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

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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



Research Grants




Speaker’s Fees



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)



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)


(93)


(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


**

** 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



Placebo

***p<0.001 vs placebo (unadjusted)

***

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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


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

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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)



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)




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



Research Grants




Speaker’s Fees



15

-300

-250

-200

-150

-100

-50

0

-114.7

-239.9

-113.6

-207.3

Ad

jus

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an

nu

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ate

of

de

clin

e in

FV

C m

L/y

ea

r

Annual rate of decline in FVC


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)


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


Ad

jus

ted

ab

solu

te m

ean

ch

an

ge

fro

m

bas

elin

e in

FV

C %

pre

dic

ted



3.1 % predicted(95% CI: 1.9, 4.3)

p<0.0001

3.2 % predicted(95% CI: 2.1, 4.3)

p<0.0001


16

17

20 4 6 12 24 36 52

-50

-100

-150

-200

-250

Primary efficacy endpoint in pooled data


109.9 mL/year(95% CI: 75.9, 144.0)

p<0.0001


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

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

19

Disclosures



Research Grants




Speaker’s Fees



Key inclusion criteria

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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


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Demographic data and baseline characteristics



(n=309)

Placebo (n=204)


(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)


*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

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ate

(SE

) o

f d

ecli

ne

in F

VC

(m

L/y

ear)



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

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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)


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

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Eligibility Criteria based on HRCT


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)


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.

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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.

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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

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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


p=0.5199

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

29

Disclosures



Research Grants




Speaker’s Fees



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%

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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


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)

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

36

Disclosures



Research Grants




Speaker’s Fees



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)


3:2 ratio

523624126420

987654321Visit

Week

Screening




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


• 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

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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



Placebo (n=508)

Patients who died, n (%) 42 (5.8) 42 (8.3)


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


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


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


45

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

46

Disclosures



Research Grants




Speaker’s Fees



47

Patient disposition



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)


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


The most common adverse events were of gastrointestinal natureMost frequent adverse events (incidence of >10% in any treatment group)


No of patients (%) Nintedanib 150 mg bid

(n=309)

Placebo (n=204)


(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


(n=309)

Placebo(n=204)


(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)


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 (

%)


51

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

52

Side effects management recommendations


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

http://www.cancernetwork.com/oncology-nursing/diarrhea-cancer-patients

http://www.cancernetwork.com/oncology-nursing/diarrhea-cancer-patients

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Cardiac disorder adverse events



(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)


• 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

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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

Documents

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