bid) or placebo using a stepwise increasing dose approach for serial cohorts. The decision to proceed to the next step was based on the decision of an independent Data Monitoring Committee (DMC) to assure patients’ safety. Blinding was maintained by continuing randomization to the previously established lower dose groups throughout the randomization period. Richeldi L et al. N Engl J Med 2011; 365: Review by DMC N=432 Randomized 1:1:1:1:1 Nintedanib 150 mg bid (n=86) Placebo (n=87) DMC: Data Monitoring Committee Richeldi L et al. N Engl J Med 2011; 365:

TOMORROW: Decline in FVC by final dose
** Twenty patients (23.3%) randomized to nintedanib 150 mg bid had their dose reduced during the trial, compared with 7 (8.0%) in the placebo group. When data were analyzed by final dose rather than randomized dose, annual rates of decline in FVC were similar to those of the primary analysis (-0.04 L/year with 150 mg bid vs L/year with placebo; p=0.026 [closed testing procedure], p=0.005 [hierarchical procedure]). Richeldi L et al. N Engl J Med 2011; 365: ** p<0.01 vs. placebo (hierarchical testing procedure) Richeldi L et al. N Engl J Med 2011; 365:

TOMORROW: Absolute change in FVC from baseline over time
Nintedanib 150 mg bid *** The change in FVC from baseline was significantly lower in the nintedanib 150 mg bid group than in the placebo group FVC values after discontinuation were included where available, but last observations were not carried forward in case of missing values. Data included are from visits at planned time points only. Richeldi L et al. N Engl J Med 2011; 365: Placebo ***p<0.001 vs placebo (unadjusted) Richeldi L et al. N Engl J Med 2011; 365:

TOMORROW: Conclusions
Treatment with nintedanib 150 mg bid reduced the annual rate of decline in FVC by 68% compared with the placebo group The annual rate of decline in FVC was 60 ml in the nintedanib 150 mg bid group compared to 190 ml in the placebo group (pre-specified primary multiplicity-corrected analysis: p=0.064; pre-specified hierarchical testing analysis: p=0.014) Incidence of exacerbations was reduced with nintedanib 150 mg bid compared to placebo Nintedanib had an acceptable safety profile, with a risk-benefit ratio that justified investigation in Phase III trials Richeldi L et al. N Engl J Med 2011; 365:

INPULSIS®: two replicate, randomized, double-blind, 52-week, phase III trials recruited 1066 patients 4 Visit Follow-up Nintedanib 150 mg bid (n=638) Placebo (n=423) 52 36 24 12 6 2 Screening 56 Week 1 3 5 7 8 9 3:2 ratio R Primary endpoint: Annual rate of decline in forced vital capacity (FVC) (mL/year) Key secondary endpoints: Time to first acute exacerbation (investigator-reported) over 52 weeks Change from baseline in SGRQ total score over 52 weeks Safety: Assessed by clinical and laboratory evaluation and adverse events Richeldi L et al, Respir Med 2014; 108:

Methodology and analysis of the annual rate of decline in FVC
Baseline 2 4 6 12 24 36 52 Follow up To calculate the slope for an individual patient, all FVC measurements from baseline to week 52 were used The slope was calculated: Δ in Y / Δ in X FVC (mL) The treatment effect was determined using mean slopes for each treatment group Random coefficient regression model including sex, age and height as covariates Allows for missing data (assumes missing at random) Missing data were not imputed for the primary analysis Richeldi L et al, Respir Med 2014; 108:

Sensitivity analyses for annual rate of decline in FVC in INPULSIS® -1
Primary analysis 125.3 (77.7, 172.8) Only on-treatment data 142.5 (93.4, 191.6) Including data post-lung transplant Multiple imputation sensitivity analysis 1 120.3 (75.8, 164.8) Multiple imputation sensitivity analysis 2 114.8 (69.9, 159.7) Multiple imputation sensitivity analysis 3 113.9 (69.2, 158.5) Forest plot showing the sensitivity analyses results of the primary endpoint in INPULSIS®-1 In both trials, the results of pre-specified sensitivity analyses on data handling were consistent with the primary analysis of the primary endpoint. In particular, in the multiple imputation analyses that conservatively assumed that missing data were informative rather than at random, the treatment effect estimates and their confidence intervals were consistent with the primary analysis in each study. This confirms that the primary results are robust and not influenced by alternate assumptions on missing data. Favours placebo Favours nintedanib 150 mg bid Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

Sensitivity analyses for annual rate of decline in FVC in INPULSIS® -2
Primary analysis 93.7 (44.8, 142.7) Only on-treatment data 86.0 (37.3, 134.6) Including data post-lung transplant Multiple imputation sensitivity analysis 1 101.3 (52.3, 150.3) Multiple imputation sensitivity analysis 2 82.9 (32.6, 133.3) Multiple imputation sensitivity analysis 3 83.3 (37.6, 129.0) Forest plot showing the sensitivity analyses results of the primary endpoint in INPULSIS®-2 In both trials, the results of pre-specified sensitivity analyses on data handling were consistent with the primary analysis of the primary endpoint. In particular, in the multiple imputation analyses that conservatively assumed that missing data were informative rather than at random, the treatment effect estimates and their confidence intervals were consistent with the primary analysis in each study. This confirms that the primary results are robust and not influenced by alternate assumptions on missing data. Favours placebo Favours nintedanib 150 mg bid bid, twice daily; FVC, forced vital capacity. Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

Primary endpoint Could you please discuss the overall efficacy of nintedanib reported in the INPULSIS® trials?

Annual rate of decline in FVC
INPULSIS®-1 INPULSIS®-2 125.3 mL/year (95% CI: 77.7, 172.8) p<0.0001 93.7 mL/year (95% CI: 44.8, 142.7) p=0.0002 Nintedanib 150 mg bid (n=309) Placebo (n=204) Nintedanib 150 mg bid (n=329) Placebo (n=219) Treated set (observed cases); data are adjusted rate (SEM). bid, twice daily; CI, confidence interval; FVC, forced vital capacity. Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

Absolute changes from baseline in FVC % predicted at week 52
INPULSIS®-1 INPULSIS®-2 Adjusted absolute mean change from baseline in FVC % predicted 3.2 % predicted (95% CI: 2.1, 4.3) p<0.0001 3.1 % predicted (95% CI: 1.9, 4.3) p<0.0001 Nintedanib 150 mg bid (n=307) Placebo (n=204) Nintedanib 150 mg bid (n=327) Placebo (n=217) Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

Primary efficacy endpoint in pooled data
50 Nintedanib 150 mg bid Placebo -50 Adjusted annual rate (SE) of decline in FVC (mL/year) Mean (SE) observed change from baseline in FVC (mL) -100 -150 -200 -250 2 4 6 12 24 36 52 109.9 mL/year (95% CI: 75.9, 144.0) p<0.0001 Week No. pf patients Nintedanib 626 616 613 604 587 569 519 Placebo 417 408 407 403 395 383 345 Nintedanib 150 mg bid (n=638) Placebo (n=423) Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

Trial population How relevant to clinical practice is the trial population of the INPULSIS® trials?

Key inclusion criteria
Age ≥40 years Diagnosis of IPF within 5 years of randomisation Chest HRCT performed within 12 months of screening HRCT pattern, and if available surgical lung biopsy pattern, consistent with diagnosis of IPF as assessed by central review FVC ≥50% of predicted value DLCO 30-79% of predicted value FEV1 / FVC ≥ 0.7 To be eligible to participate in the INPULSIS® trials, patients had to be ≥40 years of age with a diagnosis of IPF established within 5 years before randomization, to have undergone chest HRCT within 12 months before screening, and to have an FVC ≥50% of predicted value and a carbon monoxide diffusion capacity (DLCO) of 30–79% of predicted value. The diagnosis of IPF was established based on the central review of chest HRCT scans from all patients by an expert radiologist according to protocol-specified criteria. Surgical lung biopsy specimens were also centrally evaluated if available by an expert pathologist. Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

Demographic data and baseline characteristics
INPULSIS®-1 INPULSIS®-2 Nintedanib 150 mg bid (n=309) Placebo (n=204) Nintedanib 150 mg bid (n=329) Placebo (n=219) FVC, mL, mean (SD) (735.1) (820.1) ) ) FVC, mL, median 2700.0 2721.0 2615.0 2591.0 FVC, % predicted, mean (SD) 79.5 (17.0) 80.5 (17.3) 80.0 (18.1) 78.1 (19.0) FEV1/FVC ratio, % mean (SD) 81.5 (5.4) 80.8 (6.13) 81.8 (6.3) 82.4 (5.7) SGRQ total score, mean (SD)* 39.6 (17.6) 39.8 (18.5) 39.5 (20.5) 39.4 (18.7) DLCO, mmol/min/kPa, mean (SD) 4.0 (1.2) 4.0 (1.1) 3.8 (1.2) 3.7 (1.3) DLCO, %predicted, Mean (SD) 47.8 (12.3) 47.5 (11.7) 47.0 (14.5) 46.4 (14.8) The mean baseline FVC in the pooled trials was mL, corresponding to a mean 79.55% in FVC% predicted. Mean baseline FVC was balanced between treatment groups, but slightly lower in trial ( mL) than in trial ( mL). Mean FVC% predicted in the 2 trials was comparable, suggesting that the difference in mean baseline FVC in the 2 trials is likely due to the higher proportion of Asian patients in trial The mean baseline SGRQ values for the total score and the individual components were balanced between the treatment groups and the 2 trials. *n=202 for placebo and n=298 for nintedanib in INPULSIS® -1; n=217 for placebo and n=329 for nintedanib in INPULSIS®-2. bid, twice daily; DLCO, carbon monoxide diffusion capacity; FVC, forced vital capacity; FEV1, forced expiratory volume in 1 second; SD, standard deviation; SGRQ, St Georges respiratory Questionnaire. Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

Adjusted annual rate (SE) of decline in FVC (mL/year)
Nintedanib was effective independent of lung function impairment at baseline Annual rate of decline in FVC by baseline FVC 70% predicted FVC ≤70% predicted FVC >70% predicted Adjusted annual rate (SE) of decline in FVC (mL/year) ∆113.5 mL (95% CI: 51.3,175.7) ∆109.0 mL (95% CI: 68.2, 149.9) Treatment by time by subgroup interaction p=0.9505 Nintedanib 150 mg bid (n=207) Placebo (n=154) Nintedanib 150 mg bid (n=431) Placebo (n=269) Costabel U, et al. Oral presentation at the ERS International Congress, Munich, 6 – 10 September 2014

Treatment by time by subgroup interaction p=0.5300
Nintedanib was effective independent of lung function impairment at baseline Annual rate of decline in FVC by baseline FVC 90% predicted FVC ≤90% predicted FVC >90% predicted Placebo (n=315) Nintedanib (n=472) Placebo (n=108) Nintedanib (n=166) Post-hoc subgroup analyses of patients with baseline FVC ≤90% vs >90% predicted were performed to determine whether patients with minimal lung function impairment receive the same benefit from nintedanib. The annual rate of decline in FVC in the nintedanib group was comparable between the subgroups by baseline FVC ≤90% vs >90% predicted. This means that nintedanib was efficacious even in patients with minimal lung function impairment at baseline. The annual rate of decline in FVC in the placebo group was also comparable between the subgroups. There was no significant treatment by subgroup interaction (p=0.5300); this means that the treatment effect of nintedanib was not significantly different between the subgroups by baseline FVC ≤90% vs >90% predicted. Once again, the treatment effect in both subgroups was consistent with the treatment effect in the overall population (109.9 mL/year [95% CI: 75.9, 144.0]; p<0.0001). 102.1 mL/year (95% CI: 61.9, 142.3) 133.1 mL/year (95% CI: 68.0, 198.2) Treatment by time by subgroup interaction p=0.5300 Treatment effect within each subgroup was analyzed using a random coefficient regression model (with random slopes and intercepts) including trial, sex, age, and height as covariates. For calculation of the interaction p-value, baseline FVC % predicted and the treatment by time by baseline FVC % predicted interaction were added as covariates. Kolb M, et al. Am J Respir Crit Care Med 191;2015:A1021. Notes to Programming Please program so that when the audio begins, the subtitle ‘Annual rate of decline…’ enters followed by the title and graph axes and footer. When the audio says ‘ The annual rate of decline….’ please then introduce the left-hand bars, followed by the right-hand bars and then the associated yellow boxes. When the audio says ‘There was no significant treatment….’ please introduce the ‘Treatment by time’ box below the graph. When the audio says ‘….this means that the treatment effect….’ please fade in the orange comment box on top of the graph. When the Next button is selected, the learner should be taken to the next screen. Please program this screen so that, if the learner alternatively selects the tabs at the top of the screen, s/he is taken to the tab selected.

Patients with no honeycombing on HRCT
Eligibility Criteria based on HRCT To qualify to enter the INPULSIS® trials if a surgical lung biopsy was not available, criteria A and B and C; or A and C; or B and C had to be met A Definite honeycomb lung destruction with basal and peripheral predominance B Presence of reticular abnormality and traction bronchiectasis consistent with fibrosis with basal and peripheral predominance C Atypical features are absent, specifically nodules and consolidation. Ground glass opacity, if present, is less extensive than reticular opacity pattern Also patients with features of Possible UIP were included in the INPULSIS® trials (B and C). This patient population had not been studied before in clinical trials for IPF Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

Nintedanib was effective independent of the presence of honeycombing on HRCT and/or biopsy
Annual rate of decline of FVC by HRCT and biopsy diagnostic criteria Honeycombing on HRCT and/or confirmation of UIP by biopsy No honeycombing on HRCT and no biopsy Placebo (n=298) Nintedanib (n=425) Placebo (n=125) Nintedanib (n=213) A post-hoc subgroup analysis of patients with IPF diagnosis based on honeycombing on HRCT and/or confirmation of UIP by biopsy vs patients with no honeycombing on HRCT and no biopsy to support the diagnosis of UIP was undertaken in the INPULSIS® trials. 723 patients (68%; 425 nintedanib, 298 placebo) had honeycombing on HRCT and/or confirmation by biopsy and 338 (32%; 213 nintedanib, 125 placebo) had no honeycombing on HRCT or biopsy for diagnosis of IPF. Nintedanib slowed FVC decline in both subgroups. Decline in FVC in the placebo group was also comparable in both subgroups. Nintedanib was effective independent of the presence of honeycombing on HRCT and/or biopsy. There was no significant treatment by subgroup interaction (p=0.8139). Nintedanib slowed FVC decline equally in both sub-groups. The treatment effect in both subgroups was consistent with the treatment effect in the overall population (109.9 mL/year [95% CI: 75.9, 144.0]; p<0.0001). This is the first publication of data that shows the efficacy of an IPF treatment in patients with no honeycombing on HRCT and no biopsy to confirm the diagnosis of IPF, which have major implications for diagnosis and clinical trial design. 117.0 mL/year (95% CI: 76.3, 157.8) 98.9 mL/year (95% CI: 36.4, 161.5) Treatment by time by subgroup interaction p=0.8139 Based on a random coefficient regression with fixed effects for trial, treatment, gender, age, height, HRCT diagnosis of usual interstitial pneumonia (UIP), treatment by time by HRCT diagnosis of UIP interaction and random effect of patient specific intercept and time. Raghu G, et al. . Am J Respir Crit Care Med 191;2015:A1022. Notes to Programming When the audio begins, the subtitle ‘Annual rate of decline…’ enters followed by the title and graph axes and footer When the audio says ‘723 patients (68%...’ please introduce the left-hand bars, followed by the right-hand bars and then the associated yellow boxes. When the audio says ‘There was no significant treatment….’ please introduce the ‘Treatment by time’ box below the graph.

Patients with concomitant emphysema
Presence of emphysema (yes/no) at baseline was determined by qualitative assessment of chest HRCT scans, centrally reviewed by a single radiologist Post-hoc subgroup analyses of patients with/without emphysema at baseline were conducted using pooled data from the two INPULSIS® trials Subgroup analyses were conducted on the primary and key secondary endpoints Cottin V, et al. Abstract presented at the International Colloquium on Lung and Airway Fibrosis, Mont Tremblant, Canada, 20–24 September 2014.

In the nintedanib group the annual rate of decline in FVC was comparable for patients with and without emphysema at baseline No emphysema at baseline Emphysema at baseline n=384 n=257 n=254 n=166 Adjusted annual rate (SE) of decline in FVC (mL/year) ∆115.4 mL (95% CI: 73.8,157.1) ∆102.0 mL (95% CI: 43.2,160.9) Treatment by time by subgroup interaction p=0.5199 Nintedanib 150 mg bid Placebo Cottin V, et al. Abstract presented at the International Colloquium on Lung and Airway Fibrosis, Mont Tremblant, Canada, 20–24 September 2014.

Exacerbations How do you interpret the INPULSIS® results with regard to acute exacerbations of IPF?

IPF: Cause of death Modified from Natsuizaka M, et al. Am J Respir Crit Care Med 2014;190:773–779.

IPF: Natural history Disease Progression Asymptomatic Time
Microinjuries to the lung Acute exacerbations Disease Progression Asymptomatic IPF + emphysema Slow Rapid Time Patient becomes symptomatic Adapted from King TE, et al. Lancet 2011;378:1949–1961.

Nintedanib reduced the risk of acute IPF exacerbations
Incidence of investigator-reported acute IPF exacerbations in the INPULSIS® trials INPULSIS®-1 INPULSIS®-2 Pooled Nintedanib (n=309) Placebo (n=204) Placebo (n=210) Nintedanib (n=329) Placebo (n=423) Nintedanib (n=638) 5.4% 6.1% 9.6% 3.6% 7.6% 4.9% 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=0.64 (95% CI=0.39, 1.05) P=0.08 Acute exacerbations were defined as events meeting all of the following criteria: unexplained worsening or development of dyspnoea within 30 days, new diffuse pulmonary infiltrates on chest X-ray and/or HRCT, or parenchymal abnormalities with no pneumothorax or pleural effusion (new ground-glass opacities) since last visit. Causes of the acute worsening, including infection, left heart failure, pulmonary embolism or any identifiable cause of acute lung injury were to be excluded as per routine clinical practice and microbiological studies. Kaplan-Meier estimates were derived for the probability of a first acute exacerbation over time, and time to first acute exacerbation were primarily analyzed using the log rank test. The hazard ratios and their confidence intervals were computed using a Cox proportional hazards model adjusted for gender, age and height. These covariates were chosen in order to be consistent with the analyses performed in the phase II TOMORROW trial and are the same covariates as included in the primary endpoint model. The key secondary endpoint uses data on acute exacerbations as reported by the site investigators, in keeping with the phase II methodology. Boehringer Ingelheim International GmbH. OFEV® summary of product characteristics. 19/01/2015

Adjudicated acute exacerbations
The adjudication committee categorized the investigator- reported acute exacerbations according to pre-specified criteria* Confirmed acute exacerbation Suspected acute exacerbation Not an acute exacerbation The adjudication committee was blinded to treatment allocation and events were adjudicated before database lock and data unblinding As the definition of acute exacerbations used in the clinical programme of nintedanib is largely based on exclusion of alternative causes for worsening of the disease as per routine clinical practice, investigator-reported exacerbations are considered to reflect regional clinical practice and availability of diagnostic tools. Due to this complexity, the investigator-reported exacerbations were also reviewed by an adjudication committee, and the effect of nintedanib on these adjudicated events was assessed as well. The adjudication committee classified each reported case as ‘not’ acute IPF exacerbation, ‘confirmed’, or ‘suspected’ exacerbation. The primary analysis of acute exacerbations was based on investigator-reported adverse events. To assess the robustness of the analysis of investigator-reported acute IPF exacerbations, a pre-specified sensitivity analysis using ‘confirmed’ or ‘suspected’ acute IPF exacerbations based on adjudication of the investigator-reported events from the pooled studies was performed. The IPF literature suggests that ‘suspected’ exacerbations are clinically indistinguishable from ‘confirmed’ exacerbations and carry a similar risk of disease progression and short-term mortality. As ‘suspected’ exacerbations are more common in clinical trials than ‘confirmed’ ones, their inclusion in the analyses was justified. *Collard HR, et al. Am J Respir Crit Care Med. 2007;176:

Time to first confirmed/suspected acute exacerbation (days)
Time to first confirmed/suspected acute exacerbation per adjudication: Pooled data Placebo Nintedanib 150 mg bid 15 14 13 12 HR (95% CI; 0.16, 0.65) p=0.0010 11 10 9 Cumulative incidence of first confirmed/suspected acute exacerbation (%) 8 7 6 5 4 3 2 1 The numerical difference in favour of nintedanib on investigator-reported acute exacerbations based on the pooled dataset was confirmed by the results of the pre-specified sensitivity analysis of adjudicated exacerbations. Based on the pooled analysis, the proportion of patients with events adjudicated as a ‘confirmed’ or ‘suspected’ acute exacerbation was smaller in the nintedanib group than in the placebo group, and the hazard ratio of 0.32 (95% CI 0.16, 0.65) indicated a significantly lower risk of having a first acute IPF exacerbation (based on adjudication) in the nintedanib group than in the placebo group at any time point over 52 weeks. 30 60 90 120 150 180 210 240 270 300 330 360 373 Time to first confirmed/suspected acute exacerbation (days) No. of patients Nintedanib 638 634 629 613 610 602 597 593 589 580 572 563 548 503 Placebo 423 419 416 409 408 404 396 393 390 384 380 3671 363 345 Nintedanib 150 mg bid (n=638) Placebo (n=423) Patients with ≥1 acute exacerbation, n (%) 12 (1.9) 24 (5.7) bid, twice daily; CI, confidence interval; HR, hazard ratio. Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

Mortality in IPF What is your opinion on the mortality data reported in the INPULSIS® trials?

Nintedanib in IPF INPULSIS® and TOMORROW trials design
INPULSIS®: TWO REPLICATE; RANDOMIZED; DOUBLE-BLIND; 52-WEEK; PHASE III TRIALS TOMORROW: A RANDOMIZED; DOUBLE-BLIND; 52-WEEK; PHASE II, DOSE-FINDING TRIAL 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) R 3:2 ratio Screening Placebo (n=423) Follow-up Nintedanib 150 mg bid (n=85) 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 56 Week 2 4 6 12 24 36 52 Richeldi L, et al. Oral presentation at the International Colloquium on Lung and Airway Fibrosis, Mont Tremblant, Canada, 20–24 September 2014.

Mortality as an endpoint
Many consider mortality to be the most clinically meaningful and robust endpoint in clinical trials in IPF Relatively low death rates in patients with mild or moderate impairment of lung function limit the feasibility of this endpoint All-cause and respiratory mortality were secondary endpoints in the TOMORROW and INPULSIS® trials None of these trials was powered to show a difference in mortality between nintedanib and placebo Analyses using pooled data from the TOMORROW and INPULSIS® trials were conducted to obtain a more precise estimate of the effect of nintedanib 150 mg bid on mortality Richeldi L, et al. Oral presentation at the International Colloquium on Lung and Airway Fibrosis, Mont Tremblant, Canada, 20–24 September 2014.

All-Cause Mortality Rate in Patients with IPF
All-Cause Mortality Rate in Patients with Idiopathic Pulmonary Fibrosis Implications for the Design and Execution of Clinical Trials Talmadge E. King, Jr.1, Carlo Albera2, Williamson Z. Bradford3, Ulrich Costabel4, Roland M. du Bois5, Jonathan A. Leff3, Steven D. Nathan6, Steven A. Sahn7, Dominique Valeyre8, and Paul W. Noble9 100 80 60 Percent Survival 40 20 N=622 13 26 39 52 65 78 91 104 Weeks Figure 1. Kaplan-Meier estimate of overall survival in the pooled placebo populations from the INSPIRE and CAPACITY studies. King TE, et al. Am J Respir Crit Care Med 2014;189:825–831.

Statistical methodology used in TOMORROW and INPULSIS® trials
Vital status at week 52 was collected for all patients who prematurely discontinued trial drug An adjudication committee that was unaware of the group assignments reviewed medical documentation to adjudicate the primary cause of all deaths All-cause and respiratory mortality over 52 weeks, measured as time to death, were analyzed using data from patients treated with nintedanib or placebo using a log rank test and Cox model, with terms for trial, treatment, sex, age and height Analyses were based on data collected up to 372 days after randomization in patients who received ≥1 dose of trial drug Richeldi L, et al. Oral presentation at the International Colloquium on Lung and Airway Fibrosis, Mont Tremblant, Canada, 20–24 September 2014

INPULSIS® trials ALL-CAUSE MORTALITY OVER 52 WEEKS
RESPIRATORY MORTALITY OVER 52 WEEKS HR 0.70 (95% Cl; 0.46, 1.08) P=0.0954 HR 0.62 (95% Cl; 0.37, 1.06) P=0.0779 Nintedanib 150 mg bid (n=723) Placebo (n=508) Patients who died, n (%) 42 (5.8) 42 (8.3) Nintedanib 150 mg bid (n=723) Placebo (n=508) Patients who died, n (%) 26 (3.6) 29 (5.7) Richeldi L, et al. Oral presentation at the International Colloquium on Lung and Airway Fibrosis, Mont Tremblant, Canada, 20–24 September 2014.

All cause mortality pooled data from the TOMORROW and INPULSIS® trials
Time to death due to all cause over 52 weeks No. of patients Time to death (days) 100 99 98 96 97 95 94 93 92 91 80 90 88 87 86 85 84 83 82 81 89 Kaplan-Meier estimate of death (%) 30 60 120 150 180 210 240 270 300 330 360 373 Nintedanib 150mg bid Placebo 723 508 722 712 717 702 720 692 704 685 707 680 660 698 562 506 501 490 504 483 496 479 498 471 453 487 375 HR 0.70 (95% CI; 0.46, 1.08) p=0.0954 Richeldi L, et al. Presented at the International Colloquium on Lung and Airway Fibrosis, Mont Tremblant, Canada, 20–24 September 2014.

Patients who died due to respiratory causes, n (%)
Respiratory mortality pooled data from the TOMORROW and INPULSIS® trials Respiratory mortality over 52 weeks Nintedanib 150 mg bid (n=723) Placebo (n=508) Patients who died due to respiratory causes, n (%) 26 (3.6) 29 (5.7) HR (95% CI) 0.62 (0.37, 1.06) P-value 0.0779 Richeldi L, et al. Presented at the International Colloquium on Lung and Airway Fibrosis, Mont Tremblant, Canada, 20–24 September 2014.

Effect of nintedanib on mortality Conclusions
A pooled analysis of data from the TOMORROW and INPULSIS® trials showed a trend toward a reduction in all-cause and respiratory mortality in patients treated with nintedanib These findings reflect the consistent effect of nintedanib on slowing disease progression in patients with IPF These data support the concept that mortality is not a feasible primary endpoint to use in a population of patients with mild to moderate lung function impairment over a 1-year period Richeldi L, et al. Oral presentation at the International Colloquium on Lung and Airway Fibrosis, Mont Tremblant, Canada, 20–24 September 2014.

Safety Could you please give us your opinion on the safety of nintedanib in the treatment of IPF?

Patient disposition INPULSIS®-1 INPULSIS®-2 Nintedanib 150 mg bid
Placebo Number of randomized patients 309 206 331 220 Number of treated patients 204 329 219 Prematurely discontinued trial medication, n (%) 78 (25.2) 36 (17.6) 78 (23.7) 44 (20.1) Prematurely discontinued trial medication due to adverse event, n (%) 65 (21.0) 24 (11.8) 62 (18.8) 35 (16.0) Completed planned observation time, n (%) 260 (84.1) 174 (85.3) 272 (82.7) 179 (81.7) In INPULSIS®-1, 513 patients received at least one dose of trial medication (309 with nintedanib and 204 with placebo). A total of 78 patients (25.2%) in the nintedanib group and 36 patients (17.6%) in the placebo group prematurely discontinued trial medication. Of these patients, 31 (39.7%) and 11 (30.6%) patients in the nintedanib and placebo groups, respectively, completed visits up to week 52. The most frequent reason for premature discontinuation of trial medication was adverse event(s) (65 [21.0%] and 24 [11.8%] patients in the nintedanib and placebo groups, respectively). In INPULSIS®-2, 548 patients received at least one dose of trial medication (329 with nintedanib and 219 with placebo). A total of 78 patients (23.7%) on nintedanib and 44 patients (20.1%) on placebo prematurely discontinued trial medication. Of these patients, 26 patients (33.3%) in the nintedanib group and 10 patients (22.7%) in the placebo group completed visits up to week 52. The most frequent reason for premature discontinuation of trial medication was adverse events (62 [18.8%] and 35 [16.0%] patients in the nintedanib and placebo groups. Completed planned observation time = all visits completed or, if patient prematurely discontinued study medication, all visits until Week 52 completed. Patients who died were not considered completers. bid, twice daily. Boehringer Ingelheim International GmbH. OFEV® summary of product characteristics. 19/01/2015

Nintedanib demonstrated a favorable risk-benefit profile
The most common adverse events were of gastrointestinal nature Most frequent adverse events (incidence of >10% in any treatment group) INPULSIS®-1 INPULSIS®-2 No of patients (%) Nintedanib 150 mg bid (n=309) Placebo (n=204) Nintedanib 150 mg bid (n=329) (n=219) Diarrhoea 190 (61.5) 38 (18.6) 208 (63.2) 40 (18.3) Nausea 70 (22.7) 12 (5.9) 86 (26.1) 16 (7.3) Nasopharyngitis 39 (12.6) 34 (16.7) 48 (14.6) 34 (15.5) Cough 47 (15.2) 26 (12.7) 38 (11.6) 31 (14.2) Progression of IPF† 31 (10.0) 21 (10.3) 33 (10.0) Bronchitis 36 (11.7) 28 (13.7) 31 (9.4) 17 (7.8) Upper respiratory tract infection 28 (9.1) 18 (8.8) 30 (9.1) 24 (11.0) Dyspnea 22 (7.1) 23 (11.3) 27 (8.2) 25 (11.4) Decreased appetite 26 (8.4) 14 (6.9) 42 (12.8) 10 (4.6) Vomiting 40 (12.9) 4 (2.0) 34 (10.3) 7 (3.2) Weight decreased 25 (8.1) 13 (6.4) 37 (11.2) 2 (0.9) Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

Diarrhoea INPULSIS® -1 INPULSIS®-2 No of patients (%)
Nintedanib 150 mg bid (n=309) Placebo (n=204) (n=329) Placebo (n=219) Diarrhoea serious adverse event(s) 1 (0.3) 0 (0.0) 1 (0.5) Diarrhoea adverse event(s) leading to premature treatment discontinuation 14 (4.5) 14 (4.3) Intensity of most severe event, for patients with any diarrhoea adverse event(s) Mild 103 (54.2) 29 (76.3) 123 (59.1) 31 (77.5) Moderate 75 (39.5) 9 (23.7) 75 (36.1) 7 (17.5) Severe 11 (5.8) 10 (4.8) 2 (5.0) The most frequent adverse event in the nintedanib group in both trials was diarrhoea. Of the patients in the nintedanib group who experienced diarrhoea, most (93.7% in INPULSIS®-1 and 95.2% in INPULSIS®-2) reported events that were of mild or moderate intensity. Fourteen patients (4.5%) on nintedanib and none on placebo in INPULSIS®-1, and 14 patients on nintedanib (4.3%) and 1 patient (0.5%) on placebo in INPULSIS®-2 experienced diarrhoea that led to premature discontinuation of study drug. Boehringer Ingelheim International GmbH. OFEV® summary of product characteristics. 19/01/2015

Time to first onset of diarrhoea: Pooled data
100 90 80 70 60 50 Kaplan-Meier estimate of first diarrhoea adverse event (%) 40 30 20 Based on crude frequencies, the first diarrhoea episode started within the first month of treatment in 44.0% of the patients with diarrhoea in the nintedanib group; 67.1% reported the first onset of diarrhoea within the first 3 months of treatment. In 32.9% of the patients with diarrhoea in the nintedanib group, the first onset was later than 3 months after the start of treatment. The median time to first onset of diarrhoea in the nintedanib group was 148 days. 10 Nintedanib 150mg bid Placebo 30 60 90 120 150 180 210 240 270 300 330 360 390 420 No. of patients Time to first diarrhoea advers event (days) Nintedanib 150mg bid 638 462 401 345 309 286 255 242 221 199 191 180 169 131 Placebo 423 378 361 353 347 340 329 321 314 304 299 293 287 218 Boehringer Ingelheim International GmbH. Data on file.

Side effects can be managed effectively in most patients
Summary diarrhoea events In patients who experienced diarrhoea events, 95% were mild or moderate in intensity Diarrhoea occured mostly within the first 3 months of treatment Less than 5% of patients receiving nintedanib discontinued treatment due to diarrhoea events Boehringer Ingelheim International GmbH. OFEV® summary of product characteristics. 19/01/2015

Side effects management recommendations
1. Supportive Medications 2. Dose Adjustment 3. Dietary Changes Antidiarrhoeals, such as loperamide Antiemetic therapy, such as a dopamine receptor antagonist or a H1- antihistaminic Treatment interruption or dose reduction (100 mg twice daily) should be considered if symptomatic treatment is ineffective) Adequate hydration at first sign of diarrhoea Avoidance of certain foods/drinks, such as high- fiber foods, dairy products, coffee, tea, and alcohol Diet of bland, low-fibre foods, such as white bread, bananas, eggs, cooked potatoes without the skin, and fish, chicken, or turkey without the skin Boehringer Ingelheim International GmbH. OFEV® summary of product characteristics. 19/01/2015 Cancer Network.

Cardiac disorder adverse events
INPULSIS®-1 INPULSIS®-2 No of patients (%) Nintedanib 150 mg bid (n=309) Placebo (n=204) (n=329) Placebo (n=219) Any adverse event cardiac disorder 30 (9.7) 19 (9.3) 34 (10.3) 26 (11.9) Serious adverse event cardiac disorder 14 (4.5) 11 (5.4) 18 (5.5) 12 (5.5) Fatal adverse event cardiac disorder 1 (0.3) 2 (1.0) 2 (0.6) 4 (1.8) Ischemic heart disease 13 (4.2) 10 (4.9) 14 (4.3) 7 (3.2) Serious ischemic heart disease 8 (2.6) 7 (3.4) 7 (2.1) 3 (1.4) Myocardial infarction INPULSIS® -1: 5 patients (1.6%) in the nintedanib group; 1 patient (0.5%) in the placebo group INPULSIS® -2: 5 patients (1.5%) in the nintedanib group; 1 patient (0.5%) in the placebo group 2 events in the nintedanib groups and 1 in the placebo groups had fatal outcomes Richeldi L, et al. N Engl J Med 2014;370:2071–2082.

Overall conclusions Nintedanib is the first treatment that has consistently demonstrated a slowing of disease progression in three placebo controlled trials in IPF patients Nintedanib reduced the annual decline in lung function by 50% Nintedanib has a manageable side-effect profile

Interpreting INPULSIS® results Speaker: Luca Richeldi

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Interpreting INPULSIS® results Speaker: Luca Richeldi

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