Università di Padova

Dipartimento di Medicina (DIMED)

Allergologia ed Immunologia Clinica

Le interstiziopatie polmonari

Nuove prospettive terapeutiche

Carlo Agostini

Disclosure

In relation to this presentation, I declare the following, real or perceived conflicts of interest:

• C.A. participated in advisory board meetings for Intermune, Inc, Roche, Inc, CSL Behring

GmbH, Inc, Baxter Int, Inc, LFB, Inc, Baxalta Int, Inc, Novartis, Inc

• C.A. received consultancy fees from Intermune, Inc, Baxter Int., Boehringer Ingelheim,

Centocor, Inc, Baxalta Int, Inc

• C.A. received travel grants from CSL Behring GmbH, Inc, Boehringer Ingelheim,

Intermune/Roche, Inc, Baxalta Int, Inc

• His institution (Dipartimento di Medicina) received grants from Intermune/Roche, Inc, CSL

Behring GmbH, Inc, Baxter International, Inc, Boehringer Ingelheim, Actelion, Inc, Gilead,

Inc, Janssen Phar. Comp.

• No other fees or grants relevant to this lecture are reported

Internal Medicine - Allergy Clinical Immunology Department of Medicine – DIMEDCentre for Immune Mediated Rare Diseases

Diagnosis and treatment of immunological and allergic

diseases, including patients with primary and

secondary immunodeficiency, autoimmune diseases,

autoinflammatory disorders, immunomediated and

other rare interstitial lung diseases, including

sarcoidosis

Venetian Institute

of Molecular Medicine

Identification of potential

therapeutic targets

in immune mediated and

allergic disorders

Carlo Agostini

Padua University Hospital

MALATTIA RARA POLMONARE PREVALENZA (PER 100.000) INCIDENZA

DEFICIT ALFA-1 ANTITRIPSINA 33 1:2.500

FIBROSI POLMONARE IDIOPATICA 30 1:4.500

SCLEROSI SISTEMICA 26 1:6.300

IPERTENSIONE ARTERIOSA POLMONARE 19.5 1:6.300

DERMATOMIOSITE-POLIMIOSITE 17 1:6.500

RENDU-OSLER 16 1:6.500

SARCOIDOSI 15 1:6.500

DISPLASIA BRONCOPOLMONARE 13 1:6.500

FIBROSI CISTICA 12.6 1:8.000

CARCINOMA POLMONARE (PICCOLE CELLULE) 11.2 1:8.000

GRANULOMATOSi CON POLIANGIOITE 6.6 1:10.000

IMMUNODEFICIENZA COMUNE VARIABILE 4 1:25.000

SINDROME IPEREOSINOFILA 1.5 1:60.000

GRANULOMATOSi EOSINOFILA CON POLIANGITE 1 1:100.000

LINFANGIOLEIOMIOMATOSI 0.56 1:200.000

ISTIOCITOSI A CELLULE DI LANGERHANS 0.2 1.500.000

PROTEINOSI ALVEOLARE 0.1 1:1.000.000

Prevalenza stimata in Europa delle principali malattie rare polmonari(dati Orphanet)

Lancet Respir Med 2013; 1: 479–87

Incidence and Prevalence of Idiopathic Pulmonary Fibrosis

a large United States' health plan

3 million 18 yr or older persons in total residing in 20 states

1,943 had one or more diagnoses of IPF at any time during a 5-yr period of observation

prevalence of IPF was estimated to range from 4.0 per 100,000 persons aged 18 to 34 yr to 227.2 per 100,000 among those aged 75 yr or older

considerando una popolazione di 60 milioni di individui la stima è di circa 19.000 malati di IPF

IPF: An Italian real life study

AGE CLASS

< 60 anni 13.3%

61-65 anni 15.6%

> 65 anni 71.1%

9,3 nuovi casi all'anno ogni 100.000 persone

Harari S. et al. Respiration 2015, dx.doi.org/10.1016/j.rmed.2015.04.010

Idiopathic Pulmonary Fibrosis Not Aging CouldBe Causing Breathlessness

Ridotta sopravvivenza

• immunodeficienza combinata grave• fibrosi polmonare idiopatica• ipertensione arteriosa polmonare• linfangioleiomiomatosi• graft-versus-host disease• dermatomiosite-polimiosite• mesotelioma• ca. polmonare a piccole cellule

Lungasopravvivenza

• deficit alfa-1 antitripsina• alcune vasculiti• malattie del connettivo• fibrosi cistica• proteinosi alveolare• sarcoidosi• immunodeficienza comune

variabile

Malattie rare polmonari e prognosi

a-SMA

IPF

Natural History of Idiopathic Pulmonary Fibrosis

Bottlenecks between research and developmentof therapies for rare diseases

part of the research and development process is the ‘translation gap’ where there is no obvious funding body

2012 EUCERD Report on the State of the Art of Rare Disease Activities in Europe

Clinical Trials in IPF

TWO PATHWAYS TO PULMONARY

FIBROSIS

Epithelial cell

injury& activation

interstitium

ALVEOLAR

SPACE

Inflammation

epithelium

endothelium

VASCULAR

SPACE

FIBROTIC PHASE

persistence of

etiologic agent

genetic

backgroundFibrotic

phase

fibroblastsIL-13

TGFb

PDGFb

Lymphocyte Th2

IL-4

Agostini et al. Blood 93: 1277-1286 (1996)

PROTEOMEprotein content

The Omes Revolution

TRANSCRIPTOMERNA content

GENOMEDNA information

METABOLOMEmetabolites

Idiopathic

pulmonary fibrosis

MHC

CD4 and CD8 activated T cells

Chemokines/Receptors

Adhesion molecules

Interleukins/Receptors

Myofibroblasts

Cell proliferation

Epithelial activation

Tissue remodeling

Selman M et al. AJCCM

DOI: 10.1164/rccm.200504-644OC

Pulmonary Fibrosis in

HP

Old Concept

Cellular Inflammation

(Alveolitis/DIP)

Fibroblast Proliferation

Fibrosis (Collagen)

New Concept

Epithelial-Fibroblast

Pathway

(fibroblastic foci)

± Interstitial Inflammation

Fibrosis (Collagen)

Epithelial

transition

TWO PATHWAYS TO IDIOPATHIC

PULMONARY FIBROSIS

IPF: Survival in the 2000-2009 EraTransplant Recipents Excluded

Till 2011

Prednisone + AZA + NAC

=

the therapeutic standard in IPF

Not supported by placebo controlled study

PANTHER trial

Avoiding use of steroids,

immunosuppressants and

antioxidants

a simple way to improve

patients survival…

First lesson

Clinical Trials in IPF

End of the death valley

Since 2014 pirfenidone

EMT

MigrationProliferation

Growth factors

FibroblastsMyofibroblasts

TGF-beta

Th2-like factors

CXCL12

Fibrocytes

Wound clot

Procoagulant factors and PDGF

MMPs

PDGF-R

Noble, Lancet 2011;377:1760

FVC decline

Grouped analysis

% patients with ΔFVC > 10%

2403 mg Placebo P

21% 31% 0.003

• Progression free survival

RR=0.74 P=0.025

• Distance 6MWT

Δ=24m P=0.009

• Positive trend for mortality

reduction

• EMEA Approval

• AIFA Approval

The pirfenidone lessons

• A drug that works in the bleomycin model

can work in humans

• A trial of a drug can be positive in IPF

• A drug without a definitive molecular target

may work

• An IPF drug is approved by EMEA and

consequently by AIFA and FDA (october 2014)

24 october 2014

CHMP recommends label update for Esbriet

in idiopathic pulmonary fibrosis (IPF),

strengthening mortality benefit and

reinforcing safety profile

• slows the progression in patients with early disease

• even if there is progression in terms of FVC% (>10%)

mantains its efficacy both in terms of function and

survival during the following 6 months

Esbriet appears beneficial accross of IPF patients enrolled in different trials

Pirfenidone and moderate severe disease: An Italian real life study

In our national experience,

pirfenidone reduces the

rate of annual FVC decline

and provides significant

treatment benefit for

patients with moderate-

severe disease, suggesting

that the drug may also be

effective in patients with

more advanced disease

Harari S. et al. Respiratory Medicine 2015 DOI:

http://dx.doi.org/10.1016/j.rmed.2015.04.010

April 7 2016 nintedanib

Growth factors bind to receptors

How does nintedanibwork?

Signalling pathways inhibited

Nintedanib

indolidone derived drug

able to inhibit

neoangiogenesis

OFEV (NINTEDANIB)

Hilberg, Cancer Res 2008

Triple angiokinase

Inhibitor

Involved in IPF

pathogenesis

Nintedanib is a multi-target Tyrosine Kinase (TK) inhibitor

EMT

MigrationProliferation

Growth factors

FibroblastsMyofibroblasts

TGF-beta

Th2-like factors

CXCL12

Fibrocytes

Wound clot

Procoagulant factors and

PDGF

MMPs

PDGF-R

Signal blocker

The primary end point was the annual rate of decline in forced vital capacity (FVC) Key secondary end points were over a 52-week period•the time to the first acute exacerbation• the change from baseline in the total score on the St. George’s Respiratory Questionnaire

Main Results of INPULSIS-1 and INPULSIS-2

a) Nintedanib reduces the decline in FVC, which is

consistent with a slowing of disease progression;

b) Difference between the nintedanib and placebo

groups in the time to the first acute exacerbation

and quality of life (SGRQ) are not clear due to

the result differences between the 2 trials

c) Nintedanib is frequently associated with diarrhea,

which led to discontinuation of the study

medication in less than 5% of patients

• the FVC% baseline value, the presence of emphysema, the degreeof honeycombing at HTCT do not affect the rate of diseaseprogression of the size of nintedanib effect

• the FVC% values do affect the rate of acute exacerbations

Nintedanib 150 mg bid on slowing disease progression wasmainained up to 76 weeks

Key Points: Using Pirfenidone or Nintedanib?

Key Points: Several Unanswered Questions

MonotherapyCombination

therapyor

I am sure you will ask

Ongoing Clinical Trials with Biologicals in IPF

persistence of

etiologic agent

genetic

background

Fibrotic

phase

fibroblastsIL-13

TGFb

PDGFb

Lymphocyte Th2

IL-4

Agostini et al. Blood 93: 1277-1286 (1996)

PADOVA Allergology and Clinical Immunology Study Group

DEPARMENT OF MEDICINE & VENETIAN INSTITUTE OF MOLECULAR MEDICINE

Carlo Agostini

Francesco CinettoMonica Facco

Nicolò CompagnoRiccardo ScarpaGiacomo MalipieroMarcus KuhnSperanza Di MaggioStefania CelesteMaddalena MarconatoIlaria LazzaratoFrancesca RizzoAnna KuzenkoSandra Iannacone

Elisa Boscaro