Carlo Vancheri

Centro Riferimento Regionale Malattie Rare del Polmone

Università di Catania

Le nuove terapie della UIP

Quanti sono i pazienti con IPF?

• In Europa ci sono tra 80.000 e 120.000pazienti con IPF

• Ogni anno si ammalano di IPF circa 35.000cittadini europei

• La malattia è lievemente più frequente nelsesso maschile

• L’IPF colpisce soggetti adulti con un piccomassimo intorno ai 65 anni

1. Meltzer EB and Noble PW. Orphanet J Rare Dis 2008;3:822.

2. Hodgson U et al. Thorax 2002;57:338342.

3. Coultas DB et al. Am J Respir Crit Care Med 1994;150:967997.

Orphanet 2010; www.orphanet.net; Eurostat News Release. 110/2010

Incidenza IPF (solo UIP) in ITALIA

Abitanti = 60.000.000

Pazienti con IPF 4.800-9.200

Popolazione residente in Sicilia = 5.042.781 abitanti

Seguendo il modello di calcolo proposto

da Raghu negli USA, si stima che

in Siciliadovrebbero esserci

da 400 a 800casi di IPF ogni

anno !!!

Popolazione residente in Sicilia = 4.087.000 abitanti

Seguendo il modello di calcolo proposto

da Raghu negli USA, si stima che

in Pugliadovrebbero esserci

da 320 a 640casi di IPF ogni

anno !!!

•Modified from: American Thoracic Society/European Respiratory Society. Am J Respir Crit Care Med 2002;165:277304;•Ryerson CJ and Collard HR. Curr Opin Pulm Med 2013;19:453459. PRC-2184

Interstitial Lung Disease (ILD)

ILD of known causes

(e.g. drugs, collagen vascular disease, exposures, genetic)

Idiopathic interstitial pneumonias (IIPs)

IPF: idiopathic pulmonary

fibrosis

Other IIPs

NSIP: non-specific interstitial pneumonia

RB-ILD: respiratory bronchiolitis interstitial

lung disease

AIP: acute interstitial pneumonia

DIP: desquamative interstitial pneumonia

COP: cryptogenic organising pneumonia

LIP: lymphocytic interstitial pneumonia

AFOP: acute fibrinous and organising

pneumonia

Granulomatous ILDs

(e.g. sarcoidosis, fungal, mycobacterial)

Unique entities

(e.g. PAP, EG and EP, LAM, capillaritis, idiopathic PPFE,

unclassifiable ILD)

55%

25%

<2%

5% <1%

10

15

%

rare

UIP

fibroblasti

spazio alveolare

pneumociti tipo I

pneumociti tipo II

macrofagi alveolari

membrana basale

cellule endoteliali

surfattante

interstizio

globuli rossi

fibroblasti

Idiopathic Pulmonary Fibrosis

Normal Lung Usual Interstitial Pneumonia

http://ajrccm.atsjournals.org/content/vol157/issue4/images/large/RCCM9707039.f2.jpeg

IL-1, TNF-

IL-8, RANTES

IL-5, GM-CSF

APC T-Linfocita

MHC II TCR

CD28

CD40

CD40L

Noxa patogena B7.2

B7.1

Proteasis, oxidants

Damage and repair

STEROIDS

IMMUNOSUPPRESSORS

PANTHER 2012 Interim Results

• Triple therapy has no benefit for FVC

• Increased risk of death

Primary Triple Therapy Placebo P-value

FVC (liters) -0.24 -0.23 0.85

Raghu G, et al. N Engl J Med. 2012;366:1968-1977.

Pro

bab

ility

Time to DeathKaplan–Meier Analysis

Weeks Since Randomization

HR 9.26 (95% CI 1.16-74.1)

P = 0.01

ATS 2011

2011-2013 2014Pre-2011

Genetic background

ACTIVATION OF FIBROBLASTS AND FIBROSIS

smoking

Alveolar cells

Altered response to damageloss of epithelial integrity Apoptosis, ER stress

Aging

The importance of a proper substrate

Come si è arrivati alla terapia dell’IPF con Pirfenidone?

PRC-2063

Possible Mechanisms of Pirfenidone Action

Hilberg O, et al. Clin Respir J. 2012;6:131-143.

TNF-αIL-6

Pirfenidone

TGF-βIL-6

MMPsCollagenases

ROIs

Collagen

• Antifibrotic

• Molecular target unclear

• Active in several animal models of fibrosis (lung,

liver, kidney)

ASCEND 2014

ATS 2011

2011-2013Pre-2011 2014

Pirfenidone Reduces Loss of FVC

<0.000001King TE, et al. N Engl J Med. 2014;370(22):2083-2092.

235 ml

428 ml

Rank ANCOVA P-value < 0.00001 at each indicated time point

Me

an C

han

ge (

ml)

Week

Riduzione del declino funzionale e poi?

PRC-2063

Pirfenidone Increased Progression-Free Survival*

King TE, et al. N Engl J Med. 2014;370(22):2083-2092.

*Progression is first occurrence of death, 10% ↓ FVC, or 50 m ↓ 6MWD

More Pirfenidone Patients Maintain Walk Distance or Survive

King TE, et al. N Engl J Med. 2014;370(22):2083-2092.

Pro

po

rtio

n o

f P

atie

nts

wit

h

≥50

m D

ecl

ine

or

De

ath

(%

)

Week

0 3 6 9 12

Month

0.0

2.5

5.0

7.5

De

ath

s (

%)

Placebo (N=624)

Pirfenidone 2403 mg/d (N=623)

Patients at Risk, n

Pirfenidone

Placebo

623 618 609 596 509

624 619 603 586 490

10.0

HR 0.52 (95% CI 0.31, 0.87)*

P=0.011†

* Cox proportional hazards model)

† Log-rank test

Pooled All-cause Mortality (Week 52): Treatment

group curves diverge early and continue separating

throughout the study period

25

MRC-2161King TE et al. N Engl J Med 2014 May 18. doi:10.1056/NEJMoa1402582

Quando dobbiamo iniziare a trattare con pirfenidone?

PRC-2063

“Wait and see or early treatment?”

Roche Medical Affairs 29

Confidential for internal use only

Natural history of disease progressionPooled placebo population

6MWD, 6-minute walk distance; FVC, forced vital capacity; HR, hazard ratio;

UCSD SOBQ, University of California—San Diego Shortness of Breath Questionnaire.

FVC < 80%

Event/TotalFVC ≥ 80%

Event/Total

FVC decline ≥ 10%

or death

99/450 (22.0%) 30/168 (17.9%)

6MWD decline ≥ 50 m

or death150/450 (33.3%) 36/168 (21.4%)

UCSD total score change

≥ 20 points or death

141/451 (31.3%) 22/169 (13.0%)

0.1 1 10

↑ Risk for FVC ≥ 80% ↑ Risk for FVC < 80%

2.68 (1.71-4.21) < 0.0001

1.67 (1.16-2.41) 0.0049

1.28 (0.85-1.92) 0.2403

HR (95% CI)

Between-

Subgroup

P Value

The risk of disease progression (especially FVC decline ≥ 10% or death) is comparable

in patients with FVC above versus below 80%

5-YEAR SURVIVAL OF IPF AND CANCER

Leukaemia

IPF

Lung

Pancreas

Skin

Thyroid

Bladder

Prostate

Lymphoma

Uterus

Kidney

Colon

Breast

1008060402005-year survival (%)

Modified by Richeldi L.

Risk factors for IPF

Susceptible individuals

Environmental and/or

occupational factors?

Cigarette smoking?

Viral infection? (Epstein-Barr)

Chronic injury? (GERD and

tractional injury)

Risk factors for cancer

Susceptible individuals

Environmental and/or

occupational factors?

Cigarette smoking?

Viral infection? (Epstein-Barr)

Chronic injury?

(wound that doesn’t heal)

• Tumour suppressor gene mutations

• Telomere shortening

Genetic alterations

• Hypermethylation of the Thy-1 promoter regionEpigenetic alterations

• Myofibroblasts recruitment and differentiation

• Myofibroblasts infiltrative ability

• Expression invasive molecules

Tissue invasion

• Self-sufficiency in growth signals• Insensitivity to growth inhibitory signals• Evasion of apoptosis• Altered cell-to-cell communications

Uncontrolled proliferation

• Activation Wnt/β-catenin pathway

• Activation PI3K/PTEN-AKT pathway

• Activation of tyrosine kinases

Signal transduction

pathways

• P53, FHIT, microsatellite instability, microRNA alterations, MUC5B

• (Loss of Thy-1 protein) invasive behaviour of fibroblasts

• Myofibroblasts behaviour• Invasive molecules

(HSP-27, laminin, fascin)

• Autocrine TGF-β production• Connexin 43 reductio

• Proliferation, differentiation, activation

Common pathways in IPF and cancer

Vancheri and Du Bois ERJ 2013

Activation of Wnt/β-catenin pathway

Activation of PI3K/AKT pathway

Activation of tyrosine kinase pathway

Common pathways in IPF and cancer

Signal transduction pathways

Overall survivalPatients with adenocarcinoma histology

100

80

60

40

20

0

322 263 203 163 131 96 72 46 25 10

336 269 184 139 101 73 55 33 15 7

Pro

bab

ilit

y o

f su

rviv

al

(%)

Nintedanib + docetaxel

Placebo + docetaxel

Median, mo 12.6 10.3

HR (95% CI) 0.83 (0.70 to 0.99)

p-value 0.0359

52.7%

44.7% 25.7%

19.1%

No. at risk

Nintedanib

Placebo

0 4 8 12 16 20 24 28 32 36

Time (months)

Presented at ASCO 2013

Effect of the kinase inhibitor nintedanib on NSCLC

Various tyrosine kinases play key roles in the pathologic activation of fibroblasts during

fibrogenesis, rendering them attractive molecular targets in the treatment of fibrosis

FIBROGENESIS

Rationale for investigating nintedanib (BIBF 1120) in IPF

• PDGF is implicated in the fibrotic process1

• Liver fibrosis was decreased in FGF-1/FGF-2 deficient mice2

• Experimental evidence in rats suggests that inhibition of VEGFR may reduce fibrosis3

1. Selman M et al. Am J Respir Cell Mol Biol 20032. Yu C et al. Am J Pathol 20033. Hamada N et al. J Immunol 2005

PDGF

Collagen deposition

FIBROSIS

Alveolar epithelial cells

Myofibroblast differentiation

FGF VEGF

4. Hilberg F et al. Cancer Res 20085. Chaudhary NI et al. Eur Respir J 2007

• Nintedanib is a kinase inhibitor that targets PDGF, FGF and VEGF receptors4

• Nintedanib prevented development of lung fibrosis in a bleomycin rat model5

• Nintedanib reduces TGF-β-induced fibroblast to myofibroblast transformation5

N Engl J Med 2011

INPULSIS 2014ATS

20112011-2013Pre-2011 2014

PRIMARY EFFICACY ENDPOINT IN INPULSIS-1

125.3 mL/year

(95% CI: 77.7, 172.8)

p<0.0001

Nintedanib 150 mg bid (n=309)

Placebo (n=204)

Ad

juste

d a

nnua

l ra

te (

SE

) o

f d

eclin

ein

FV

C (

mL

/ye

ar)

2 4 6 12 24 36 52

Week

No. of patients

Nintedanib 303 301 298 292 284 274 250

Placebo 202 198 200 194 192 187 165

0

Placebo

Nintedanib 150 mg bid

Me

an

(S

E)

ob

se

rve

d c

ha

nge

fro

m b

ase

line in F

VC

(m

L)

TIME TO FIRST ACUTE EXACERBATION (INVESTIGATOR-REPORTED) IN POOLED DATA

Nintedanib 150 mg bid

(n=638)

Placebo (n=423)

Patients with ≥1 acute exacerbation, n

(%)

31 (4.9) 32 (7.6)

Placebo

Nintedanib 150 mg bid

HR 0.64

(95% CI; 0.39, 1.05)

p=0.0823

EFFECT OF NINTEDANIB ON PATIENTS WITH BASELINE FVC>80%

Pooled INPULSIS® data; post hoc subgroup analysis of patients with baseline FVC >

80% versus ≤ 80% predicted

To assess the impact of baseline lung function impairment on the effect of nintedanib using an FVC threshold relevant for treatment reimbursement in several countries

Annual rate of decline in FVC similar in patients in both subgroups. Nintedanib slowed the decline in lung function independent of degree of lung function impairment at baseline

Most exacerbations reported in patients with baseline FVC ≤ 80% predicted

Time to first acute exacerbation and change in SGRQ total score was not significantly different between the subgroups by baseline FVC % predicted and was consistent with the results in the overall pooled population.

FVC = forced vital capacity; SGRQ = St George's Respiratory Questionnaire.Maher T, Oral presentation, Session 462, ERS 2015.

Most Frequent Adverse Events*

INPULSIS-1 INPULSIS-2

No of patients (%) Nintedani

b

150 mg

bid

(n=309)

Placebo

(n=204)

Nintedani

b

150 mg

bid

(n=329)

Placebo

(n=219)

Diarrhea 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

infection28 (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)

Based on adverse events with onset after first dose and up to 28 days after the last dose of trial medication

*Adverse events with an incidence of >10% in any treatment group. †Corresponds to the MedDRA term ‘IPF’, which included disease worsening and IPF

exacerbations

ASCEND Study: GI and skin-related events were more commonin the pirfenidone group

Occurring in ≥10% of patients in either treatment group †Coded to preferred terms in the Medical Dictionary for Regulatory Activities, version 11.0

Patients (%)

Pirfenidone

(N=278)

Placebo

(N=277)

Cough 25.2 29.6

Nausea 36.0 13.4

Headache 25.9 23.1

Diarrhea 22.3 21.7

Upper Respiratory Tract Infection 21.9 20.2

Fatigue 20.9 17.3

Rash 28.1 8.7

Dyspnea 14.7 17.7

Dizziness 17.6 13.0

Idiopathic pulmonary fibrosis 9.4 18.1

Bronchitis 14.0 13.0

Constipation 11.5 13.7

Back pain 10.8 13.4

Dyspepsia 17.6 6.1

Nasopharyngitis 11.9 10.8

Anorexia 15.8 6.5

Vomiting 12.9 8.7

Weight decreased 12.6 7.9

Gastroesophageal reflux 11.9 6.5

Insomnia 11.2 6.5

King TE et al. N Engl J Med 2014 May 18. doi:10.1056/NEJMoa1402582

Our real life experience on 220 patients treated

with pirfenidone and 40 with nintedanib

35%

65%no ADR

ADR

Adverse drug reactions (ADR) related to pirfenidone treatment

45%

13%

5%

24%

11%

2%

Gastrointestinal adverseevents Gamma GT serum elevation

Rash

Photosensitivity

ALT/AST serum elevation

Adverse drug reactions (ADR) related to pirfenidone treatment in 220 patients with IPF

21%

79%

no reversible ADR

reversible ADR

TIPS and TRICKS may help in making “adverse drug reactions” (ADR) due to pirfenidone reversible in most of the cases

In conclusione le attuali terapie consentono di:

1.Ridurre il declino funzionale dei pazienti con IPF

2.Ridurre la mortalità

3.Ridurre le esacerbazioni?

4.Trattare i pazienti fin dalle fasi iniziali

5.Trattare con un buon profilo di sicurezza

PRC-2063