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The NIHR Southampton Respiratory Biomedical Research Unit is funded by the National Institute for Health Research (NIHR) and is a partnership between University Hospital Southampton NHS Foundation Trust and the University of Southampton

NEW TREATMENT APPROACHES FORIDIOPATHIC PULMONARY FIBROSIS

Luca Richeldi MD PhD

Professor of Respiratory MedicineChair of Interstitial Lung DiseaseHonorary Consultant Physician

2016 ERS Conference

London, 4th September 2016

DISCLOSURES

Scientific Advisory Board

Roche, InterMune, Boehringer Ingelheim, Biogen, Fibrogen, AstraZeneca, Medimmune, GlaxoSmithKline, Sanofi-Aventis, Anthera, Takeda, UCB, Prometic, Promedior, ImmuneWorks, Asahi-Kasei, Nitto Denko, Bayer

Research Grants

InterMune (It and UK), Ministry of Health (It), National Drug Agency (It), National Research Council (It), The Wellcome Trust (UK)

Trial Principal Investigator

Boehringer Ingelheim, InterMune, Gilead, Roche, Takeda, UCB, Promedior

Speaker’s Fees

InterMune, Roche, Boehringer Ingelheim, Cipla

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Papers Clinical trials Reviews

“IDIOPATHIC PULMONARY FIBROSIS”

Raghu 1999

King 2011

King 2009Raghu 2004

Demedts ‘05

Azuma 2005

Ziesche 1999

Douglas 1998

King 2008

Noble 2011

Noble 2011

Taniguchi 2010Raghu 2008

Kubo 2005

IPFnet 2010

IPFnet 2012

IPFnet 2012

Raghu 2012

Shulgina 2012

Daniels 2010

Richeldi 2014

Richeldi 2014

IPFnet 2014

Richeldi 2011

King 2014

RCTs in IPF

AJRCCM 2015; 192: e3

AGAINST FORSTRENGTH STRONG CONDITIONAL STRONG CONDITIONAL

EVIDENCE L/VL M/H L/VL M/H L/VL M/H L/VL M/H

Anticoagulants (warfarin)

Imatinib

Prednisone + AZA + NAC

Ambrisentan

Nintedanib

Pirfenidone

Antiacid medication

Sildenafil

Bosentan or Macitentan

NAC monotherapyAJRCCM 2015; 192: e3

AGAINST FORSTRENGTH STRONG CONDITIONAL STRONG CONDITIONAL

EVIDENCE L/VL M/H L/VL M/H L/VL M/H L/VL M/H

Nintedanib

Pirfenidone

AJRCCM 2015; 192: e3

Issue 1: which mechanism to target

Issue 2: which patients to enrol

Issue 3: which end-points to measure

Eur Respir J 2015; 45: 1218

IPFnet 2014

NAC in IPF: primary endpoint

NEJM 2014; 370: 2093

Mathai et al, BMC Med 2015; 13: 191

Ongoing: pre-clinical studies on MUC5B directed therapy in pulmonary fibrosis

AJRCCM 2015; 192: 1475

STRATIFICATIONBY TOLLIP GENOTYPE

Oldham et al, AJRCCM 2015; 192: 1475

CC GENOTYPE

HR 3.2395% CI 0.79-13.16

P=0.10

TT GENOTYPE

HR 0.1495% CI 0.02-0.83

P=0.03

Lancet Resp Med, Published online May 5, 2016

Modified from data in Behr et al, Lancet Resp Med, Published online May 5, 2016

0 5 10 15 20

Pirfenidone + placebo (n=60)

Pirfenidone + acetylcysteine (n=62)

p=0.016

TREATMENT-EMERGENT PHOTOSENSITIVITY REACTIONS

%

www.clinicaltrials.govNEGATIVE RESULTS

POSITIVE RESULTS

PENDING RESULTS

ON GOING

PHASE I

PHASE II

PHASE III

REGISTRATION

LAUNCHED

PIRFENIDONE

BOSENTANCOTRIMOXAZOLE

AMBRISENTANOMEPRAZOLE

WARFARIN

SILDENAFILTRIPLE

THERAPY

IFN-g

THALIDOMIDE

MACITENTAN

TRALOKINUMAB

CC-930

IMATINIB

SIMTUZUMAB

LEBRIKIZUMAB

BMS-986020

ETANERCEPTQAX576

CNTO 888

STX-100

hMSC

IW001

PRM-151

GSK2126458

SAR156597

NINTEDANIBNAC

OCTREOTIDE

GC1008

TETRATHIOMOLYBDATE

ILOPROST

ZILEUTON

TREPROSTINILFG-3019

LOSARTAN

GLPG1690

TD139

SIX PHASE II TRIALS IN IPF WILL BE COMPLETED SOON

PBI-4050 BG-00011 KD025

Sponsor ProMetic Biogen Kadmon

Drug Anti-inflammatory/fibrotic

Anti-avb6integrin mAb

ROCK2inhibitor

Route Oral Subcutaneous Oral

Design OL single-arm DB placebo-controlled

OL randomized

Background Nintedanib / Pirfenidone

- SOC

Sample size 40 40 36

Duration 20 weeks 16 weeks 24 weeks

Endpoint Adverse events Adverse events Change in FVC

Start date Aug 2015 Jun 2011 Mar 2016

Last Update Feb 2016 Oct 2015 Apr 2016

End date Sept 2016 Mar 2017 Mar 2017

clinicatrials.gov

MN-001 PRM-151 FG-3019

Sponsor MediciNova Promedior FibroGen

Drug Leukotriene antagonist

Rec human pentraxin-2 Anti-CTGF mAb

Route Oral Intravenous Intravenous

Design DB placebo-controlled

DB placebo-controlled DB placebo-controlled

Background Nintedanib Nintedanib / Pirfenidone

-

Sample size 15 117 136

Duration 26 weeks 24 weeks 48 weeks

Endpoint Change in FVC Change in FVC Change in FVC

Start date Jul 2015 Aug 2015 Jun 2013

Last Update Jul 2015 Apr 2016 Apr 2016

End date Dec 2016 Mar 2019 Apr 2017

SIX PHASE II TRIALS IN IPF WILL BE COMPLETED SOON

clinicatrials.gov

LEBRIKIZUMAB SAR-156597

Sponsor Hoffmann-La Roche Sanofi

Drug Anti-IL-13 mAb ANTI-IL-13/IL-4 mAb

Route Subcutaneous Subcutaneous

Design DB placebo-controlled

DB placebo-controlled

Background Pirfenidone -

Sample size 484 300

Duration 52 weeks 52 weeks

Endpoint Change in FVC Change in FVC

Start date Oct 2013 May 2015

Last Update Dec 2016 Apr 2017

End date Mar 2018 Sept 2017

… TWO MORE A BIT LATER …

clinicatrials.gov

ART-123

Sponsor Asahi-Kasei

Drug Thrombomodulin-a

Route Intravenous

Design DB placebo-controlled

Background -

Sample size 74

Duration 90 days

Endpoint Survival

Start date May 2016

Last Update Apr 2016

End date Mar 2018

… AND ONE PHASE III

clinicatrials.gov

PHASE II TRIALS IN IPF

MN-001

LEBRIKIZUMAB

PRM-151

BG-00011

PBI-4050

FG-3019

SAR-156597

KD025

2011 20172012 2013 2014 2015 2016

clinicatrials.gov

Last Patient Visit

Time

Cohort 4

0.1 mg/kg

0.3 mg/kg

1.0 mg/kg

Start Screening

Cohort 10.015 mg/kg

Cohort 2

Cohort 3

Study Design

Randomized, double-blind, placebo-controlled, sequential dose escalation design (~10 sites, n = 40 patients; up to 5 cohorts [6 active: 2 placebo/pt/cohort])

Dose escalation after data reviewed by DSMB

Endpoints: Safety, tolerability, PK, immunogenicity, impact of BG00011 (STX-100) on biomarkers in serum and BAL

BG00011 given once weekly by subcutaneous injection

Dose escalation trial aims to refine doses based

on TGFb Downstream Signaling

Cohort 53.0 mg/kg

Enrollment completed

Background pirfenidone allowed

Biogen

Sanofi

FG-3019 Anti-CTGF Monoclonal Antibody - Results of an

Open Label Clinical Trial in IPF

Ganesh Raghu, Mary Beth Scholand, João de Andrade, Lisa Lancaster, Yolanda Mageto, Jonathan Goldin, Kevin K

Brown, Kevin R Flaherty, Mark Wencel, Jack Wanger, Thomas Neff, Frank Valone, John Stauffer , Seth Porter

Eur Respir J. May 2016

Correlation of FVC Change vs Fibrosis Changes*

Fibrosis

Sub-type Week N

r

Pearson p

QLF 24 74 −0.520 <0.0001

48 66 −0. 624 <0.001

GG 48 66 −0. 233 0.074 (n.s.)

QILD 48 66 −0. 514 <0.001

Figure 3: Categorical Changes in FVC Based on QLF

Change at Week 24 and Week 48

FibroGen

067 Phase 2 Clinical Trial (NCT01890265)

• A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and Efficacy of FG-3019 in Patients With Idiopathic Pulmonary Fibrosis

– 1:1 randomization to FG-3019 or placebo

– N=90

– Q3W iv infusions for 45 weeks

– Currently enrolling in US, CAN, S Africa, NZ, Australia, India, Romania and Bulgaria

– Expect to complete enrollment mid-2016

– Open label extension after week 48:

• All subjects assigned to placebo

• Subjects on FG-3019 whose FVC percent predicted at week 48 > BL

FibroGen

067 Phase 2 Clinical Trial (NCT01890265)Standard of Care Sub-study

• 60 subjects on stable dose of pirfenidone or nintedanib will be randomized 2:1 to FG-3019 or placebo

– Stratified at randomization by IPF background therapy (pirfenidone or nintedanib)

– 3 months on a stable dose of pirfenidone or nintedanib prior to screening

– Same study design as in the primary protocol except duration is 24 weeks instead of 48

– After completing treatment with study drug (FG-3019 or placebo), subjects may continue treatment with their background medication as part of current standard of care for IPF but will not be eligible for open label extension

– Quantitative HRCT as a secondary endpoint

– Enrolling in US and CAN

FibroGen

ENDOGENOUS PTX-2 LEVELS CORRELATE WITH LUNG FUNCTION IN IPF PATIENTS

Murray et al. Int J Biochem Cell Biol 2011; 43: 154

➡ Higher serum PTX-2 levels in IPF

patients directly correlate with

better lung function.

PTX-2 Serum Levels in IPF Patients vs. Healthy Subjects

PTX

-2 (m

g/m

l)

40

30

20

10

0Control IPF/UIP

➡ Serum PTX-2 levels are significantly

lower in IPF patients than normal

controls.

p-value < 0.05

PT

X-2

(mg/m

l)

40

30

20

10

0

FVC, % predicted

0

p-value < 0.01

PTX-2 Serum Levels in IPF Patients vs. Lung Function

Promedior

FVC % predicted relative change from baseline

Mean FVC % predicted increased by 2.4% in all PRM-151 treated subjectsMean FVC % predicted decreased by 1.5% in placebo subjects

% C

han

ge F

rom

Bas

elin

e

-15

-10

-5

0

5

10

15

6/14 PRM-151 treated patients show5-10% relative Change from Baseline at 8 weeks

Placebo

1 mg/kg

5 mg/kg

10 mg/kg

Eur Respir J 2016; 47: 889 Promedior

PROMOTE study of PRM-151 in IPFPhase 2 Trial currently enrolling in EU and US

Patients on pirfenidone

or nintedanib > 3 months

ORon no

therapy

PRM-151 10 mg/kg IV days 1, 3, 5 and then every 4 weeks

Placebo IV Days 1, 3, 5 and then every 4 weeks

80

40

• Eligibility: Patients with IPF on pirfenidone or nintedanib or no treatment• 24 week study treatment period (Patients may continue in extension)• PRM-151 IV over 60 minutes Days 1, 3, 5, then once every 4 weeks• Primary endpoint: Mean change from baseline in FVC % Predicted • Secondary endpoints: Quantitative Image Analysis via HRCT, 6MWT

Promedior

Secondary endpoints: Quantitative Image Analysis via Spirometry guided-HRCT

Poster ID 8505 Session C39 | IPF: MORE ON DIAGNOSIS AND THERAPY | Tuesday, May 17, 2016 9:00 Am-4:15 Pm

Example of automated analysis of parenchymal lung abnormalities

20

30

40

50

60

70

40.00% 60.00% 80.00% 100.00%

DLC

O %

pre

dic

ted

% Normal Lung by CALIPER

Correlation between DLCO and % Normal lung as quantified by automated analysis

Promedior

MA29895RIFF

Randomized, multicenter, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of lebrikizumabas monotherapy in the absence of background IPF therapy or as combination therapy with pirfenidone background therapy

Safety and tolerability study of pirfenidone in combination with nintedanib in participants with IPF

Primary Outcome: percentage of participants who complete 24 weeks of combination treatment on pirfenidone at a dose of 1602-2403 mg/day and Nintedanib at a dose of 200-300 mg/day

Primary Outcome: absolute change from baseline in percent predicted forced vital capacity (FVC) from baseline to Week 52

ISLAND-2

A safety and tolerability study of oral vismodegib in combination with pirfenidone in participants with IPF

Primary Outcome: percentage of participants with serious and non-serious adverse events

Roche

INSTAGE (1199.36)

A 24-week, double-blind, randomized, parallel-group study evaluating the efficacy and safety of oral nintedanib co-

administered with oral sildenafil, compared to treatment with nintedanib alone, in patients with idiopathic pulmonary fibrosis

(IPF) and advanced lung function impairment

Boehringer Ingelheim

INJOURNEY (1199.222)

A twelve week, open-label, randomised, parallel-group study evaluating safety, tolerability and pharmacokinetics (PK) of oral nintedanib when taken in combination with oral pirfenidone,

compared to treatment with nintedanib alone, in patients with IPF

Boehringer Ingelheim

Final Protocol May 2015

Study Initiation October 2015

Database Lock February 2017

Countries

Canada Italy

France Netherlands

Germany USA

INMARKTM (1199.227)

A 12-week, double blind, randomised, placebo controlled, parallel group trial followed by a single active arm phase of 40 weeks

evaluating the effect of oral nintedanib 150 mg twice daily on change in biomarkers of extracellular matrix (ECM) turnover in

patients with IPF and limited forced vital capacity (FVC) impairment

Boehringer Ingelheim

Final Protocol Feb 2016

Study Initiation May 2016

Database Lock May 2018

Countries

Australia Japan France UK

Belgium Poland Germany USA

Czech Republic South Korea Hungary

Finland Spain

Dickinson RP, Martinez FJ and Huffnagle GB, Lancet 2014; 384: 691

Study of Clinical Efficacy of Antimicrobial Therapy Strategy Using Pragmatic Design in Idiopathic Pulmonary Fibrosis (CleanUP IPF)

Fernando J. Martinez

Kevin J. Anstrom

Imre Noth

Michael Durheim

Robert Kaner

Xiaoping Wu

Kevin Flaherty

Ganesh Raghu

Harold Collard

Brett Ley

• Inclusion criteria

• > 40 years of age

• IPF diagnosis by enrolling investigators

• Signed informed consent

• 500 patients over a 30 month window with a minimum of 12 months of follow-up on all patients

• Primary endpoint

• Time to from randomization to first respiratory hospitalization or all-cause mortality

Biomarkers: saliva and stool

BRonchial Sample Analysis for a NoVel GEnomic Test

Veracyte

BRAVE-1

Patients: undergoing diagnostic surgical lung

biopsy

A Bronchoscopy with samples for Veracyte

Veracyte pays for Bronchoscopy

BRAVE-2

Patients: undergoing diagnostic

bronchoscopy

No additional procedures, only extra

samples

BRAVE-3

Patients: undergoing diagnostic cryo-

biopsies

No additional procedures, only extra

samples

IN SILICO MIXTURE MODELING

Veracyte

RA-ILD? IPF?

55 year old manRF and CCP both high-positive, no arthritis

©Aryeh Fischer

SENSCISTM (1199.214)

A double blind, randomized, placebo-controlled trial evaluating efficacy and safety of oral nintedanib treatment for at least 52

weeks in patients with Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD)

Final Protocol July 2015

Study Initiation November 2015

Database Lock June 2018

Countries

Australia Israel France Switzerland

Belgium Italy Germany Poland

Canada Japan Greece Portugal

China Netherlands India UK

Denmark Spain Ireland USA

Boehringer Ingelheim

RA Lung Study III Scleroderma-ILD Study

A US Multi-Center, Phase 2 Study Combining the Anti-Fibrotic Effects of Pirfenidone With Mycophenolate to Treat Scleroderma-Related Interstitial Lung Disease

An International, Multi-Center Phase 2 Study of Safety, Tolerability and Efficacy of Pirfenidone in Patients with RA-ILD

Primary Outcome: Incidence of the composite endpoint of decline in percent predicted FVC of 10% or greater or death during the 52 week study period

Primary Outcome: Mean change of percent predicted FVC over 18 months

Principal Investigator: Ivan Rosas, MD (Harvard, Brigham and Women’s Hospital)

Study will be in conjunction with the SLS consortium from the SLS I & II trials

Principal Investigators: Michael Roth MD (UCLA) & Dinesh Khanna (U. of Michigan)

Roche

EPOS RELIEF

Exploring efficacy and safety of oral pirfenidone for progressive, non-IPF lung fibrosis

A European multi-centre, randomised, double-blind placebo-controlled trial of pirfenidone in bronchiolitis-obliterans-syndrome

Primary Outcome: change in FEV1 in liters over 6 months

Primary Outcome: Absolute change in percent predicted FVC from baseline to week 48

Roche

Principal Investigators: Martin Iversen & Michael Perch, Copenhagen

Principal Investigators: A. Günther, J. Behr (University of Giessen, University of Munich)

Sponsored by the German Center for Lung Research

NOT IPF

POSSIBLE IPF

PROBABLE IPF

DEFINITEIPF

©Kevin Brown

UIP

THE (NEW) CONCEPT OF TREATING UIP(AND NOT ONLY IPF)

NIHR Southampton Respiratory Biomedical Research Unit

The NIHR Southampton Respiratory Biomedical Research Unit is funded by the National Institute for Health Research (NIHR) and is a partnership between University Hospital Southampton NHS Foundation Trust and the University of Southampton

NEW TREATMENT APPROACHES FORIDIOPATHIC PULMONARY FIBROSIS

Luca Richeldi MD PhD

Professor of Respiratory MedicineChair of Interstitial Lung DiseaseHonorary Consultant Physician

2016 ERS Conference

London, 4th September 2016