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New Therapies and Trials in

IPF

Talmadge E. King, Jr., M.D.Julius R. Krevans Distinguished Professorship in Internal Medicine

Chair, Department of Medicine

University of California San Francisco (UCSF)

San Francisco, CA

I have the following real or perceived conflicts of interest that relate to this

presentation:

� InterMune (Drug Study Steering committees)

� F. Hoffmann-La Roche/Genentech (Drug Study Steering committees)

� Actelion (Drug Study Steering Committees)

� ImmuneWorks (Scientific Advisory Committee)

� GlaxoSmithKline (Consultant)

� Boehringer Ingelheim (Consultant)

� Daiichi Sankyo (Consultant)

� Tracon (Consultant)

� NIH IPFnet (Principal investigator)

� UpToDate (Editor, Author)

Conflict of interest disclosure

Talmadge E. King, Jr., MDProfessor & Chair

UCSF Department of Medicine

• Heterogeneous group of noninfectious, nonmalignant processes of the lower respiratory tract (interstitial pneumonias) that commonly result

– Symptoms: dyspnea and cough

– Signs: crackles on chest exam; (clubbing)

– PFTs: restrictive ventilatory impairment

– Chest imaging: diffuse interstitial opacities

– Lung biopsy: granulomatous or interstitial inflammation and fibrosis

– Outcome: often progressive and often fatal

Diffuse Parenchymal Lung Diseases or

Interstitial Lung Diseases (ILD)

� Respiratory

bronchiolitis ILD

� Desquamative

interstitial pneumonia

Chronic FibrosingAcute/Subacute

FibrosingSmoking-related

� Cryptogenic organizing

pneumonia

� Acute interstitial

pneumonia

� Idiopathic pulmonary

fibrosis

� Idiopathic nonspecific

interstitial pneumonia

Idiopathic interstitial

pneumonia

(IIPs)

NonNonNonNon----familialfamilialfamilialfamilial(>80%)(>80%)(>80%)(>80%)

FamilialFamilialFamilialFamilial(2(2(2(2----20%)20%)20%)20%)

Diffuse Parenchymal Lung Diseases

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Approach to the Diagnosis of

ILD: It Often Takes A Village!

Primary Care Pulmonologists Radiologists Pathologists

Multidimensional and multidisciplinary

Clinical

� History

� Physical

� Laboratory

� PFTs

Radiology

� Chest X-ray

� HRCT

Pathology

� Surgical lung

biopsy

ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2002;165:277-304.

Rheumatologists

Idiopathic Pulmonary Fibrosis

2011 Joint ATS/ERS/JRS/ALAT Statement Am J 2011 Joint ATS/ERS/JRS/ALAT Statement Am J 2011 Joint ATS/ERS/JRS/ALAT Statement Am J 2011 Joint ATS/ERS/JRS/ALAT Statement Am J RespirRespirRespirRespir CritCritCritCrit Care Med 183: 788Care Med 183: 788Care Med 183: 788Care Med 183: 788----824.824.824.824.

• Specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring in

adults (55–75 years),

• Associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia (UIP).

Weycker D, et al. Prevalence, Incidence, and Economic Costs of Idiopathic Pulmonary

Fibrosis. Paper presented at: CHEST 2002 San Diego, CA.

Estimated 83,000 Current

Patients in the United States

Estimated 31,000 New Patients per

Year in the United States

0

50

100

150

200

250

300

45–54 55–64 65–74 75+

Male

Female

0

20

40

60

80

100

120

45–54 55–64 65–74 75+

Male

Female

PrevalenceIncidence

Pe

r H

un

dre

d T

ho

usa

nd

Pe

r H

un

dre

d T

ho

usa

nd

Incidence and prevalence of IPF

increases markedly with age

Clinical course of IPF/UIP is

variable and may be difficult to

predict.

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Heterogeneous Natural History

Pattern In Patients With IPF

King, Pardo, Selman. Lancet 2011; 378: 1949–61

IPF is not an inflammatory

disorder…

Selman, M. King TE, Jr, Pardo A. Idiopathic Pulmonary Fibrosis: Progress in Understanding Its Pathogenesis and

Implications for Therapy. Ann Intern Med 2001; 134;:136-151

It is a fibroproliferative disorder

preceded by epithelial activation.

Multiple microfoci

of epithelial injury

Focal fibroblast proliferation

Type 2 pneumocyte

proliferation and activation

Primary Sites of Ongoing Injury and

Repair Are the Fibroblast Foci

Selman, M. King TE, Jr, Pardo A. Idiopathic Pulmonary Fibrosis: Progress in Understanding Its Pathogenesis and

Implications for Therapy. Ann Intern Med 2001; 134;:136-151

IPF may represent a primary failure of

the alveolar epithelium, due in part to

age-related changes in cellular function.

Age & Pathogenesis

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October 15, 2014

The FDA granted Esbriet (pirfenidone) and Ofev (nintedanib)

fast track, priority review, orphan product, and breakthrough

designations.

Why has it taken so long

to get here?

Current animal models are NOT useful in the

development of novel therapies for IPF because

animal models do NOT produce a fibrotic injury

that looks or acts in any way like IPF/UIP!

TTTTo date…o date…o date…o date…

Need to rely more on

translational rather than

basic science.

IPFnet is a network of

~26 medical centers

across the U.S.A. dedicated

to the study of IPF

PANTHER Trials

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We “confused” ourselves about

the value of prednisone (with or

without cytotoxic agents)!

Why Did We Use Corticosteroids

to Treat IPF?

� Rationale: treat

inflammation, slow

fibroblastic proliferation and

prevent irreversible fibrosis

� Some patients experience a

precipitous decline when

steroids were stopped, so,

they appeared to be working

� No other therapy available“If you remember I did mention possible

side effects.”

ILD: Responsiveness to Treatment

Bronchiolitis

DAD

DAH

PAP

OP

““““LIP””””

NSIP Eos Pn

DIP

Vasc

RB-ILD

FamilialIPF

UIP

AmyloidLAM

AIP

We “over” valued

underpowered, poorly designed

studies of therapies.

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Cyclophosphamide Appears to

Improve Survival in IPF

Johnson et al. Randomised controlled trial comparing prednisolone alone with cyclophosphamide and

low dose prednisolone in combination in cryptogenic fibrosing alveolitis. Thorax 1989;44:280-288

% S

till

a

liv

e

Y e a r s

0 1 2 3 4 5

Prednisolone + Cyclophosphamide (n=21)

Prednisolone (n=22)

100

80

20

60

40

0

p = N.S.

“Many patients, however, failed to

respond to either treatment.”

Chest. 2004; 125:2169-74.

We “ignored” the widely

recognized adverse events

associated with common

therapies.

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We could not agree on disease

definition.

Am J Respir Crit Care Med Vol 161. pp 646–664, 2000

NO GLOBAL INVOLVEMENT UNTIL ~2000:

• More precise diagnosis• Pharmaceutical company interest• Patient encouragement and advocacy

Treatment Trials19891989 2014201420002000

JohnsonJohnson

Cyclophosphamide

RaghuRaghu

Azathioprine

WinterbauerWinterbauer

Azathioprine

DouglasDouglas

Colchicine

ZiescheZiesche

IFN-γ

RaghuRaghu

IFN-γ

KuboKubo

Warfarin

AzumaAzuma

Pirfenidone

DemedtsDemedts

NAC

KingKing

IFN-γ

CAPACITY 1/2CAPACITY 1/2

Pirfenidone

KingKing

Bosentan

TOMORROWTOMORROW

Nintedanib

BUILD-3BUILD-3

Bosentan

Anti-TGFβAnti-TGFβImatinibImatinib

InfliximabInfliximab

STEPSTEP

Sildenafil

Anti-CCL2Anti-CCL2

AmbrisentanAmbrisentan

PANTHERPANTHER

NAC

ShionogiShionogi

Pirfenidone

ACEACE

Warfarin

RaghuRaghu

Pirfenidone

RaghuRaghu

Etanercept

Slide courtesy of Luca Richeldi

What have we tried…

ImmunomodulationAnti-inflammatory

Immunosuppression

Anti-fibrotic

Anti-oxidant Anti-proliferative

ASCENDASCEND

Pirfenidone

INPULSIS 1 & 2INPULSIS 1 & 2

Nintedanib

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There is no cure for IPF/UIP.

Can we slow the

progression or improve

survival of IPF/UIP?

• IFIGENIA Trial• PANTHER trial• NAC Trial• INPLUSIS-1 and INPLUSIS-2 • ASCEND Trial

IFIGENIANAC + azathioprine + steroids

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N Engl J Med 2005;353:2229-2242.

NEJM 2005; 353: 2229-42

-10

-8

-6

-4

-2

0

2 Baseline Endpoint 6m Endpoint 12m

NAC

Placebo

Pred/Aza/NAC (n=)Pred/Aza/Placebo (n=)

8075

6360

5551

VC

(%

Pre

dict

ed)

Mortality

9%

11%

IFIGENIA Trial

• Addition of NAC to low-dose prednisone and azathioprine may help to preserve

pulmonary function in patients with IPF.

• However, a drop-out rate of ∼30% (including deaths) raised concerns

regarding the clinical relevance and

robustness of the treatment effect.

IMPLICATIONS FOR PATIENT CARE“NAC Treatment for IPF”

PANTHERNAC + azathioprine + steroids

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N Engl J Med 2012; 366:1968-1977

Time Until Disease Progression or Death

(Decrease in Forced Vital Capacity of ≥10%)

The Idiopathic Pulmonary Fibrosis Clinical Research Network. N Engl J Med 2012;366:1968-1977

HR 1.46 (95% CI: 0.70–3.05)

P = 0.30Kaplan–Meier

Curve

Time Until Hospitalization or Death

The Idiopathic Pulmonary Fibrosis Clinical Research Network. N Engl J Med 2012;366:1968-1977

HR: 3.74 (95% CI: 1.68–8.34)

p

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Triple therapy had higher incidence of

adverse events than placebo

0

5

10

15

20

25

30

35

Placebo Pred/Aza/NACP-values < 0.05

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

Percentage

IMPLICATIONS FOR PATIENT CARE“Treatment of IPF”

• Compelling evidence against the use of the combination of azathioprine, prednisone,

and NAC for patients with IPF who have

mild-to-moderate impairment in pulmonary

function.

• Death rates in clinical trials are below historical expectation.

Demonstrates Mild to Moderate IPF

Patients Have a Low Mortality Rate

100

80

90

95

0 1047813

Weeks

Per

cent

Sur

viva

l

65 9126 39 52

85

Placebo patients from INSPIRE and CAPACITY Trials (n=622)

Death Rate in IPF Has Declined?

Years

76543210

0

20

40

60

80

100

UIP

NSIP

% A

live

Daniil ZD et al. Am J Respir Crit Care Med. 1999;160:899.

IPF patients in placebo groups from INSPIRE and CAPACITY

Trials (n=622)

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PANTHERN-acetylcysteine (NAC)

∂

N Engl J Med 2014; 370:2093-2101.

N Engl J Med 2014; 370:2093-2101

NAC Does Not Reduce FVC Decline

Martinez FJ, et al. N Engl J Med. 2014;370(22):2093-2101. N Engl J Med 2014; 370:2093-2101

Acetylcysteine offered no significant benefit with respect to

the preservation of FVC in patients with IPF with mild-to -

moderate impairment in lung function.

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NAC Trial: Conclusions

• As compared with placebo, acetylcysteine offered no significant benefit with respect to

the preservation of FVC in patients with

idiopathic pulmonary fibrosis with mild-to -

moderate impairment in lung function.

INPULSISNintedanib

Possible Mechanisms of Nintedanib Action

• Triple kinase inhibitor• Phosphatase activator• Antiangiogenic,

antitumor activity

VEGF

Nintedanib

PDGF FGF SHP-1

Hilberg F, et al. Cancer Res. 2008;68(12):4774-4782.

Tai WT, et al. J Hepatol. 2014;61(1):89-97.

Pleiotropic Effects

www.PILOTforIPF.ORG

N Engl J Med. 2014;370:2071-82

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Annual rate of change in FVC was

significantly lower in the nintedanib

INPULSIS – 1 INPULSIS – 2

45% Relative

Reduction

52% Relative

Reduction

Nintedanib Reduces Loss of FVC

INPULSIS – 1

INPULSIS – 2

A significantly greater proportion of patients

in nintedanib group had no absolute decline in

the % predicted FVC ≥5% points

Time to 1st acute exacerbation

INPULSIS – 1

INPULSIS – 2

No

Yes

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Common Nintedanib Adverse Events

Event

INPULSIS-1 INPULSIS-2

Nintedanib

(n = 309)

Placebo

(n = 204)

Nintedanib

(n = 329)

Placebo

(n = 219)

Any (%) 96 89 94 90

Diarrhea (%) 62 19 63 18

Nausea(%) 23 6 26 7

Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.

59

• “Nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression…”

• “There was significant differences in favor of nintedanib for the time to first acute exacerbation

and the change from baseline in the total SGRQ

score in INPULSIS-2 but not INPULSIS-1.”

• “Nintedanib was frequently associated with diarrhea, which lead to discontinuation of the

study medication in less than 5% of patients.”

INPULSIS trials: CONCLUSION

Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.

ASCENDPirfenidone

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61

Possible Mechanisms of Pirfenidone Action

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

TNF-α

IL-6

Pirfenidone

TGF-β

IL-6

MMPsCollagenases

ROIs

Collagen• Antifibrotic• Molecular target unclear• Active in several animal models of fibrosis

(lung, liver, kidney)

www.PILOTforIPF.ORG

63

Primary Efficacy Analysis: Treatment with pirfenidone

resulted in a significant between-group difference in the

rank ANCOVA analysis (P

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65

ASCEND Study Supportive Analysis:

Annual rate of FVC decline at week 52 favored

Pirfenidone (Linear Slope Analysis)

Absolute Difference, 116 mL/yrRelative reduction: 41.5%

P

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69

• Treatment with pirfenidone for 52 weeks significantly reduced disease progression, as measured by

– Changes in % predicted FVC (p

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Goals of effective IPF management

• Relieve symptoms• Improve exercise tolerance• Improve health status

• Prevent and treat complications• Prevent and treat exacerbations

• Prevent disease progression

• Reduce mortality

Cough, Depression, Sleep,

Pulmonary rehab., GERD,

Supplemental Oxygen

Lung transplantation

These goals should be reached with a minimum of side effects from treatment

New approaches

needed??

•Pirfenidone•N-acetylcysteine (Fluimucil®) •Nintedanib•Sildenafil (advanced disease)

IPF Drugs in the Works

� Gilead: Simtuzumab (anti-LOXL2)

� Fibrogen: FGCL (anti-CTGF)

� Centocor: CNTO 0888 (anti-CCL2)

� Novartis: QAX 576 (anti-IL13)

� Promedior: PRM151 (Petraxin-2)

� Biogen: ST 100 (anti integrin αVβ6)

� MedImmune: Tralokinumab (anti-IL13)

� Sanofi: SAR156597 (anti IL-4 and IL-13)

THANK YOU FOR THANK YOU FOR THANK YOU FOR THANK YOU FOR

YOU ATTENTION.YOU ATTENTION.YOU ATTENTION.YOU ATTENTION.