Recently Completed Trials in IPF: What have we learned? Where do we go from here?

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Recently Completed Trials in IPFWhat have we
learned?Where do we go from here?

• Charlene D Fell
• University of Calgary

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Disclosures

• Scientific Advisory Board
• Actelion
• InterMune
• Speakers Fees
• GSK, AstraZeneca, Boehringer Ingelheim

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Objectives

• List recent clinical trials in IPF and their
  outcomes
• Discuss the challenges in selecting clinically
  meaningful endpoints for clinical trials in IPF
• Discuss how the natural history of IPF and IPF
  phenotypes contribute to challenges faced in
  designing clinical trials for this disease

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Recent Phase 3 Trials in IPF
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Recent Phase 3 Trials in IPF
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Challenges in selecting endpoints for IPF trials

• Optimal endpoint characteristics
• Clinically meaningful
• Reproducible
• Responsive
• Safe
• Simple
• Cheap

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CAPACITY Trials

• Phase III, RDBPC trial
• PIPF-004 pirfenidone 1197mg/day vs.
  2403mg/day vs. placebo
• PIPF-006 pirfenidone 2403mg/day vs. placebo
• Early IPF
• 1º Endpoint change in FVC at w 72

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PIPF-004
CE-14
0
-5
Mean change from
baseline in FVC
-10
Pirfenidone 2403 mg/d
Pirfenidone 1197 mg/d
Placebo
-15
0
12
24
36
48
60
72
Weeks
Slide courtesy of InterMune
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PIPF-006
CE-23
Pirfenidone 2403 mg/d Placebo
Slide courtesy of InterMune
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PIPF-004 and PIPF-006
? In PIPF-006, patients in the placebo arm had
more stable disease
Data courtesy of InterMune
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CAPACITY Analysis

• Did we choose the right endpoint?
• ?FVC of 10 an accepted surrogate marker for
  mortality in IPF
• Was the trial long enough?
• - 72 weeks
• Was n large enough?
• - gt 750 patients

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BUILD-3

• Phase III RDBPC trial
• Bosentan 125 mg BID vs. placebo (21)
• Early IPF
• Biopsy proven UIP
• lt5 honeycombing on HRCT
• Composite 1º endpoint
• Time to death, disease progression, or
  hospitalization

King, TE. AJRCCM. 181A6838. 2010
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BUILD-3 Primary Outcome
HR 0.85 (0.66 - 1.1), p0.21
King, TE. AJRCCM. 181A6838. 2010
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BUILD-3 Analysis

• Did we choose the right outcome?
• - Time to death, disease progression, or
  hospitalization
• Was the trial long enough?
• - 4 week intervention
• - 1 year follow up
• Was n large enough?
• - Needed 202 events to detect a 35 RRR in 1º
  endpoint

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STEP-IPF

• Phase III, RDBPC trial
• Sildenafil 20 mg TID vs. placebo (11)
• Late IPF
• DLCO lt35 predicted
• 1º outcome proportion of patients with an
  increase in 6MWD of 20 or more

Zisman, D et al. NEJM. 363620. 2010
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STEP-IPF

• 1º Outcome
• Improvement of 20 or more in 6MWD
• Sildenafil 9 of 89
• Placebo 6 of 91
• p0.39

Zisman, D et al. NEJM. 363620. 2010
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STEP-IPF Analysis

• Did we choose the right outcome?
• 20 increase in 6MWD at 12 w
• Baseline 6MWD 265m 20 51m
• After 12 w pulmonary rehab 53m
• MCID in 6MWD is estimated to be 24-40m
• Was the trial long enough?
• 12 weeks of blinded therapy
• Was n large enough?
• 180 patients

Zisman, D et al. NEJM. 363620. 2010
Salhi B. et al. CHEST. 137273-9. 2010
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ARTEMIS

• ARTEMIS-IPF

• ARTEMIS-PH

• Phase III, RDBPC trial
• Ambrisentan 10 mg OD vs. placebo
• IPF
• 1? Outcome Time to death or disease
  progression

• Phase III, RDBPC trial
• Ambrisentan 10 mg OD vs. placebo
• IPF PAH
• 1? Outcome change in 6MWD

Early termination failed to meet endpoints at
interim analysis
www.ClinicalTrials.gov
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Selecting trial outcomes for IPF
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3 Important Lessons from Recent Clinical Trials

• Most patients have stable disease
• Stable disease is punctuated by periods of acute
  deterioration
• There are probably multiple phenotypes of IPF

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Survival in IPF may be better than we think it is
1.0
0.8
0.6
Survival
0.4
0.2
0.0
0
2
4
6
8
Years
Flaherty et al. AJRCCM. 2003 King et al. Lancet.
2004
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Change in FVC and dyspnea in 36 patients in the
placebo arm of GIPF-001 who died during follow up.
Change in physiologic and dyspnea indices In
patients in the placebo arm of GIPF-001 Who
survived during follow up.
FVC
Dyspnea
Martinez, FJ et al. Ann Int Med. 2005
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GIPF-001 Trial IFN-gamma in IPF

• The majority of patients with IPF have a stable
  course.
• Patients with mild/moderate disease can have
  acute exacerbations of IPF.
• More frequent evaluation of patients
• Early referral for lung transplantation

Martinez, FJ et al. Ann Int Med. 2005
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Raghu, G. et al. AJRCCM 183.788-824. 2011
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Pulmonary hypertension and IPF
Lettieri C J et al. Chest 2006129746-752
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Gender differences in PH in IPF
patientsSubanalysis of the STEP-IPF Trial
Han, MK et al. AJRCCM. 181A1112. 2010
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Emphysema and IPF
Mejía M et al. Chest 200913610-15
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Challenges in selecting endpoints for IPF trials

• Optimal endpoint characteristics
• Clinically meaningful
• Reproducible
• Responsive
• Safe
• Simple
• Cheap

? Applicable across all phenotypes
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Some challenges in clinical research in IPF

• Patients with IPF are more stable than once
  thought
• There are likely multiple phenotypes of IPF
• Males vs. Females
• IPF and PAH
• IPF and emphysema
• .others?
• Acute exacerbations must be accounted for in
  trial outcomes

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Summary

• Pirfenidone is promising but lacks regulatory
  approval in Canada
• The role of ET antagonists in IPF is unclear
• Clinical trials have been negative
• Most patients have stable disease
• Stable disease is punctuated by acute
  exacerbations
• There are probably multiple IPF phenotypes

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What can we learn from these trials?
www.ClinicalTrials.gov
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Thank You
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What is Idiopathic Pulmonary Fibrosis?

• Chronic, progressive fibrotic pulmonary disease
• No known cause
• No effective therapies currently available
  outside Japan
• Mean survival after diagnosis is 3 years

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Slides courtesy of Dr. M Kelly
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Thannickal VJ et al. Annu Rev Med. 2004.
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Management of IPF

• Refer for lung transplantation
• Enroll in a clinical trial
• Weak evidence against the use of
• Combined NAC/AZA/prednisone
• NAC monotherapy
• Anticoagulation
• Pirfenidone
• Pulmonary rehabilitation
• Supportive care/palliation

Raghu, G. et al. AJRCCM 183.788-824. 2011
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• Retrospective analysis of patients in the
  placebo arm of GIPF-001
• 36 patients in the placebo arm died
• 31 had deaths related to IPF

Martinez, FJ et al. Ann Int Med. 2005
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INSPIRE Trial IFN-gamma in IPF
Du Bois et al. AJRCCM. 2010A1103
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A classification of IPF based on simple lung
function criteria
Egan JJ et al. Thorax 60270-273. 2005
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I like to say that we can describe the conduct
of a trial three ways it can be trustworthy,
fast, or cheap. Generally speaking, a trial can
have only two of these characteristics. If a
trial is fast and cheap, it is unlikely to be
trustworthy.
Zivin, JA. Scientific American 282(4)69-75. 2000
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Some challenges in clinical research in IPF

• Heterogeneity in outcomes
• Uncertain surrogate markers of mortality
• FVC ?10 or ?5?
• The problem of missing data (LOCF not appropriate
  in this disease)
• Inadequate of expert clinical sites
• Agents are expected to stabilize disease, not
  reverse it.
• Treatment effects will be small.
• Therefore need longer/larger trials to see an
  effect.
• Patients are referred late in their course -
  ineligible for early IPF trials

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