1. 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

2. 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– Richeldi L, et al. NEJM 2014;370:2071–2082.
references

3. FVC Decline

4. 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– Richeldi L, et al. NEJM 2011;365:1079– OFEV® SmPC. Boehringer Ingelheim International GmbH OFEV® Prescribing Information. Boehringer Ingelheim Pharmaceuticals Inc
references

5. 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– Richeldi L, et al. NEJM 2014;370:2071– Richeldi L, et al. NEJM 2011;365:1079–1087.
references

6. 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– Richeldi L, et al. NEJM 2011;365:1079– OFEV® SmPC. Boehringer Ingelheim International GmbH
references

7. 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– Richeldi L, et al. NEJM 2014;370:2071–2082.
references

8. Acute Exacerbations of IPF

9. 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– Richeldi L, et al. NEJM 2014;370:2071– OFEV® SmPC. Boehringer Ingelheim International GmbH
references

10. 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– Richeldi L, et al. NEJM 2014;370:2071– Richeldi L, et al. NEJM 2011;365:1079–1087.
references

11. Survival

12. 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 Richeldi L, et al. Poster presented at ICLAF Cottin V. Clin Invest. 2015;5(2):
references

13. 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 Richeldi L, et. al. Respir Med 2016;113:74– Richeldi L, et al. Presented at the annual congress of the German Respiratory Society Richeldi L, et al. NEJM 2014;370:2071– Richeldi L, et al. NEJM 2011;365:1079–1087.
references

14. 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 Richeldi L, et. al. Respir Med 2016;113:74– Richeldi L, et al. NEJM 2014;370:2071– Richeldi L, et al. NEJM 2011;365:1079–1087.
references

15. 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 (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 Richeldi L, et. al. Respir Med 2016;113:74– Richeldi L, et al. NEJM 2014;370:2071– Richeldi L, et al. NEJM 2011;365:1079–1087.
references

16. Pooled Analysis of 3 Clinical Trials
Conclusions

17. 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.