Marilyn K. Glassberg Csete, M.D.

Professor of Medicine, Surgery, and Pediatrics

Director, Interstitial and Rare Lung Disease Program

University of Miami Miller School of Medicine

April 8, 2016

INTERSTITIAL LUNG DISEASES:

FOCUS ON IDIOPATHIC

PULMONARY FIBROSIS (IPF)

Advisory Boards: Boehringer Ingelheim, Genentech,

Mesoblast

Research Grants: Genentech; Lester and Sue Smith

Foundation, Marcus Foundation; NIH

DISCLOSURES

74-YEAR-OLD MALE EX-SMOKER WITH COUGH & DYSPNEA History: 12 months ago developed productive cough and shortness of breath

Referred to pulmonologist with abnormal CXR and had HRCT of chest

Hospitalized 14 months later with increased dyspnea and hypoxemia– treated with antibiotics and steroids

Dyspnea with ADLs

Since discharge, requires continuous oxygen therapy

Frequent heartburn

Reports poor sleep, snoring and daytime fatigue

Past Medical/Family/Social History

+HTN, Hyperlipidemia

Family history of CAD,

Former 30 pack year smoker

Exam

140/66, 86, 22, SpO2 90% at rest on RA; BMI 27

Bibasilar inspiratory crackles, no wheeze

No peripheral edema or signs of CHF

FEV1 FVC FEV1/FVC DLCO

February 15 2.42 (84%) 2.80 (64%) 0.86 8.75 (34%)

74-YEAR-OLD MALE EX-SMOKER WITH COUGH & DYSPNEA

HRCT 14 MONTHS LATER

Normal Lung Usual Interstitial Pneumonia

IDIOPATHIC PULMONARY FIBROSIS

WHERE DOES IPF FIT IN THE CONTEXT OF THE

ILDS?

The most common ILD: 42,000 new cases per year

Definition of IPF:

Specific form of chronic, progressive fibrosing

interstitial pneumonia of unknown cause

Occurring primarily in males above the age of 55

Limited to the lungs

80% are ex-smokers

Raghu G, et al, and the ATS/ERS/JRS/ALAT Committee on IPF. Am J Respir Crit Care Med. 2011;183:788-824

Pleuroparenchymal Fibroelastosis

MAJOR IIPs

HISTORICAL CLASSIFICATION OF INTERSTITIAL LUNG DISEASES

Adapted from Ryu JH, et al. Mayo Clin Proc. 1998;73:1085-1101

Adapted from ATS/ERS. Am J Respir Crit Care Med. 2013;188: 733-

748.

1970s 2016 Idiopathic

IPs Heterogeneous

group that included

a number of

diseases

IPF

NSIP

DIP RB-

ILD

AIP

Cellular

Fibrotic

Sarcoidosis

Hypersensitivity Pneumonitis

(EAA)

Asbestosis

LAM

BML

LG

COP

ILIP

Unclassifiable

IIPs Rare IIPs

IPF IS THE MOST COMMON

IDIOPATHIC INTERSTITIAL PNEUMONIA

Interstitial lung disease (ILD)

ILD of known cause Idiopathic interstitial

pneumonias Other forms of ILD Granulomatous ILD

Unclassifiable idiopathic interstitial

pneumonias

Rare idiopathic interstitial

pneumonias

Major idiopathic interstitial

pneumonias

Idiopathic nonspecific

interstitial pneumonia

Desquamative interstitial pneumonia

Cryptogenic organizing

pneumonia

Acute interstitial pneumonia

Respiratory

bronchiolitis-interstitial

lung disease

Idiopathic pulmonary fibrosis (IPF)

Idiopathic

pleuroparenchymal

fibroelastosis

Idiopathic lymphoid

interstitial pneumonia

Travis WD et al. Am J Respir Crit Care Med. 2013;188(6):733-748.

1. Raghu G, 2013; 2. Go AS, et al. Circulation. 2013;127:e6–e245. 3. Wheaton AG, et al. MMWR Morb Mortal Wkly Rep. 2015;64:289–295.

DISTINGUISHING DYSPNEA

IPF

COPD

Heart

failure

Million

9 3 15 6 0 18

Disease Prevalence, United States

1

3

2

136,170

15.7 million

5.1 million

12

THE INCIDENCE OF IPF INCREASES WITH AGE

Raghu G et al. Lancet Respir Med. Appendix. 2014;2:566-572.

0

10

20

30

40

50

60

66-69 70-74 75-79 80+

Pe

rce

nta

ge

of

Pa

tie

nts

Age of Incident Medicare Patients with IPF

at Diagnosis in 2011

Age

Male sex

Hispanic ethnicity

Geography

RISK FACTORS/LOCATION OF IPF IN US

Raghu G, et al. Lancet Respir Med. 2014;2(7):566-572.

Highest Medium

Lowest

0

20

40

60

80

100

Lung Cancer IPF Ovarian Cancer PAH Colorectal Cancer Breast Cancer

5-Y

ear

Su

rviv

al R

ate

,a %

SURVIVAL IN IPF IS WORSE THAN MOST

CANCERS

17

44

57

65

89

IPF survival

is comparable

to that of lung

cancer

203

PATIENTS WITH IPF ARE OFTEN MISDIAGNOSED

1-2 Years (average) Disease Onset Diagnosis

Patients are often

misdiagnosed with bronchitis,

asthma, COPD, emphysema,

or heart disease

0

5

10

15

Cellular NSIP Fibrotic NSIP IPF

Mo

nth

s

Duration of Time from Disease Onset to Diagnosis

PROGRESSION OF IPF

Normal Progressive destruction of lung architecture

5-year survival rate from diagnosis = 20 to 40% Age of onset : 2/3 over age 60

IPF: A DISEASE WITH AN UNPREDICTABLE CLINICAL COURSE

0 1 2 3 4

Years

Resp

irato

ry

Fu

ncti

on

/Sym

pto

ms

Acute exacerbations

Slowly progressive

Kim DS, et al. Proc Am Thorac Soc. 2006; 3: 285-292

Rapidly progressive

0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 6 1 0 8 1 2 0

0

2 0

4 0

6 0

8 0

1 0 0D L c o = > 5 0 %

D L c o 3 5 -4 9 %

D L c o < 3 5 %

M o n th s

Pe

rc

en

t s

urv

iva

l

P=0.0001

DIFFUSING CAPACITY PREDICTS SURVIVAL IN IPF

Nathan SD, et al. Chest. 2011;140:221-229.

0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 6 1 0 8 1 2 0

0

2 0

4 0

6 0

8 0

1 0 0D L c o = > 5 0 %

D L c o 3 5 -4 9 %

D L c o < 3 5 %

M o n th s

Pe

rc

en

t s

urv

iva

lDLco ≥ 50%

DLco 35-49%

Dlco < 35%

Months

Pe

rce

nt

Su

rviv

al

P=0.0053

FVC PREDICTS SURVIVAL IN IPF

Nathan SD, et al. Chest. 2011;140:221-229.

0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 6 1 0 8 1 2 0

0

2 0

4 0

6 0

8 0

1 0 0F V C > o r= 7 0 %

F V C 5 5 -6 9 %

F V C < 5 5 %

M o n th s

Pe

rc

en

t s

urv

iva

l

FVC ≥ 70%

FVC 55-69%

FVC < 55%

Months

Pe

rce

nt

Su

rviv

al

0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 6 1 0 8 1 2 0

0

2 0

4 0

6 0

8 0

1 0 0F V C > o r= 7 0 %

F V C 5 5 -6 9 %

F V C < 5 5 %

M o n th s

Pe

rc

en

t s

urv

iva

l

6MWT: PARAMETERS PREDICT SURVIVAL IN IPF

du Bois RM, et al. Eur Respir J. 2014;43(5):1421-1429.

Swigris JJ, et al. Chest. 2009;136:841-848

6MWT distance at 24 weeks Baseline 6MWT distance

Lee JS, et al. Am J Respir Crit Care Med. 2011;184(12):1390-1394.

GERD TREATMENT AND SURVIVAL

Su

rviv

al

Time to Event (days)

OBSTRUCTIVE SLEEP APNEA IS COMMON IN IPF

55 subjects with IPF

Sleep apnea evaluation

– Epworth Sleepiness Scale

– Sleep Apnea Scale of Sleep Disorders

– Nocturnal polysomnography

Findings that did not correlate with OSA

– Spirometry

– Lung volume

– DLCO

– ESS

Lancaster LH, et al. Chest. 2009;136:772-778.

12%

20%

68%

Moderate/Severe

AHI > 15 events/h

Mild AHI 5–15/h

No OSA

AHI 5/h

AHI: apnea-hypopnea index

Clinical presentation:

• Typically affects adults

>50 years of age

• Chronic exertional dyspnea

• Dry, nonproductive cough

• Crackles or rales on

auscultation

• Digital clubbing

Patient presents with

suspected ILD

• Detailed history

• Physical exam

• PFT

DIAGNOSTIC ALGORITHM FOR IPF

Adapted from Raghu G et al.1 CTD, connective tissue disorder; MDD, multidisciplinary discussion; PFT, pulmonary function testing.

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824. 2. Flaherty KR, Khanna D. Thorax. 2014;69(3):205-206.

• Exposures (environmental,

occupational, pets)1

• Skin, joint, or muscle

findings including arthritis,

pleurisy, skin thickening, and

Raynaud’s phenomenon

may indicate a connective

tissue disorder1

Not IPF

Yes

No

Patient presents with

suspected ILD

• Detailed history

• Physical exam

• PFT

Identifiable cause of

ILD?

Serologic testing to

exclude CTD

Diagnostic Algorithm for IPF

Adapted from Raghu G et al.1 CTD, connective tissue disorder; MDD, multidisciplinary discussion; PFT, pulmonary function testing.

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824. 2. Flaherty KR, Khanna D. Thorax. 2014;69(3):205-206.

Not IPF

Yes

Positive No

Patient presents with

suspected ILD

• Detailed history

• Physical exam

• PFT

Identifiable cause of

ILD?

Serologic testing to

exclude CTD

Diagnostic Algorithm for IPF

Adapted from Raghu G et al.1 CTD, connective tissue disorder; MDD, multidisciplinary discussion; PFT, pulmonary function testing.

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824. 2. Flaherty KR, Khanna D. Thorax. 2014;69(3):205-206.

HRCT is critical to making an

accurate diagnosis of IPF1

• UIP

• Possible UIP

• Inconsistent with UIP

Not IPF

Yes

Positive No

Negative

Patient presents with

suspected ILD

• Detailed history

• Physical exam

• PFT

Identifiable cause of

ILD?

HRCT

Serologic testing to

exclude CTD

Diagnostic Algorithm for IPF

Adapted from Raghu G et al.1 CTD, connective tissue disorder; MDD, multidisciplinary discussion; PFT, pulmonary function testing.

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824. 2. Flaherty KR, Khanna D. Thorax. 2014;69(3):205-206.

• HRCT is critical to making an

accurate diagnosis of IPF1

o UIP

o Possible UIP

o Inconsistent with UIP

UIP

Not IPF IPF

Yes

Positive No

Negative

Definite UIP

Patient presents with

suspected ILD

• Detailed history

• Physical exam

• PFT

Identifiable cause of

ILD?

HRCT

Serologic testing to

exclude CTD Image courtesy of and used with permission from Jonathan

Goldin, MD, PhD.

Diagnostic Algorithm for IPF

Adapted from Raghu G et al.1 CTD, connective tissue disorder; MDD, multidisciplinary discussion; PFT, pulmonary function testing.

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824. 2. Flaherty KR, Khanna D. Thorax. 2014;69(3):205-206.

Not UIP

Image courtesy of and used with permission from Jonathan

Goldin, MD, PhD.

Not IPF IPF

Yes

Positive

Not UIP

No

Negative

Definite UIP

Patient presents with

suspected ILD

• Detailed history

• Physical exam

• PFT

Identifiable cause of

ILD?

HRCT

Serologic testing to

exclude CTD

Diagnostic Algorithm for IPF

Adapted from Raghu G et al.1 CTD, connective tissue disorder; MDD, multidisciplinary discussion; PFT, pulmonary function testing.

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824. 2. Flaherty KR, Khanna D. Thorax. 2014;69(3):205-206.

Not UIP

Possible UIP

Image courtesy of and used with permission from Jonathan

Goldin, MD, PhD.

Image courtesy of and used with permission from Jonathan

Goldin, MD, PhD.

Not IPF IPF

Yes

Surgical lung biopsy

Positive

Not UIP

No

Negative

Possible UIP

Definite UIP

Patient presents with

suspected ILD

• Detailed history

• Physical exam

• PFT

Identifiable cause of

ILD?

HRCT

Serologic testing to

exclude CTD

Diagnostic Algorithm for IPF

Adapted from Raghu G et al.1 CTD, connective tissue disorder; MDD, multidisciplinary discussion; PFT, pulmonary function testing.

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824. 2. Flaherty KR, Khanna D. Thorax. 2014;69(3):205-206.

Possible UIP

Not UIP

Image used with permission from the American Thoracic

Society. © 2015. Raghu G et al.1

Not IPF IPF

Yes

Surgical lung biopsy

Positive

Not UIP

No

Negative

Possible UIP

Definite UIP

Patient presents with

suspected ILD

• Detailed history

• Physical exam

• PFT

Identifiable cause of

ILD?

HRCT

Serologic testing to

exclude CTD

Not UIP

Diagnostic Algorithm for IPF

Adapted from Raghu G et al.1 CTD, connective tissue disorder; MDD, multidisciplinary discussion; PFT, pulmonary function testing.

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824. 2. Flaherty KR, Khanna D. Thorax. 2014;69(3):205-206.

Image used with permission from the American Thoracic

Society. © 2015. Raghu G et al.1

Image used with permission from the American Thoracic

Society. © 2015. Raghu G et al.1

Not UIP

Not IPF IPF

Yes

Surgical lung biopsy

Positive

Not UIP

No

Negative

Possible UIP

MDD UIP

Definite UIP

Patient presents with

suspected ILD

• Detailed history

• Physical exam

• PFT

Identifiable cause of

ILD?

HRCT

Serologic testing to

exclude CTD

Not UIP

Not UIP

UIP/Probable UIP

Diagnostic Algorithm for IPF

Adapted from Raghu G et al.1 CTD, connective tissue disorder; MDD, multidisciplinary discussion; PFT, pulmonary function testing.

1. Raghu G et al. Am J Respir Crit Care Med. 2011;183:788-824. 2. Flaherty KR, Khanna D. Thorax. 2014;69(3):205-206.

PATHOGENESIS OF IPF

Ahluwalia N, et al. Am J Respir Crit Care Med. 2014;190(8):867–78.

INJURY

Angiogenesis

Fibroblast migration and proliferation

Wound clot

Basement

membrane

disruption

Epithelial apoptosis

Epithelial cell injury and activation

Myofibroblast accumulation

Progressive fibrosis and

impaired reepithelialization

Pre-2011

Noth I et al. Am J Respir Crit Care Med. 2012;186:88-95.

Trial n Primary Endpoint Result

Interferon-beta (1999) 167 Progression-free survival time Negative

Interferon-gamma (GIPF-001) 330 Progression-free survival Negative

Interferon-gamma (Inspire) 826 Survival time Negative

Pirfenidone (CAPACITY 1) 344 Change in FVC Negative

Etanercept 100 Change in DLco, FVC Negative

Imatinib Mesylate 120 Progression-free survival Negative

Bosentan (BUILD 1 and 2) 132 Change in 6MW Negative

Bosentan (BUILD 3) 390 Progression-free survival time Negative

Sildenafil (STEP) 29 Change in 6MWD, Borg

dyspnea index Negative

Ambrisentan (Artemis-IPF) 478 Progression-free survival Stopped –

Ambrisentan (Artemis-PH) 50 6MWD Stopped –

Everolimus 89 Progression Negative

PAST NEGATIVE CLINICAL TRIALS IN IPF 2000-PRESENT

PHARMACOLOGIC APPROACHES FDA

APPROVED IN OCTOBER 2014

Two drugs: Nintedanib and Pirfenidone

Effective in slowing functional decline and

disease progression

Current evidence supports timely diagnosis

and administration of treatment

Neither drug cures IPF

MSCS: A UNIQUE IMMUNOPRIVILEGED CELL

Williams and Hare. Circ Res 2011; 109:923-40

YOUNG MSCS PREVENT LUNG FIBROSIS

Tashiro J., et al. Transl Res. 2015 Dec;166(6):554-67

No infusion related adverse events

Most common adverse event was

bronchitis

Promising exploratory endpoints:

Walk test distance

Lung Function

Oxygen usage

PRELIMINARY SAFETY RESULTS FIRST IN MAN FDA APPROVED

CLINICAL TRIAL COMPLETED DECEMBER 2015

KEY POINTS:

WORK-UP SHORTNESS OF BREATH

WWW.BREATHLESSIPF.COM

REFER EARLY TO SPECIALIST

March 14, 2016