new therapies and trials in...am j respircritcare med vol161. pp646–664, 2000 no global...
TRANSCRIPT
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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.