1
Interpreting INPULSIS® resultsSpeaker: Luca RicheldiProfessor of Respiratory Medicine
Chair of Interstitial Lung Disease
University of Southampton, United Kingdom
2
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
3
Importance of the INPULSIS® trialsProf Richeldi, how would you describe the overall importance of the INPULSIS® trials?
4
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
5
TOMORROW: Study design
Richeldi L et al. N Engl J Med 2011; 365: 1079-1087.
Nintedanib 50 mg qd(n=87)
N=432Randomized
1:1:1:1:1
• 92 sites in 25 countries (non-US)
• Study medication was administered for 52 weeks
Nintedanib 50 mg bid(n=86)
Nintedanib 100 mg bid(n=86)
Nintedanib 150 mg bid(n=86)
ScreeningBefore Day-4
Day 1
Placebo(n=87)
Review by DMC
Review by DMC
Review by DMC
DMC: Data Monitoring Committee
RANDOMIZATION
6
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)
-0.3
-0.25
-0.2
-0.15
-0.1
-0.0500000000000001
-5.55111512312578E-17
-0.19-0.17
-0.2
-0.17
-0.04
An
nu
al F
VC
de
clin
e,
L/y
ea
r[M
ea
n (
SE
)]
TOMORROW: Decline in FVC by final dose
Richeldi L et al. N Engl J Med 2011; 365: 1079-1087.
**
** p<0.01 vs. placebo (hierarchical testing procedure)
7
0 50 100 150 200 250 300 350-0.25
-0.2
-0.15
-0.1
-0.05
0
0.05
0.1
Day
Ch
an
ge
in F
VC
, L
/ye
ar
[Me
an
(S
E)]
TOMORROW: Absolute change in FVC from baseline over time
Richeldi L et al. N Engl J Med 2011; 365: 1079-1087.
Nintedanib 150 mg bid
Placebo
***p<0.001 vs placebo (unadjusted)
***
8
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.
9
INPULSIS®: two replicate, randomized, double-blind, 52-week, phase III trials recruited 1066 patients
• 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
4
Visit
Follow-up
Nintedanib 150 mg bid (n=638)
Placebo (n=423)
5236241262
Screening
560Week
1 2 3 4 5 6 7 8 9
3:2 ratioR
10
Methodology and analysis of the annual rate of decline in FVC
Richeldi L et al, Respir Med 2014; 108: 1023-30
Baseline 2 4 6 12 24 36 52 Follow up
FV
C (
mL)
The treatment effect was determined using mean slopes for each treatment group
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
• 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
11
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)
Sensitivity analyses for annual rate of decline in FVC in INPULSIS® -1
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.
-200 -150 -100 -50 0 50 100 150 200
Favours placebo Favours nintedanib 150 mg bid
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)
Sensitivity analyses for annual rate of decline in FVC in INPULSIS® -2
18Richeldi L, et al. N Engl J Med 2014;370:2071–2082.
-200 -150 -100 -50 0 50 100 150 200
Favours placebo Favours nintedanib 150 mg bid
bid, twice daily; FVC, forced vital capacity.
13
Primary endpoint
Could you please discuss the overall efficacy of nintedanib reported in the INPULSIS® trials?
14
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
15
-300
-250
-200
-150
-100
-50
0
-114.7
-239.9
-113.6
-207.3
Ad
jus
ted
an
nu
al r
ate
of
de
clin
e in
FV
C m
L/y
ea
r
Annual rate of decline in FVC
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.
93.7 mL/year(95% CI: 44.8, 142.7)
p=0.0002
INPULSIS®-1 INPULSIS®-2
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.
125.3 mL/year(95% CI: 77.7, 172.8)
p<0.0001
Absolute changes from baseline in FVC % predicted at week 52
-8
-6
-4
-2
0
-2.8-3.1
-6.0 -6.2
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.
Ad
jus
ted
ab
solu
te m
ean
ch
an
ge
fro
m
bas
elin
e in
FV
C %
pre
dic
ted
Nintedanib 150 mg bid (n=307)Placebo (n=204)
Nintedanib 150 mg bid (n=327)Placebo (n=217)
3.1 % predicted(95% CI: 1.9, 4.3)
p<0.0001
3.2 % predicted(95% CI: 2.1, 4.3)
p<0.0001
INPULSIS®-1 INPULSIS®-2
16
17
20 4 6 12 24 36 52
-50
-100
-150
-200
-250
Primary efficacy endpoint in pooled data
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.
109.9 mL/year(95% CI: 75.9, 144.0)
p<0.0001
Nintedanib 150 mg bid (n=638)Placebo (n=423)
Ad
jus
ted
an
nu
al r
ate
(SE
) o
f d
ecli
ne
in
FV
C (
mL
/yea
r)
-300
-250
-200
-150
-100
-50
0
50 Nintedanib 150 mg bid
Placebo
50
0
Me
an
(S
E)
obse
rved
ch
ang
e f
rom
bas
elin
e in
FV
C (
mL
)
No. pf patients
Nintedanib
Placebo
626 616 613 604 587 569 519
417 408 407 403 395 383 345
Week
18
Trial populationHow relevant to clinical practice is the trial population of the INPULSIS® trials?
19
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
Key inclusion criteria
20
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.
21
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)
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)
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.
*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.
22
-300
-250
-200
-150
-100
-50
0
-119.7 -111.3
-233.2 -220.3
Costabel U, et al. Oral presentation at the ERS International Congress, Munich, 6 – 10 September 2014
Ad
jus
ted
an
nu
al r
ate
(SE
) o
f d
ecli
ne
in F
VC
(m
L/y
ear)
Nintedanib 150 mg bid (n=207)Placebo (n=154)
Nintedanib 150 mg bid (n=431)Placebo (n=269)
Treatment by time by subgroup interaction
p=0.9505
∆113.5 mL (95% CI: 51.3,175.7)
FVC ≤70% predicted FVC >70% predicted
∆109.0 mL(95% CI: 68.2, 149.9)
Nintedanib was effective independent of lung function impairment at baselineAnnual rate of decline in FVC by baseline FVC 70% predicted
Nintedanib was effective independent of lung function impairment at baseline
23
Series1
-300
-250
-200
-150
-100
-50
0
-223.6 -224.6
-121.5
-91.5
Ad
jus
ted
an
nu
al r
ate
(S
E)
of
de
clin
e
in F
VC
(m
L/y
ea
r)Annual rate of decline in FVC by baseline FVC 90% predicted
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
FVC ≤90% predicted FVC >90% predicted
Placebo(n=315)
Nintedanib(n=472)
Placebo(n=108)
Nintedanib(n=166)
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.
Patients with no honeycombing on HRCT
24
Eligibility Criteria based on HRCT
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.
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
A Definite honeycomb lung destruction with basal and peripheral predominance
BPresence of reticular abnormality and traction bronchiectasis
consistent with fibrosis with basal and peripheral predominance
CAtypical features are absent, specifically nodules and consolidation. Ground glass
opacity, if present, is less extensive than reticular opacity pattern
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
Annual rate of decline of FVC by HRCT and biopsy diagnostic criteria
Nintedanib was effective independent of the presence of honeycombing on HRCT and/or biopsy
Series1
-300
-250
-200
-150
-100
-50
0
-225.7-221.0
-108.7-122.0
Ad
jus
ted
an
nu
al r
ate
(S
E)
of
de
clin
e
in F
VC
(m
L/y
ea
r)
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.
Honeycombing on HRCT and/or confirmation of UIP by biopsy
Placebo(n=298)
Nintedanib(n=425)
Placebo(n=125)
Nintedanib(n=213)
No honeycombing on HRCTand no biopsy
Raghu G, et al. . Am J Respir Crit Care Med 191;2015:A1022.
26
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.
27
In the nintedanib group the annual rate of decline in FVC was comparable for patients with and without emphysema at baseline
-300
-250
-200
-150
-100
-50
0
-118.8
-105.1
-234.2
-207.2
Cottin V, et al. Abstract presented at the International Colloquium on Lung and Airway Fibrosis, Mont Tremblant, Canada, 20–24 September 2014.
Ad
jus
ted
an
nu
al r
ate
(SE
) o
f d
ecli
ne
in F
VC
(m
L/y
ear)
Nintedanib 150 mg bid Placebo
∆115.4 mL (95% CI:
73.8,157.1)
No emphysema at baseline Emphysema at baseline
∆102.0 mL(95% CI:
43.2,160.9)
n=384 n=257 n=254 n=166
Treatment by time by subgroup interaction
p=0.5199
28
ExacerbationsHow do you interpret the INPULSIS® results with regard to acute exacerbations of IPF?
29
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
30
IPF: Cause of death
Modified from Natsuizaka M, et al. Am J Respir Crit Care Med 2014;190:773–779.
Acute exac-erbation;
40%
Chronic respiratory failure; 24%
Lung cancer; 11%
Pneumonia; 7%
Cardiovascular disease; 3%
Other; 10%
Unknown; 5%
31
IPF: Natural history
Adapted from King TE, et al. Lancet 2011;378:1949–1961.
Patient becomes symptomatic
Acute exacerbations
IPF + emphysema
Rapid
Time
Microinjuries to the lung
Asymptomatic
Dis
ease
Pro
gres
sion
Slow
32
Nintedanib reduced the risk of acute IPF exacerbations
Incidence of investigator-reported acute IPF exacerbations in the INPULSIS® trials
Boehringer Ingelheim International GmbH. OFEV® summary of product characteristics. 19/01/2015
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
33
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
*Collard HR, et al. Am J Respir Crit Care Med. 2007;176:636-643.
34
Time to first confirmed/suspected acute exacerbation per adjudication: Pooled data
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.
PlaceboNintedanib 150 mg bid
HR 0.32 (95% CI; 0.16, 0.65)
p=0.0010
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
151413121110
9876543210
0 120 150 180 210 240 270 300 330 360 37330 60 90
Time to first confirmed/suspected acute exacerbation (days)
Cu
mu
lativ
e in
cid
en
ce o
f fir
st
con
firm
ed
/su
spe
cte
d a
cute
exa
cerb
atio
n
(%)
bid, twice daily; CI, confidence interval; HR, hazard ratio.
Nintedanib 150 mg bid (n=638) Placebo (n=423)
Patients with ≥1 acute exacerbation, n (%) 12 (1.9) 24 (5.7)
35
Mortality in IPFWhat is your opinion on the mortality data reported in the INPULSIS® trials?
36
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
37
Nintedanib in IPFINPULSIS® and TOMORROW trials design
Richeldi L, et al. Oral presentation at the International Colloquium on Lung and Airway Fibrosis, Mont Tremblant, Canada, 20–24 September 2014.
56523624126420
987654321Visit
Week
Screening Follow-upR
Placebo (n=423)
Nintedanib 150 mg bid (n=638)
3:2 ratio
523624126420
987654321Visit
Week
Screening
Nintedanib 150 mg bid (n=85)
Nintedanib 100 mg bid (n=86)
Nintedanib 50 mg bid (n=86)
Nintedanib 50 mg qd (n=86)
Placebo (n=85)
INPULSIS®: TWO REPLICATE; RANDOMIZED; DOUBLE-BLIND; 52-WEEK; PHASE III TRIALS
TOMORROW: A RANDOMIZED; DOUBLE-BLIND; 52-WEEK; PHASE II, DOSE-FINDING TRIAL
R1:1:1:1:1
ratio
38
Mortality as an endpoint
Richeldi L, et al. Oral presentation at the International Colloquium on Lung and Airway Fibrosis, Mont Tremblant, Canada, 20–24 September 2014.
• 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
39
All-Cause Mortality Rate in Patients with IPF
King TE, et al. Am J Respir Crit Care Med 2014;189:825–831.
Figure 1. Kaplan-Meier estimate of overall survival in the pooled placebopopulations from the INSPIRE and CAPACITY studies.
100
80
60
40
20
00 13 26 39 52 65 78 91 104
Weeks
N=622
Pe
rce
nt
Su
rviv
al
All-Cause Mortality Rate in Patients with Idiopathic Pulmonary FibrosisImplications 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
40
Statistical methodology used in TOMORROW and INPULSIS® trials
Richeldi L, et al. Oral presentation at the International Colloquium on Lung and Airway Fibrosis, Mont Tremblant, Canada, 20–24 September 2014
• 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
41
INPULSIS® trials
Richeldi L, et al. Oral presentation at the International Colloquium on Lung and Airway Fibrosis, Mont Tremblant, Canada, 20–24 September 2014.
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)
RESPIRATORY MORTALITY OVER 52 WEEKSALL-CAUSE MORTALITY OVER 52 WEEKS
HR 0.70(95% Cl; 0.46, 1.08)
P=0.0954HR 0.62
(95% Cl; 0.37, 1.06)P=0.0779
42
All cause mortality pooled data from the TOMORROW and INPULSIS® trials
Richeldi L, et al. Presented at the International Colloquium on Lung and Airway Fibrosis, Mont Tremblant, Canada, 20–24 September 2014.
Time to death due to all cause over 52 weeks
No. of patientsTime to death (days)
100
99
98
96
97
95
94
93
92
91
80
90
88
87
86
85
84
83
82
81
89
0
Kap
lan-
Mei
er e
stim
ate
of d
eath
(%
)
0 30 60 90 120 150 180 210 240 270 300 330 360 373
Nintedanib 150mg bidPlacebo
Nintedanib 150mg bidPlacebo
723
508
722 712717 702720 692704 685707 680 660698 562506 501501 490504 483496 479498 471 453487 375
HR 0.70(95% CI; 0.46, 1.08)
p=0.0954
43
Respiratory mortality pooled data from the TOMORROW and INPULSIS® trials
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.
Respiratory mortality over 52 weeks
44
Effect of nintedanib on mortalityConclusions
• 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.
45
SafetyCould you please give us your opinion on the safety of nintedanib in the treatment of IPF?
46
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
47
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
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)
Boehringer Ingelheim International GmbH. OFEV® summary of product characteristics. 19/01/2015
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.
48
Nintedanib demonstrated a favorable risk-benefit profile
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.
The most common adverse events were of gastrointestinal natureMost 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)
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)
49
Diarrhoea
INPULSIS® -1 INPULSIS®-2
No of patients (%) 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)
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) 0 (0.0) 10 (4.8) 2 (5.0)
Boehringer Ingelheim International GmbH. OFEV® summary of product characteristics. 19/01/2015
Time to first onset of diarrhoea: Pooled data
50Boehringer Ingelheim International GmbH. Data on file.
100
90
80
70
60
50
40
30
20
10
0
30 60 90 120 150 180 210 240 270 300 330 3600 390 420
No. of patients
Nintedanib 150mg bid
Placebo
638
423
462 309345 242401 199255 180286 169 131221
378 347353 321361 304329 293340 287 218314
191
299
Time to first diarrhoea advers event (days)
Kap
lan-
Mei
er e
stim
ate
of fi
rst d
iarr
hoea
adv
erse
eve
nt (
%)
Nintedanib 150mg bidPlacebo
51
Side effects can be managed effectively in most patients
Boehringer Ingelheim International GmbH. OFEV® summary of product characteristics. 19/01/2015
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
52
Side effects management recommendations
Boehringer Ingelheim International GmbH. OFEV® summary of product characteristics. 19/01/2015
Cancer Network. http://www.cancernetwork.com/oncology-nursing/diarrhoea-cancer-patients
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
53
Cardiac disorder adverse events
INPULSIS®-1 INPULSIS®-2
No of patients (%) 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)
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)
Richeldi L, et al. N Engl J Med 2014;370:2071–2082.
• 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
54
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