Fell by A2O6N02

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


          Charlene D Fell
         University of Calgary
Disclosures

Scientific Advisory Board
     –   Actelion
     –   InterMune
Speaker’s Fees
     –   GSK, AstraZeneca, Boehringer Ingelheim
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
                       Recent Phase 3 Trials in IPF

      Intervention         N            Primary Outcome                 Status
Pirfenidone (CAPACITY)
  PIPF-004                 435   Change in FVC%                         Positive
  PIPF-006                 344   Change in FVC%                         Negative

N-acetylcysteine
 IFIGENIA                  182   Change in VC and DLCO                  Positive
(NAC+predinsone+AZA)

IFN-1b
  GIPF-001                 330   Progression-free survival              Negative
  INSPIRE                  826   Survival time from randomization       Negative

Imatinib                   119   Time to disease progression or death   Negative

Bosentan
 BUILD 1                   158   Change in 6MWD                         Negative
 BUILD 3                   616   Death or disease progression           Negative

Sildenafil
 STEP-IPF                  180   Change in 6MWD                         Negative

Ambrisentan
 ARTEMIS-IPF               600   Death or disease progression           Negative
 ARTEMIS-PH                225   Change in 6MWD                         Negative
                       Recent Phase 3 Trials in IPF

      Intervention         N            Primary Outcome                 Status

Pirfenidone (CAPACITY)
  PIPF-004                 435   Change in FVC%                         Positive
  PIPF-006                 344   Change in FVC%                         Negative

N-acetylcysteine
 IFIGENIA                  182   Change in VC and DLCO                  Positive
(NAC+predinsone+AZA)

IFN-1b
  GIPF-001                 330   Progression-free survival              Negative
  INSPIRE                  826   Survival time from randomization       Negative

Imatinib                   119   Time to disease progression or death   Negative

Bosentan
 BUILD 1                   158   Change in 6MWD                         Negative
 BUILD 3                   616   Death or disease progression           Negative

Sildenafil
 STEP-IPF                  180   Change in 6MWD                         Negative

Ambrisentan
 ARTEMIS-IPF               600   Death or disease progression           Negative
 ARTEMIS-PH                225   Change in 6MWD                         Negative
Challenges in selecting endpoints for IPF trials


Optimal endpoint characteristics
    –   Clinically meaningful
    –   Reproducible
    –   Responsive
    –   Safe
    –   Simple
    –   Cheap
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
                                                                                         CE-14
   PIPF-004

                              0
           Mean change from
           baseline in %FVC


                               -5




                              -10
                                     Pirfenidone 2403 mg/d
                                     Pirfenidone 1197 mg/d
                                     Placebo
                              -15
                                 0       12       24      36     48    60           72
                                                         Weeks
Pirfenidone 2403 mg/d vs Placebo
Absolute difference, %         1.4               2.5    4.6     4.8     4.1    4.4
Relative difference, %        53.5               65.2  63.7    52.3    38.3   35.3
p-value                      0.061              0.014 < 0.001 < 0.001 < 0.001 0.001
                                                                       Slide courtesy of InterMune
                                                                                           CE-23

PIPF-006
                             0
         Mean change from
         baseline in %FVC

                             -5



                            -10

                                      Pirfenidone 2403 mg/d
                                      Placebo
                            -15
                                  0      12       24      36      48      60          72
                                                         Weeks
Absolute difference, %                 -0.4      2.8      2.4     1.9     0.6        0.6
Relative difference, %                -31.5     62.1     48.2    27.3     7.6        6.5
p-value                               0.021    < 0.001   0.011   0.005   0.172      0.501
                                                                           Slide courtesy of InterMune
                              PIPF-004 and PIPF-006
Mean change from     0
baseline in %FVC



                     -5



                    -10



                    -15
                          0      12   24    36     48   60         72
                                           Weeks

                    In PIPF-006, patients in the placebo arm
                   had more stable disease
                                                             Data courtesy of InterMune
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?
   −   > 750 patients
BUILD-3
Phase III RDBPC trial

Bosentan 125 mg BID vs. placebo (2:1)

“Early IPF”
    – Biopsy proven UIP
    – <5% honeycombing on HRCT


Composite 1º endpoint:
    – Time to death, disease progression, or hospitalization




                                                          King, TE. AJRCCM. 181:A6838. 2010
BUILD-3 Primary Outcome

                             Bosentan              Placebo
                              (n=407)              (n=209)
 Death                          11                     6

 Hospitalization                19                     6

 FVC 10%                      128                    82
 DLCO 15%
 Combined                    158 (38%)            94 (45%)




                   HR 0.85 (0.66 - 1.1), p=0.21

                                            King, TE. AJRCCM. 181:A6838. 2010
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
STEP-IPF
Phase III, RDBPC trial

Sildenafil 20 mg TID vs. placebo (1:1)

“Late IPF”
    – DLCO <35% predicted


1º outcome: proportion of patients with an increase in 6MWD of
   20% or more




                                               Zisman, D et al. NEJM. 363:620. 2010
STEP-IPF

1º Outcome
Improvement of 20% or
more in 6MWD
  – Sildenafil: 9 of 89
  – Placebo: 6 of 91
  – p=0.39




                          Zisman, D et al. NEJM. 363:620. 2010
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. 363:620. 2010
                                                 Salhi B. et al. CHEST. 137:273-9. 2010
ARTEMIS

    ARTEMIS-IPF                        ARTEMIS-PH
•   Phase III, RDBPC trial             •   Phase III, RDBPC trial
•   Ambrisentan 10 mg OD vs. placebo   •   Ambrisentan 10 mg OD vs. placebo
•   IPF                                •   IPF + PAH
•   1 Outcome: Time to death or       •   1 Outcome: change in 6MWD
    disease progression




Early termination: failed to meet endpoints at interim analysis



                                                               www.ClinicalTrials.gov
Selecting trial outcomes for IPF:

                     Survival   FVC   6MWD
    • Clinically                     
      meaningful
    • Reproducible                   
    • Responsive        ?        ?     ?
    • Safe                           
    • Simple                         
    • Cheap                          
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
Survival in IPF may be better than we think it is…

                 1.0
                 0.8



                               IFN (INSPIRE)
      Survival
                 0.6
                 0.4
                 0.2
                 0.0




                       0   2    4         6             8

                               Years




                                                Flaherty et al. AJRCCM. 2003
                                                      King et al. Lancet. 2004
                                                 Change in FVC and dyspnea in 36
                                                patients in the placebo arm of GIPF-
Change in physiologic and dyspnea indices          001 who died during follow up.
In patients in the placebo arm of GIPF-001
       Who survived during follow up.


                                      FVC

                                      Dyspnea




                                                         Martinez, FJ et al. Ann Int Med. 2005
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
Raghu, G. et al. AJRCCM 183.788-824. 2011
Pulmonary hypertension and IPF




                       Lettieri C J et al. Chest 2006;129:746-752
Gender differences in PH in IPF patients
Subanalysis of the STEP-IPF Trial

                  Characteristic    Men        Women           p
                                    N=86        N=19
     Age                            67.8         67.6        0.92
     FVC%                           56.8         55.6        0.73
     DLCO%                          25.7         26.0        0.60
     Mean RVSP                      45.2         32.5        0.002
     Prevalence of PH (PASP≥40)     34%          0%        <0.0001
     RA Hypertrophy                 13%          0%         0.0004
     RV Systolic Dysfunction        20%          10%         0.03
     LV Systolic Dysfunction        5%           10%         0.91



                                           Han, MK et al. AJRCCM. 181:A1112. 2010
Emphysema and IPF




                    Mejía M et al. Chest 2009;136:10-15
Challenges in selecting endpoints for IPF trials


Optimal endpoint characteristics
    –   Clinically meaningful
    –   Reproducible
    –   Responsive
    –   Safe
    –   Simple
    –   Cheap
       Applicable across all phenotypes
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
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
          Intervention               N               Primary Outcome                      Status

N-acetylcysteine
 PANTHER                             390   Change in FVC                                Recruiting
(NAC vs. NAC+predinsone+AZA vs. P)



Anticoagulation (warfarin)                 Time to death, hospitalization, or
 ACE-IPF                             256   FVC by 10%                                  Recruiting
Macitetan
 MUSIC                               156   Change in FVC                                Recruiting

  BIPF 1120                          485   Annual rate of decline of FVC (ml/52 wk)   Not yet recruiting

  CC-930                             36    Safety of CC-930                             Recruiting
   (phase 2)

  FG-3019                            48    Safety of FG-3019                            Recruiting
(phase 2a open label)




What can we learn from these trials?


                                                                                       www.ClinicalTrials.gov
Thank You
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




   May 2005                    Nov 2005                    Apr 2006
Slides courtesy of Dr. M Kelly
Thannickal VJ et al. Annu Rev Med. 2004.
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
• Retrospective analysis of patients in the placebo arm
of GIPF-001
    • 36 patients in the placebo arm died
    • 31 had deaths related to IPF

       Primary Cause   Acute Deaths   Subacute Deaths
          of Death        (n=15)          (n=16)
      Progression of        6                14
      IPF
      Pneumonia             4                 0

      ARDS                  2                 0

      Cor Pulmonale         1                 0

      Other                 0                 1

      Unknown               2                 1


                                         Martinez, FJ et al. Ann Int Med. 2005
   INSPIRE Trial: IFN-gamma in IPF

                         HR    95% CI           p
Baseline    <250         2.7   1.5,4.8          0.001
6MWD
            250-349      1.5   0.9, 2.6         0.106


            >350


Change in   <-50         4.3   2.6, 7.1         <0.001
6MWD
            -50 to -26   3.6   2.0, 6.7         <0.001


            >-25




                                          Du Bois et al. AJRCCM. 2010:A1103
A classification of IPF based on simple lung function criteria




                                      Egan JJ et al. Thorax 60:270-273. 2005
“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
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
FVC




      Time

								
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