Interpreting INPULSIS® results
Speaker: Luca Richeldi
Professor of Respiratory Medicine
Chair of Interstitial Lung Disease
University of Southampton, United Kingdom
1
Disclosures
Scientific Advisory Board
InterMune, Boehringer Ingelheim, Fibrogen, GlaxoSmithKline, SanofiAventis, 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
2
Importance of the INPULSIS® trials
Prof Richeldi, how would you describe the overall importance of the INPULSIS® trials?
3
Disclosures
Scientific Advisory Board
InterMune, Boehringer Ingelheim, Fibrogen, GlaxoSmithKline, SanofiAventis, 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
4
TOMORROW: Study design
Day 1
Screening
Before Day-4
R
A
N
D
O
M
I
Z
A
T
I
O
N
Nintedanib 50 mg qd
(n=87)
Review
by DMC
Nintedanib 50 mg bid
(n=86)
Review
by DMC
Nintedanib 100 mg bid
(n=86)
Review
by DMC
N=432
Randomized
1:1:1:1:1
Nintedanib 150 mg bid
(n=86)
Placebo
(n=87)
Richeldi L et al. N Engl J Med 2011; 365: 1079-1087.
• 92 sites
in 25 countries
(non-US)
• Study medication
was administered
for 52 weeks
DMC: Data Monitoring Committee
5
TOMORROW: Decline in FVC by final dose
Placebo
(n=87)
Nintedanib
50 mg qd
(n=82)
Nintedanib
50 mg bid
(n=95)
Nintedanib
100 mg bid
(93)
Nintedanib
150 mg bid
(n=66)
Annual FVC decline, L/year
[Mean (SE)]
0
-0.05
-0.04 **
-0.1
-0.15
-0.2
-0.17
-0.25
-0.19
-0.3
Richeldi L et al. N Engl J Med 2011; 365: 1079-1087.
-0.17
-0.2
** p<0.01 vs. placebo (hierarchical testing procedure)
6
TOMORROW: Absolute change in FVC from baseline over
time
0.1
Change in FVC, L/year
[Mean (SE)]
0.05
Nintedanib 150 mg bid
0
***
-0.05
-0.1
-0.15
-0.2
Placebo
-0.25
0
50
100
150
200
250
300
350
Day
***p<0.001 vs placebo (unadjusted)
Richeldi L et al. N Engl J Med 2011; 365: 1079-1087.
7
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: 1079-1087.
8
INPULSIS®: two replicate, randomized, double-blind, 52-week,
phase III trials recruited 1066 patients
Nintedanib 150 mg bid (n=638)
R
3:2 ratio
Screening
Visit
Week
1
Follow-up
Placebo (n=423)
2
3
4
5
6
7
8
9
0
2
4
6
12
24
36
52
56
•
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: 1023-30
9
Methodology and analysis of the annual rate of decline in
FVC
To calculate the slope for an individual patient, all FVC
measurements from baseline to week 52 were used
FVC (mL)
The slope was calculated: Δ in Y / Δ in X
The treatment effect was determined using mean slopes for
each treatment group
Baseline 2
•
•
•
4
6
12
24
36
52 Follow up
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: 1023-30
10
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
125.3 (77.7, 172.8)
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)
-200
-150
-100
-50
Favours placebo
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.
0
50
100
150
200
Favours nintedanib 150 mg bid
11
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
93.7 (44.8, 142.7)
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)
-200
-150
-100
-50
Favours placebo
0
50
100
150
200
Favours nintedanib 150 mg bid
bid, twice daily; FVC, forced vital capacity.
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.
18
Primary endpoint
Could you please discuss the overall efficacy of nintedanib reported in the INPULSIS®
trials?
13
Disclosures
Scientific Advisory Board
InterMune, Boehringer Ingelheim, Fibrogen, GlaxoSmithKline, SanofiAventis, 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
14
Annual rate of decline in FVC
INPULSIS®-1
INPULSIS®-2
Adjusted annual rate of
decline in FVC mL/year
0
-50
-100
-150
-113.6
-114.7
-200
-250
-239.9
-207.3
-300
125.3 mL/year
(95% CI: 77.7, 172.8)
p<0.0001
Nintedanib 150 mg bid (n=309)
Placebo (n=204)
93.7 mL/year
(95% CI: 44.8, 142.7)
p=0.0002
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.
15
Absolute changes from baseline in FVC % predicted at week
52
Adjusted absolute mean change from
baseline in FVC % predicted
INPULSIS®-1
INPULSIS®-2
0
-2
-2.8
-3.1
-4
-6
-6.0
-8
3.2 % predicted
(95% CI: 2.1, 4.3)
p<0.0001
Nintedanib 150 mg bid (n=307)
Placebo (n=204)
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.
-6.2
3.1 % predicted
(95% CI: 1.9, 4.3)
p<0.0001
Nintedanib 150 mg bid (n=327)
Placebo (n=217)
16
0
-50
-100
-150
-113.6
-200
-250
-223.5
Mean (SE) observed change from baseline in FVC (mL)
Adjusted annual rate (SE) of decline in
FVC (mL/year)
Primary efficacy endpoint in pooled data
Nintedanib 150 mg bid
50
Placebo
0
-50
-100
-150
-200
-250
0 2 4 6
-300
109.9 mL/year
(95% CI: 75.9, 144.0)
p<0.0001
12
24
36
52
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.
17
Trial population
How relevant to clinical practice is the trial population of the INPULSIS® trials?
18
Disclosures
Scientific Advisory Board
InterMune, Boehringer Ingelheim, Fibrogen, GlaxoSmithKline, SanofiAventis, 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
19
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
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.
20
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)
2756.8
(735.1)
2844.5
(820.1)
2672.8
776.0)
2619.0
787.3)
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)
4.0 (1.2)
4.0 (1.1)
3.8 (1.2)
3.7 (1.3)
47.8 (12.3)
47.5 (11.7)
47.0 (14.5)
46.4 (14.8)
DLCO, mmol/min/kPa, mean (SD)
DLCO, %predicted, Mean (SD)
*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.
21
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)
0
-50
-100
-111.3
-150
-200
-119.7
∆113.5 mL
(95% CI: 51.3,175.7)
∆109.0 mL
(95% CI: 68.2, 149.9)
-250
-233.2
-300
Nintedanib 150 mg bid (n=207)
Placebo (n=154)
Treatment by time by
subgroup interaction
p=0.9505
Costabel U, et al. Oral presentation at the ERS International Congress, Munich, 6 – 10 September 2014
-220.3
Nintedanib 150 mg bid (n=431)
Placebo (n=269)
22
Nintedanib was effective independent of lung function
impairment at baseline
Annual rate of decline in FVC by baseline FVC 90% predicted
FVC ≤90% predicted
Placebo
(n=315)
FVC >90% predicted
Nintedanib
(n=472)
Placebo
(n=108)
Nintedanib
(n=166)
Adjusted annual rate (SE) of decline
in FVC (mL/year)
0
-50
-100
-91.5
-150
-121.5
-200
102.1 mL/year
(95% CI: 61.9, 142.3)
-250
-223.6
-300
Treatment by time by
subgroup interaction
p=0.5300
133.1 mL/year
(95% CI: 68.0, 198.2)
-224.6
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.
23
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
B
C
Definite honeycomb lung destruction with basal and peripheral predominance
Presence of reticular abnormality and traction bronchiectasis
consistent with fibrosis with basal and peripheral predominance
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.
24
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
Placebo
(n=298)
No honeycombing on HRCT
and no biopsy
Nintedanib
(n=425)
Placebo
(n=125)
Nintedanib
(n=213)
Adjusted annual rate (SE) of decline
in FVC (mL/year)
0
-50
-100
-108.7
-150
-122.0
-200
-250
-300
117.0 mL/year
(95% CI: 76.3, 157.8)
98.9 mL/year
(95% CI: 36.4, 161.5)
-221.0
-225.7
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.
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.
26
In the nintedanib group the annual rate of decline in FVC was
comparable for patients with and without emphysema at
baseline
Adjusted annual rate (SE) of
decline in FVC (mL/year)
0
No emphysema at baseline
n=257
n=384
Emphysema at baseline
n=166
n=254
-50
-100
-150
-105.1
-118.8
-200
-250
-300
∆115.4 mL
(95% CI:
73.8,157.1)
-234.2
Treatment by time by
subgroup interaction
p=0.5199
∆102.0 mL
(95% CI:
43.2,160.9)
-207.2
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.
27
Exacerbations
How do you interpret the INPULSIS® results with regard to acute exacerbations of
IPF?
28
Disclosures
Scientific Advisory Board
InterMune, Boehringer Ingelheim, Fibrogen, GlaxoSmithKline, SanofiAventis, 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
29
IPF: Cause of death
Unknown, 5%
Cardiovascular
disease, 3%
Other,
10%
Acute
exacerbation,
40%
Pneumonia,
7%
Lung cancer,
11%
Chronic
respiratory
failure, 24%
Modified from Natsuizaka M, et al. Am J Respir Crit Care Med 2014;190:773–779.
30
IPF: Natural history
Disease Progression
Microinjuries to
the lung
Acute
exacerbations
Asymptomatic
IPF +
emphysema
Slow
Rapid
Time
Patient becomes
symptomatic
Adapted from King TE, et al. Lancet 2011;378:1949–1961.
31
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
Boehringer Ingelheim International GmbH. OFEV® summary of product characteristics. 19/01/2015
HR=0.64 (95% CI=0.39, 1.05)
P=0.08
32
Adjudicated acute exacerbations
• The adjudication committee categorized the investigatorreported 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
*Collard HR, et al. Am J Respir Crit Care Med. 2007;176:636-643.
33
Cumulative incidence of first
confirmed/suspected acute exacerbation
(%)
Time to first confirmed/suspected acute exacerbation per
adjudication: Pooled data
Nintedanib 150 mg bid
Placebo
15
14
13
12
11
10
9
8
7
6
5
4
3
2
1
0
HR 0.32
(95% CI; 0.16, 0.65)
p=0.0010
0
30
60
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
No. of patients
90
120
150
180
210
240
270
300
Time to first confirmed/suspected acute exacerbation (days)
Patients with ≥1 acute exacerbation, n (%)
330
Nintedanib 150 mg bid (n=638)
Placebo (n=423)
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.
360 373
34
Mortality in IPF
What is your opinion on the mortality data reported in the INPULSIS® trials?
35
Disclosures
Scientific Advisory Board
InterMune, Boehringer Ingelheim, Fibrogen, GlaxoSmithKline, SanofiAventis, 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
36
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 50 mg bid (n=86)
Nintedanib 150 mg bid (n=638)
Screening
R
Screening
3:2 ratio
Placebo (n=423)
Follow-up
R
1:1:1:1:1
ratio
Nintedanib 100 mg bid (n=86)
Nintedanib 150 mg bid (n=85)
Placebo (n=85)
Visit 1
2 3 4 5
6
7
8
9
Visit
Week
0 2 4 6
12
24
36
52 56
Week
1
2 3 4 5
6
7
8
9
0 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.
37
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.
38
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
Percent Survival
80
60
40
20
N=622
0
0
13
26
39
52
65
Weeks
78
91
104
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.
39
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
40
INPULSIS® trials
ALL-CAUSE MORTALITY OVER 52 WEEKS
HR 0.70
(95% Cl; 0.46, 1.08)
P=0.0954
Patients who died, n (%)
RESPIRATORY MORTALITY OVER 52 WEEKS
HR 0.62
(95% Cl; 0.37, 1.06)
P=0.0779
Nintedanib
150 mg bid
(n=723)
Placebo
(n=508)
42 (5.8)
42 (8.3)
Patients who died, n (%)
Nintedanib
150 mg bid
(n=723)
Placebo
(n=508)
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.
41
All cause mortality pooled data from the TOMORROW and
INPULSIS® trials
Time to death due to all cause over 52 weeks
100
99
Kaplan-Meier estimate of death (%)
98
97
96
95
94
93
92
91
90
89
HR 0.70
(95% CI; 0.46, 1.08)
p=0.0954
88
87
86
85
84
83
Nintedanib 150mg bid
Placebo
82
81
80
0
0
30
60
90
120
150
180
210
240
270
300
330
360 373
692
483
685
479
680
471
660 562
453 375
Time to death (days)
No. of patients
Nintedanib 150mg bid
Placebo
723
508
722
506
720
504
717
501
712
501
707
498
704
496
702
490
698
487
Richeldi L, et al. Presented at the International Colloquium on Lung and Airway Fibrosis, Mont Tremblant, Canada, 20–24
September 2014.
42
Respiratory mortality pooled data from the TOMORROW and
INPULSIS® trials
Respiratory mortality over 52 weeks
Patients who died due to
respiratory causes, n (%)
Nintedanib 150 mg bid
(n=723)
Placebo
(n=508)
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.
43
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.
44
Safety
Could you please give us your opinion on the safety of nintedanib in the treatment of
IPF?
45
Disclosures
Scientific Advisory Board
InterMune, Boehringer Ingelheim, Fibrogen, GlaxoSmithKline, SanofiAventis, 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
46
Patient disposition
INPULSIS®-1
INPULSIS®-2
Nintedanib
150 mg bid
Placebo
Nintedanib
150 mg bid
Placebo
Number of randomized patients
309
206
331
220
Number of treated patients
309
204
329
219
78 (25.2)
36 (17.6)
78 (23.7)
44 (20.1)
65 (21.0)
24 (11.8)
62 (18.8)
35 (16.0)
260 (84.1)
174 (85.3)
272 (82.7)
179 (81.7)
Prematurely discontinued trial
medication, n (%)
Prematurely discontinued trial
medication due to adverse event,
n (%)
Completed planned observation
time, n (%)
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
47
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
No of patients (%)
INPULSIS®-2
Nintedanib
150 mg bid
(n=309)
Placebo
(n=204)
Nintedanib
150 mg bid
(n=329)
Placebo
(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)
40 (18.3)
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.
48
Diarrhoea
INPULSIS® -1
No of patients (%)
INPULSIS®-2
Nintedanib
150 mg bid
(n=309)
Placebo
(n=204)
Nintedanib
150 mg bid
(n=329)
Placebo
(n=219)
Diarrhoea serious adverse event(s)
1 (0.3)
0 (0.0)
1 (0.3)
1 (0.5)
Diarrhoea adverse event(s) leading to
premature treatment discontinuation
14 (4.5)
0 (0.0)
14 (4.3)
1 (0.5)
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)
0 (0.0)
10 (4.8)
2 (5.0)
Intensity of most severe event, for patients
with any diarrhoea adverse event(s)
Boehringer Ingelheim International GmbH. OFEV® summary of product characteristics. 19/01/2015
49
Kaplan-Meier estimate of first diarrhoea adverse event (%)
Time to first onset of diarrhoea: Pooled data
100
90
80
70
60
50
40
30
20
10
Nintedanib 150mg bid
Placebo
0
0
30
60
90
120
Placebo
180
210
240
270
300
330
360
390
180
293
169
287
131
218
420
Time to first diarrhoea advers event (days)
No. of patients
Nintedanib 150mg bid
150
638
423
462
378
401
361
345
353
309
347
286
340
Boehringer Ingelheim International GmbH. Data on file.
255
329
242
321
221
314
199
304
191
299
50
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
51
Side effects management recommendations
1. Supportive Medications
2. Dose Adjustment
3. Dietary Changes
•
Antidiarrhoeals, such as
loperamide
•
•
Adequate hydration at first
sign of diarrhoea
•
Antiemetic therapy, such as
a dopamine receptor
antagonist or a H1antihistaminic
•
Avoidance of certain
foods/drinks, such as highfiber 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
Treatment interruption or
dose reduction (100 mg
twice daily) should be
considered if symptomatic
treatment is ineffective)
Boehringer Ingelheim International GmbH. OFEV® summary of product characteristics. 19/01/2015
Cancer Network. http://www.cancernetwork.com/oncology-nursing/diarrhoea-cancer-patients
52
Cardiac disorder adverse events
INPULSIS®-1
No of patients (%)
INPULSIS®-2
Nintedanib
150 mg bid
(n=309)
Placebo
(n=204)
Nintedanib
150 mg bid
(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)
13 (4.2)
10 (4.9)
14 (4.3)
7 (3.2)
8 (2.6)
7 (3.4)
7 (2.1)
3 (1.4)
Ischemic heart disease
Serious ischemic heart disease
•
•
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.
53
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
54