ipf treatment update › media › ... · 2% 9% 10. insipre cohort (n=438) chicago cohort (n=148)...

IPF treatment update

Ulrich Costabel

Professor of Medicine

University of Duisburg-Essen

Ruhrlandklinik

University Hospital

Essen, GermanyRuhrlandklinik

Disclosure StatementDr. Costabel has served on a Scientific

Advisory Board for the following companies:

• Actelion

• Bayer

• Boehringer Ingelheim

• Centocor

• Gilead

• GSK

• InterMune

• Roche

• Wyeth

Overview of Idiopathic Pulmonary Fibrosis (IPF)

• IPF: a progressive and fatal lung disease

– HRCT and pathology: ‘Usual Interstitial Pneumonia’ (UIP) – Age of onset 50-80 years– Incidence: 10.7/100,000 Males; 7.4/100,000 Females– 70 % smokers/exsmokers

• Natural History of IPF

– Rate of decline in lung function appears to predict mortality– Median survival only 3 years after diagnosis

• Limited therapeutic options, but hope for the future

– Corticosteroids and cytotoxic therapies: side effects– Antifibrotic drugs: 2 drugs have shown efficacy

MUC5B Promoter Polymorphism and Interstitial Lung Abnormalities

Hunnninghake GM et al, N Engl J Med 2013;368:2192-2200

General population

(n=2633)

• Chest CT

• MUC5B genotyping

Correlate:

CT with MUC5B

Od

ds

ra

tio

MUC5Bminor allele

ILD

2.8

6.3

definite fibrosis

% o

f p

ati

en

ts

ILD on CT

<50 yrs >50 yrs

2%

9%10 10

INSIPRE cohort (n=438) Chicago cohort (n=148)

Peljto et al, JAMA 2013

Survival in IPF by MUC5B Genotypes

IPF: Goals of Treatment

• Stop disease progression

• Prolong survival

• Prevent acute exacerbations

• Reduce symptoms

Treatment of IPF:

a dynamic field since 2011

• 2011:

– Pirfenidone in

– Triple therapy out

– Anticoagulants out

• 2014 :

– Nintedanib, a tyrosine kinase inhibitor of the FGF, PDGF and VEGF

receptors, has shown consistent positive effects in 2 phase III trials

(INPULSIS trials)

– Pirfenidone: evidence on efficacy and safety observed in previous

studies reinforced (ASCEND trial)

– NAC monotherapy out (PANTHER trial)

Raghu et al., ATS, 19.5.2015

Negative Recommendation (strong):

a. Anticoagulation (warfarin) (⊕⊕⊝⊝, low confidence in effect estimates).

b. Imatinib (⊕⊕⊕⊝, moderate confidence in effect estimates).

c. Prednisone, azathioprine, and N-acetylcysteine (⊕⊕⊝⊝, low confidence

in effect estimates).

d. Ambrisentan (⊕⊕⊝⊝, low confidence in effect estimates).

Negative Recommendation (conditional):

a. Sildenafil (⊕⊕⊕⊝, moderate confidence in effect estimates.b. Macitentan, Bosentan (⊕⊕⊝⊝, low confidence in effect estimates.

Positive Recommendation (conditional):

a. Nintedanib (⊕⊕⊕⊝, moderate confidence in effect estimates.b. Pirfenidone (⊕⊕⊕⊝, moderate confidence in effect estimates.

Updated evidence syntheses related to N-acetylcysteine monotherapy (negative, conditional)

and anti-acid therapy (positive, conditional) were presented to the panel and both

recommendations were left unchanged from the 2011 guidelines.

IPF International Guideline – Update 2015Raghu et al, AJRRCM 2015

Natural History of IPF and

Prognostic Factors

Natural History of IPF

Acute

worsening

Rapid progression

Slow progression

Dis

ea

se

pro

gre

ssio

n

Time

StableD

ise

as

e p

rog

res

sio

n

Time

From Collard HR et al. Am J Respir Crit Care Med (2007)

HR-CT in acute exacerbation of IPF

IPF: Acute Exacerbation

• Incidence: 5 % per year

• Mortality: 70-90 %

Kim 2006, Okamoto 2006, Kondoh 2006

FVC as

Prognostic Factor

IPF: FVC Decline and Mortality

Decline in %FVC in the

preceding 24 weeks

Mortality in the

subsequent 48 weeks

0 – 4.9 %

5 – 9.9 %

> 10 %

5 %

12 %

24 %

du Bois et al, AJRCCM 2011

The New Era

of IPF Treatment:

Two Approved Drugs

• Pirfenidone is an orally-available small molecule

• Pirfenidone is active in cell cultures and several animal models of fibrosis– Including lung, liver, heart, and kidney– Active at clinically relevant exposures– ~40 peer reviewed preclinical publications

• Inhibits TGF- and TNF-a

Pirfenidone: key points

Pirfenidone:The first approved IPF drug

Pirfenidone (Pirespa ) approved for IPF patients in Japan (October 2008)

Pirfenidone (Esbriet ) approved for IPF patients in Europe (February 2011)

Pirfenidone (Esbriet ) approved for IPF patients in USA (October 2014)

Therapeutic indications: for mild- to moderate IPF in adults (in Europe)

Should be initiated and supervised by a physician specialized in treatment of IPF

18

Mean Change in % Predicted FVC Progression-free Survival Time

Mean Change in 6MWT Distance

Week

0

-10

-20

-30

-40

-50

-60

-70

-80

-900 12 24 36 48 60 72

Week

Mean

Ch

an

ge i

n 6

MW

D (

m)

Perc

en

t o

f P

ati

en

tsPFD 2403 (n=345)

Placebo (n=347)

100

80

60

40

20

00 12 24 36 48 60 72 84 96 108 120

Week

PFD 2403 (n=345)

Placebo (n=347)

Categorical Decline in FVC and 6MWD

60

40

20

0% FVC ≥ 10% 6MWD ≥ 50 m

CAPACITY Pirfenidone trials: Pooled Efficacy Results

Perc

en

t o

f P

ati

en

ts

PFD 2403 mg/d (n=345)

Placebo (n=347)

PFD 2403 (n=345)

Placebo (n=347)

P=0.005

P=0.001

P=0.003

P=0.001

P=0.025

HR 0.74

720

0

-5

-10

-15 12 24 36 48 60

Mean

Ch

an

ge f

rom

Baselin

e (

%)

Noble et al, Lancet 2011

ASCEND Trial

NEJM 2014;370:2083

ASCEND Trial

ASCEND:

• FVC ≥ 50% and ≤ 90%

• DLco ≥ 30% and ≤ 90%

• FEV1/FVC ratio ≥ 0.80

• Time since IPF diagnosis ≥ 6 mo

Enrichment of more rapid progressors

CAPACITY:

• FVC ≥ 50%

• DLco ≥ 35%

• ratio ≥ 0.70

• ≥ 1 year

Inclusion criteria

Primary Efficacy Analysis: Treatment with pirfenidone resulted in

a significant between-group difference in the rank ANCOVA

analysis (P<0.000001)

Proportion of Patients

with ≥10% Decline in

FVC or Death (%)

Absolute Difference 2.5% 7.9% 12.3% 15.3%

Relative Difference 54.0% 58.0% 57.8% 47.9%

Rank ANCOVA p-value <0.000001 <0.000001 0.000002 <0.000001

King et al. N Engl J Med 2014;370:2083–92

Absolute Difference, 116 mL/yr

Relative reduction: 41.5%

P<0.0001*

* Linear slope analysis: Mixed model with linear time effect adjusted for age, height, and sex

Annual Rate of FVC

Change (mL/yr)

Supportive Analysis of the primary endpoint:

Annual rate of FVC decline at week 52 favored Pirfenidone

(Linear Slope Analysis)

-164 mL/yr

Figures corrected

as per NEJM

erratum Aug 2014


6-Minute Walk Distance: Significant between-group

difference in the change from baseline to week 52

Absolute Difference 3.7% 10.9% 10.9% 9.8%

Relative Difference 24.1% 39.7% 31.8% 27.5%

Rank ANCOVA p-value* 0.401 0.119 0.041 0.036

* Tested for multiple comparisons using the Hochberg procedure

Proportion of

Patients with ≥50 m Decline

or Death

(%)


Progression-free Survival*: Pirfenidone reduced the

risk of disease progression or death by 43%

* Time to death or disease progression (confirmed ≥10% decline in FVC or confirmed ≥50 m decline in 6MWD)

† Log-rank test

Pirfenidone 276 262 243 219 144

Placebo 273 269 225 192 113

Patients at Risk:

0 13 26 39 52

Week

0

10

20

30

40

50

60

70

80

90

100

Placebo (N=277)

Pirfenidone (N=278)

P<0.001†

HR 0.57 (95% CI, 0.43–0.77)

Patients (%)


Pooled All-cause Mortality (Week 52): Treatment group

curves diverge early and continue separating throughout the

study period

Month

Cumulative Risk of

Death

(%)

Placebo (N=624)

Pirfenidone (N=623)

Patients at Risk, n

Pirfenidone

Placebo

623

624

HR 0.52 (95% CI 0.31–0.87)*

P=0.011†

* Cox proportional hazards model

† Log-rank test

618 609 596 509

619 603 586 490


Adverse events occuring in >10% of patients

in CAPACITY

Pirfenidone (n=345)

%

Placebo (n=347)

%

Nausea 36 17

Rash 32 12

Dyspepsia 19 7

Dizziness 18 10

Vomiting 14 4

Photosensitivity 12 2

Anorexia 11 4

Noble et al, Lancet 2011

Albera C, ATS 2015.

Pirfenidone reduces disease progression, with no significant differences between earlier and

later/more advanced disease groups

Pirfenidone: Summary

• Pirfenidone was the first approved drug for treatment of IPF

• Pirfenidone was tested in 5 randomized placebo-controlled trials including more than 1.600 IPF patients

• Pirfenidone reduced disease progression and 1-year-

mortality.

• The adverse events support a favourable risk-benefit ratio

- increased GI und photosensitivity/skin reactions

- only few leading to withdrawal

New Approved Therapy for IPF

Nintedanib:

Tyrosine kinase inhibitor

(PDGF, FGF, VEGF)

Nintedanib: a potent intracellular tyrosine kinase inhibitor

• Nintedanib targets the VEGF, FGF and PDGF receptors

• Nintedanib acts by blocking the intracellular ATP binding site of the receptors and with it activation and signalling

Hilberg et al. Cancer Res 2008;68:4774–82; Wollin et al. J Pharmacol Exp Ther 2014;349:209–20.

Richeldi et al, N Engl J Med 2011;365:1079–87.

TOMORROW

TOMORROW: nintedanib 150 mg bid was associated with a reduced annual rate of decline in FVC


Difference between nintedanib 150 mg bid and placebo: p=0.064 vs placebo

(pre-specified primary multiplicity-corrected analysis [closed testing]);

p=0.014 vs placebo (pre-specified hierarchical testing).

TOMORROW: nintedanib 150 mg bid was associated with fewer acute exacerbations


*p=0.02 vs placebo.

Richeldi et al. N Engl J Med 2014;370:2071–82.

INPULSIS®-1 and INPULSIS®-2

INPULSIS®: two replicate, randomised, placebo-controlled, Phase III trials in patients with IPF

• Primary endpoint

– Annual rate of decline in 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


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% predicted

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

ADefinite honeycomb lung destruction with basal and peripheral

predominance

BPresence 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

Richeldi L, et al. Respir Med. 2014;108:1023-1030; Richeldi L, et al. N Engl J Med. 2014;370:2071-2082.

A. Honeycombing

B. No honeycombing –but reticulation and traction bronchiectasis

Annual Rate of Decline and Change from Baseline

in FVC in INPULSIS-1

Richeldi et al, NEJM 2014

Annual Rate of Decline and Change from Baseline

in FVC in INPULSIS-2


Time to first acute exacerbation (investigator-reported): INPULSIS™-1

bid, twice daily; CI, confidence interval; HR, hazard ratio.

Nintedanib 150 mg bid (n=309) Placebo (n=204)

Patients with ≥1 acute exacerbation, n (%) 19 (6.1) 11 (5.4)

HR 1.15

(95% CI; 0.54, 2.42)

P=0.6728

0 30 60 90 120 150 180 210 240 270 300 330 360 373

Time to first investigator-reported acute exacerbation (days)

0

1

2

3

4

5

6

7

8

9

10

11

12

13

1415

Cum

ula

tive

incid

en

ce o

f firs

t in

ve

stiga

tor-

rep

ort

ed

acu

te e

xa

ce

rba

tion

(%

)

No. of patients

Nintedanib 309 306 304 292 290 288 283 282 280 275 271 267 258 233

Placebo 204 202 200 197 197 197 193 191 191 188 186 181 178 170

Placebo

Nintedanib 150 mg bid

Richeldi L, et al. N Engl J Med. 2014;370:2071-2082.

No. of patients

Nintedanib 329 326 323 317 315 307 306 302 300 295 291 286 279 259

Placebo 219 217 215 211 210 206 200 198 195 193 190 186 181 171

Time to first acute exacerbation (investigator-reported): INPULSIS™-2



HR 0.38

(95% CI; 0.19, 0.77)

P=0.0050

Placebo


0

1

2

3

4

5

6

7

8

9

10

11

12

13

1415

Cum

ula

tive

incid

en

ce o

f firs

t in

ve

stiga

tor-

rep

ort

ed

acu

te e

xa

ce

rba

tion

(%

)

0 30 60 90 120 150 180 210 240 270 300 330 360 373

Time to first investigator-reported acute exacerbation (days)

bid, twice daily; CI, confidence interval; HR, hazard ratio.Richeldi L, et al. N Engl J Med. 2014;370:2071-2082.

Time to first acute exacerbation (investigator-reported): pooled data



HR 0.64

(95% CI; 0.39, 1.05)

P=0.0823

Placebo


0

1

2

3

4

5

6

7

8

9

10

11

12

13

1415

Cum

ula

tive

incid

en

ce o

f firs

t in

ve

stiga

tor-

rep

ort

ed

acu

te e

xa

ce

rba

tion

(%

)

0 30 60 90 120 150 180 210 240 270 300 330 360 373

Time to first investigator-reported acute exacerbation (days)No. of patients

Nintedanib 638 632 627 609 605 595 589 584 580 570 562 553 537 492

Placebo 423 419 415 408 407 403 393 389 386 381 376 367 359 341

bid, twice daily; CI, confidence interval; HR, hazard ratio.Richeldi L, et al. N Engl J Med. 2014;370:2071-2082.

Time to first confirmed or suspected acute

exacerbation per adjudication (pooled data)

Patients with ≥ 1AE:

-N= 12 (1.9%) in Nindetanib arm (N=638)

-N= 24 (5.7%) in placebo arm (N=423)


Pooled INPULSIS® trials:all-cause mortality


PlaceboNintedanib 150 mg bid

HR 0.70

(95% CI; 0.43, 1.12)

p=0.1399

Adverse events occuring in >10% of patients

in INPULSIS

Nintedanib (n=638)

%

Placebo (n=223)

%

Diarrhea * 62 18

Nausea 24 7

Vomiting 12 3

Decreased appetite 11 6

Weight loss 10 4

* Fewer than 5% discontinued due to diarrhea


Nintedanib: summary

• This clinically relevant effect of nintedanib on disease progression is further supported by:

– A numerical reduction in the risk of acute exacerbations

– A significantly reduced risk of adjudicated confirmed or suspected exacerbations

– A numerical reduction in all-cause mortality (pooled INPULSIS®)

– Consistent positive results across a range of lung function endpoints and sensitivity analyses

• Nintedanib was associated with a manageable safety profile

Nintedanib consistently slows disease progression in IPF

by significantly reducing the annual decline in lung

function by approximately 50%


Subgroup analyses of rate of

decline in FVC

Nintedanib demonstrated a consistent effect on the annual

rate of decline in FVC across all pre-specified subgroups

Costabel U et al. Am J Respir Crit Care Med 2016.

Costabel U et al. Am J Respir Crit Care Med 2015; epub ahead of print.

Pre-specified subgroup analysis by baseline FVC ≤70% vs

>70% predicted

Ad

juste

d a

nn

ua

l ra

te (

SE

) o

f d

eclin

e in

FV

C (

mL

/ye

ar)

Nintedanib Placebo

Treatment-by-time-by-

subgroup interaction

p=0.9505

∆113.5 mL

(95% CI: 51.3, 175.7)

FVC ≤70% predicted

∆109.0 mL

(95% CI: 68.2, 149.9)

n=207 n=154 n=431 n=269

FVC >70% predicted

Kolb M et al. Presented at American Thoracic Society International Congress, Denver, Colorado, USA, 15–20 May 2015.

Subgroup analysis by baseline FVC ≤90% vs >90%

predicted

Ad

juste

d a

nn

ua

l ra

te (

SE

) o

f d

eclin

e in

FV

C (

mL

/ye

ar)

Nintedanib Placebo

FVC ≤90% predicted

n=472 n=315 n=166 n=108

FVC >90% predicted



p=0.5300

∆102.1 mL

(95% CI: 61.9, 142.3)

∆133.1 mL

(95% CI: 68.0, 198.2)

*And traction bronchiectasis.

Raghu G et al. Presented at American Thoracic Society International Congress, Denver, Colorado, USA, 15–20 May 2015.

Subgroup analysis by HRCT diagnostic subgroups

n=425 n=298 n=213 n=125

Honeycombing on HRCT and/or confirmation of

UIP pattern by surgical lung biopsyFeatures of possible UIP pattern* on

HRCT and no surgical lung biopsy

Nintedanib Placebo

Ad

juste

d a

nn

ua

l ra

te (

SE

) o

f d

eclin

e in

FV

C (

mL

/ye

ar)



p=0.8139

∆117.0 mL

(95% CI: 76.3, 157.8)

∆98.9 mL

(95% CI: 36.4, 161.5)

Subgroup analysis by presence/absence of

honeycombing on HRCT at baseline

Ad

juste

d a

nn

ua

l ra

te (

SE

) o

f d

eclin

e in

FV

C (

mL

/ye

ar)

Nintedanib Placebo



p=0.6177

∆95.0 mL

(95% CI: 49.0, 141.0)

Honeycombing on HRCT

∆127.9 mL

(95% CI: 76.8, 179.1)

n=326 n=241 n=312 n=182

No honeycombing on HRCT

Case A et al. Presented at CHEST, Montreal, Canada, 24–28 October 2015.

Cottin V et al. Presented at International Colloquium on Lung and Airway Fibrosis, Mont Tremblant, Canada, 20–24 September 2014.

Subgroup analysis by presence/absence of

emphysema at baseline

Emphysema at

baseline

No emphysema at

baselinen=254 n=166 n=384 n=257

Nintedanib Placebo

Ad

juste

d a

nn

ua

l ra

te (

SE

) o

f d

eclin

e in

FV

C (

mL

/ye

ar)



p=0.5199

∆102.0 mL

(95% CI: 43.2, 160.9)

∆115.4 mL

(95% CI: 73.8, 157.1)

Subgroup analyses of time to

first acute exacerbation

Pre-specified subgroup analyses of time to first

investigator-reported acute exacerbation

Costabel U et al. Am J Respir Crit Care Med 2016.

Time to first investigator-reported acute exacerbation by

baseline FVC ≤70% vs >70% predicted

Costabel U et al. Am J Respir Crit Care Med 2016

FVC ≤70% predicted - nintedanibFVC ≤70% predicted - placebo

FVC >70% predicted - nintedanibFVC >70% predicted - placebo

IPF Phase III Trials in Comparison

ASCEND INPULSIS

68 yr, 79% men, 64% smokers 67 yr, 79% men, 72% smokers

95% definite UIP pattern on

HRCT

97% UIP pattern on HRCT

40% emphysema on HRCT

FEV1/FVC ≥0.8 FEV1/FVC ≥0.7

30% SLB performed 21% SLB performed

FVC 68% pred.

DLCO 44% pred.

FVC 82% pred.

DLCO 47% pred.

35% pts screened enrolled 70% pts screened enrolled

Current IPF Treatment Options

Pirfenidone Nintedanib

EMA approval

FDA approval

February 2011

October 2014

January 2015

October 2014

Clinical trials

CAPACITY 1 & 2 (Phase 3)1

ASCEND (Phase 3)2

Shionogi (Phase 3)3

TOMORROW (Phase 2)5

INPULSIS (Phase 3)6

Most common

adverse eventsNausea, photosensitivity with rash1 Diarrhea, nausea6

Dosing801 mg (3 capsules)

three times daily4

150 mg (two capsules)

twice daily7

Molecular target Unknown Tyrosine kinase inhibitor8

5. Richeldi ,L et al. NEJM 2011;365:1079–1087

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

7. OFEV Summary of Product Characteristics. Boehringer Ingelheim. October

2014

8. Hilberg F, et al. Cancer Res 2008;68:4774–4782

1. Noble PW, et al. Lancet 2011;377:1760-1769

2. King TE, et al. NEJM 2014;371:1172

3. Taniguchi H, et al. ERJ 2010; 35: 821–829

4. Esbriet full Prescribing Information. InterMune, Inc. October

2014

Key Challenges and Questions 2016

• How to ensure prompt and correct diagnosis?

• Combination therapy?

• Which drug first?

• When should treatment be started?

• When should treatment be stopped?

• Current antifibrotic drugs cannot cure IPF

• They have shown to slow disease progression by 50%,

on average, in clinical trial populations but not in every

patient

• Some patients will not respond to treatment

• Should a stable patient with mild disease

be treated?

The problem

Spaghetti plot of change in FVC % predicted from baseline to 1 year (pooled placebo population)*

Change f

rom

baselin

e

(FV

C %

pre

dic

ted)

-30

-20

-10

0

10

20

Months

0 3 6 9 12

*Randomly selected sample of 50 patients. Nathan et al. Am J Respir Crit Care Med 2015;191:A1016.

How many patients with IPF

are stable or improve?

%FVC decline ≥10% or death No decline in %FVC

22.7

9.7

16.5

31.8

*Rank analysis of covariance p-value <0.000001

ASCEND Trial: %FVC change at Week 52

Pirfenidone

(N=278)

Placebo

(N=277)

Pirfenidone

(N=278)

Placebo

(N=277)

King TE Jr et al. New Engl J Med 2014;370:2083-2092 (Supplement)

INPULSIS®: patients with no absolute decline of FVC >5% predicted at week 52

OR 1.85(95% CI: 1.28, 2.66)

p=0.0010

OR 1.79(95% CI: 1.26, 2.55)

p=0.0011

OR 1.84(95% CI: 1.43, 2.36)

p<0.0001

Nintedanib 150 mg bid Placebo

INPULSIS®-1 INPULSIS®-2 Pooled data

n=309 n=204 n=329 n=219 n=638 n=423

Resp

on

ders

(%

)

Patients with missing data at week 52 were considered to be non-

respondersRicheldi et al. N Engl J Med 2014;370:2071–82.

Is antifibrotic therapy effective

in stable IPF?

Intraindividual response to pirfenidone

Annual FVC decline >10%

N=76

Loeh B et al. Am J Respir Crit Care Med 2015;191:110-113

N=71

Intraindividual response to pirfenidone

Annual FVC decline 10%

Loeh B et al. Am J Respir Crit Care Med 2015;191:110-113

How frequent is early ILD

in the elderly?

• Consecutive computed tomography study in

asymptomatic volunteers aged >75 years

• Subpleural, basal, reticular ILD in 24 / 40 (60%)

• Do they all have IPF?

• Should they all be treated prophylactically?

Lung morphology in the elderly

Copley SJ et al. Radiology 2009;251:566-573ILD, interstitial lung disease

Key Challenges and Questions 2016

• How to manage side effects?

• Long term treatment effective?

• What are realistic treatment expectations?

• Can we predict response to therapy?

Long-term efficacy?

INPULSIS® and INPULSIS®-ON: study designs

• Patients who completed the 52-week treatment period and follow-up visit 4 weeks later in an INPULSIS® trial were eligible to enter INPULSIS®-ON

• Dose reduction to 100 mg bid and treatment interruption were allowed to manage adverse events; dose re-escalation to 150 mg bid was permitted

Continuing nintedanib (n=430)

Open-label extension

INPULSIS®-ON

Double-blind, placebo-controlled

INPULSIS®

Nintedanib 150 mg bid (n=638)

No treatment*

Placebo (n=423)

ScreeningR 3:2 ratio

Week 52

Initiating nintedanib (n=304)

*Per protocol, the off-treatment period between INPULSIS® and INPULSIS®-ON could be between 4 and 12 weeks.

Crestani et. al. Presented at the European Respiratory Society International Congress, Amsterdam, The Netherlands,

September 26–30, 2015

Interim Analysis: November 2014

Exposure in INPULSIS® and INPULSIS®-ON

• Mean (SD; min–max) total duration of exposure for patients treated with nintedanib in both INPULSIS® and INPULSIS®-ON was 29.2 (6.6; 11.9–40.6) months

INPULSIS® INPULSIS®-ON

Nintedanib

(n=638)

Placebo

(n=423)

Continuing

nintedanib

(n=430)

Initiating

nintedanib

(n=304)

Exposure, months

Mean (SD) 10.3 (3.4) 10.8 (2.8) 17.2 (6.6) 16.0 (7.3)

Minimum, maximum 0.0, 12.7 0.0, 13.1 0.1, 28.8 0.0, 28.8

Crestani et. al. Presented at the European Respiratory Society International Congress, Amsterdam, The Netherlands, September 26–30,

2015

Change from baseline in FVC at week 52 in INPULSIS®

and at week 48 in INPULSIS®-ONM

ea

n (

SE

M)

ob

se

rve

d c

ha

ng

e fro

m b

ase

line

in

FV

C (

mL

)

INPULSIS®-ONINPULSIS®

Nintedanib

n=519

Placebo

n=345

Continuing

nintedanibn=352

Initiating

nintedanibn=233

Crestani et al. ERS 2015

Real-life experience with

antifibrotic therapy

Pirfenidone for IPF in the real world

– Number of patients: 45

– Average duration of treatment: 48 weeks

Safety and tolerance

– Side effects: 58%

– Dose adjustment: 18%

Discontinuation

– Total: 33%

– Due to progression: 20%

– Due to side effects: 13%

Real-world scenario

Bonella F et al. Dtsch Med Wochenschr 2013;138:518-523

Is response to IPF therapy

predictable?

TOLLIP, MUC5B and the Response to

N-acetylcysteine among Individuals with

Idiopathic Pulmonary Fibrosis

Justin M. Oldham , MD 1,2 , Shwu-Fan Ma , PhD 1 , Rekha Vij , MD 1 , Yong Huang , MD 1 ,

Ganesh Raghu , MD 3 , Kevin J. Anstrom , MD, PhD 4 , Fernando J. Martinez , MD, MS 5 ,

Imre Noth , MD 1

1. Department of Medicine, Section of Pulmonary and Critical Care Medicine; The

University of Chicago

2. Department of Internal Medicine, Weill Cornell Medical School

3. Duke Clinical Research Institute; Duke University

4. Department of Medicine, Division of Pulmonary and Critical Care Medicine; The

University of Washington Medical Center

5. Department of Medicine, The University of Colorado

Am J Respir Crit Care Med 2015; 192: 1475-82

http://ajrccm.atsjournals.org/

http://ajrccm.atsjournals.org/

• 154 PANTHER participants genotyped for 5 SNPs on Chr11:

rs35705950 in MUC5B and rs5743890, rs5744034, rs3750920 and

rs5743854 in TOLLIP

• Minor allele frequency (MAF) of each SNP compared to that of 868

IPF GWAS patients.

• Minor allele counts compared between the prednisone/azathioprine/N-

acetylcysteine, N-acetylcysteine (NAC) and placebo arms

Genetic Heterogeneity Among Patients

Enrolled In The PANTHER-IPF Clinical Trial

Oldham et al, AJRRCM 2015

Composite endpoint-free survival between NAC and

Placebo groups after stratification by

rs3750920 (TOLLIP) genotype


HR 3.23

p=0.10

Composite endpoint-free survival between NAC and

Placebo groups after stratification by

rs3750920 (TOLLIP) genotype


HR 0.14

p=0.03

Interstitial and Rare Lung Disease Unit

Prof. U. Costabel

Dr. F. Bonella

Dr. T.E. Wessendorf

Dr. E. Börner

Dr. M. Cuyas

Dr. X. Long

Prof. J. Guzman

Dr. S. Ohshimo

Prof. D. Theegarten

Mrs. L. Ngoc Tran

Thank you for your attention

ipf treatment update › media › ... · 2% 9% 10. insipre cohort (n=438) chicago cohort (n=148)...

Documents