Transcript action.lung.org

A NEW ERA in IPF:
Trials and Treatments
Craig Thurm, MD
Director, Pulmonary Medicine
Director, Pulmonary Fellowship
Medical Director, Respiratory Care
Jamaica Hospital Medical Center
Disclosure of Relevant
Financial Relationships
It is the policy of The France Foundation to ensure balance,
independence, objectivity, and scientific rigor in all its sponsored
educational activities. All faculty, activity planners, content reviewers,
and staff participating in this activity will disclose to the participants
any significant financial interest or other relationship with
manufacturer(s) of any commercial product(s)/device(s) and/or
provider(s) of commercial services included in this educational activity.
The intent of this disclosure is not to prevent a person with a relevant
financial or other relationship from participating in the activity, but
rather to provide participants with information on which they can base
their own judgments. The France Foundation has identified and
resolved any and all conflicts of interest prior to the release of this
activity.
Faculty Disclosures
Craig Thurm, MD has received research and grant support from
Boehringer Ingelheim, Bristol-Myers Squibb, Cubist, and Forest
Pharmaceuticals. He has served as a consultant for Meda
Pharmaceuticals and Sunovion Pharmaceuticals, and is a shareholder
with Teva Pharmaceuticals. He has received honoraria from Boehringer
Ingelheim, CSL Behring, Forest Pharmaceuticals, GlaxoSmithKlein,
InterMune, Janssen Pharmaceuticals, and Merck.
Activity Staff Disclosures
The planners, reviewers, editors, staff, or other members at
The France Foundation who control content have no relevant
financial relationships to disclose.
Educational Support
Supported by educational grants from Boehringer Ingelheim and
InterMune.
Accreditation / Designation Statements
The France Foundation is accredited with
commendation by the Accreditation Council for
Continuing Medical Education (ACCME) to provide
continuing medical education for physicians.
The France Foundation designates this activity for a
maximum of 1.0 AMA PRA Category 1 Credit™.
Physicians should claim only the credit commensurate
with the extent of their participation in the activity.
How to Receive CME Credit
• Complete the pretest (page one of your handout)
and give this page to the coordinator when you leave
• Keep page two of your handout and follow the
instructions to go online to claim CME credit
• Your CME certificate will be available to download
Educational Activity Learning Objective
Upon completion of this course, the participants should be able
to:
• Explain the considerations associated with clinical evaluation,
imaging, and surgical biopsy in differentially diagnosing IPF
• Identify opportunities for interdisciplinary collaboration and
consultation and key aspects of guideline recommendations
that can facilitate early and accurate IPF diagnosis
• Summarize the current understanding of the IPF disease
process and strategies that can help measure disease
progression and treatment response
• Evaluate clinical trial data on available and emerging
treatments for IPF
• Identify opportunities for referral as part of multidisciplinary
IPF management plan
Outline
• Diagnosis
• Pathophysiology model
• IPF drug trials
– PANTHER (NAC)
– ASCEND (pirfenidone)
– INPULSIS (nintedanib)
• Recent drug approvals!
• Referral of patients with IPF
Idiopathic Pulmonary Fibrosis
• Peripheral lobular fibrosis of unknown cause
• Clinical impact
•
•
– Exertional dyspnea
– Cough
– Functional and exercise limitation
– Impaired quality-of-life
– Risk for acute respiratory failure and death
Median survival time of 3-5 years
Two new drugs approved by the FDA in October 2014
‒ Nintedanib (Ofev)
‒ Pirfenidone (Esbriet)
Diffuse Parenchymal Lung Disease (DPLD)
Idiopathic
interstitial
pneumonias
DPLD of known cause, eg,
drugs or association, eg,
collagen vascular disease
Idiopathic
pulmonary
fibrosis
Granulomatous
DPLD, eg,
sarcoidosis
Other forms of
DPLD, eg, LAM,
HX, etc
IIP other than
idiopathic
pulmonary fibrosis
Desquamative interstitial
pneumonia
Respiratory bronchiolitis
interstitial lung disease
Acute interstitial pneumonia
Cryptogenic organizing
pneumonia
Nonspecific interstitial
pneumonia (provisional)
Lymphocytic interstitial
pneumonia
ATS/ERS Consensus Statement. Am J Respir Crit Care Med. 2002;165:277-304.
Major Idiopathic Interstitial Pneumonias
Category
Chronic
fibrosing
Smokingrelated
Acute/
subacute
Clinical-Radiologic-Pathologic
Diagnosis
Associated Radiographic
and/or Pathologic pattern
IPF
UIP
Idiopathic nonspecific interstitial
Pneumonia (iNSIP)
NSIP
Respiratory bronchiolitis-ILD (RB-ILD)
Respiratory bronchiolitis
Desquamative interstitial pneumonia (DIP)
Desquamative interstitial
pneumonia
Cryptogenic organizing pneumonia (COP)
Organizing pneumonia
Acute interstitial pneumonia (AIP)
Diffuse alveolar damage
Travis et al. Am J Respir Crit Care Med. 2013;188:733-748.
Diagnostic Algorithm for IPF
Suspected IPF
Identifiable causes
for ILD?
No
HRCT
Possible UIP
Inconsistent w/ UIP
Surgical Lung
Biopsy
UIP
Probable UIP
Non-classifiable fibrosis
MDD
IPF
IPF/Not IPF
Raghu G, et al. Am J Respir Crit Care Med. 2011;183:788-824.
Not IPF
2011 ATS/ERS Diagnostic Criteria for IPF
UIP pattern on HRCT without
surgical biopsy
Exclusion of known
causes of ILD*
AND
*also known as diffuse parenchymal lung disease, DPLD
Raghu G, et al. Am J Respir Crit Care Med. 2011;183:788-824.
OR
Definite/possible UIP pattern
on HRCT with a surgical lung
biopsy showing
definite/probable UIP
Idiopathic Pulmonary Fibrosis
Normal Lungs
Usual Interstitial Pneumonia
Idiopathic Pulmonary Fibrosis
Normal Lung
Usual Interstitial Pneumonia
Idiopathic Pulmonary Fibrosis
Normal Lung
Fibroblastic Focus in
Usual Interstitial Pneumonia
Clinical-Radiologic-Pathologic Approach to ILD
Radiologic
pattern (HRCT)
Pathologic
pattern
(lung biopsy)
Clinical
picture
Specific
diagnosis
ILD Disease Progression
Exogenous and
Endogenous stimuli
Dust
Fumes
Cigarette smoke
Autoimmune conditions
Drugs
Infections-viruses
Radiation
Other diseases
Microscopic lung injury:
Separated spatially and temporally
Intact
Wound healing
Aberrant
Genetic
predisposition
Lung homeostasis
Steele MP, Schwartz DA. Annu Rev Med. 2013;64:265-276.
Interstitial lung disease
Eras of Care for IPF
Pre-ATS
Statement 2011
ATS Statement
2011
2011-2013
2014
Completed Trials for IPF:
Prior to 2011 Consensus Statement
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
Pirfenidone (CAPACITY 2)
435
Change in FVC
Positive
Pirfenidone (Ogura)
275
Change in FVC
Positive
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
Anticoagulation
56
N-acetylcysteine (NAC) (IFIGENIA)
184
Sildenafil (STEP)
29
Subsequent Survival
trials showed that warfarin
Positive
and NAC/azathioprine/prednisone
Change in FVC, DLco
Positive
should not be used for IPF
Change in 6MWD, Borg dyspnea index
Noth I, et al. Am J Respir Crit Care Med. 2012 Jul 1;186(1):88-95.\
Negative
2011 Guidelines on Management of IPF
Treatment
Strong
For
Weak
For
Weak
Against
Strong
Against
Corticosteroid
X
Colchicine
X
Cyclosporine A
X
Interferon γ 1b
X
Bosentan
X
Etanercept
X
NAC/Azathioprine/Prednisone
X
NAC
X
Anticoagulation
X
Pirfenidone
X
Mechanical ventilation
X
Pulmonary rehab
X
Long-term oxygen
X
Lung transplantation
X
Three Recent IPF Clinical Trials
American Thoracic Society 2014
• PANTHER
• ASCEND
• INPULSIS
N-acetylcysteine (NAC)
pirfenidone
nintedanib (BIBF1120)
PANTHER
N-acetylcysteine (NAC)
NAC Does Not Reduce FVC Decline
Conclusion: NAC offered
no significant benefit
with respect to the
preservation of FVC in
patients with IPF with
mild-to-moderate
impairment in lung
function
Martinez FJ, et al. N Engl J Med. 2014;370(22):2093-2101.
ASCEND
Pirfenidone
Possible Mechanisms of Pirfenidone Action
• Antifibrotic
• Molecular target
•
unclear
Active in several
animal models of
fibrosis (lung,
liver, kidney)
Hilberg O, et al. Clin Respir J. 2012;6:131-143.
Pirfenidone
TNF-α
IL-6
TGF-β
IL-6
MMPs
Collagenases
Collagen
ROIs
Pre-2011
ATS
2011
2011-2013
CAPACITY 2011
CAPACITY-2
CAPACITY-1
• One pirfenidone trial was positive, one was negative
• CAPACITY-1 placebo group FVC declined more slowly than expected
Noble P, et al. Lancet. 2011;377:1760-1769.
2014
CAPACITY Endpoints
Endpoint
CAPACITY-2
CAPACITY-1
FVC

X
Overall survival
X
X
Progression-free survival

X
Six-minute walk distance
X

DLCO
X
X
Dyspnea
X
X
Exertional desaturation
X
X
Noble P, et al. Lancet. 2011;377:1760-1769.
Pre-2011
ASCEND 2014
ATS
2011
2011-2013
2014
ASCEND Study Design
52 Weeks
Inclusion Criteria
•
•
•
•
•
•
Age 40-80
Confirmed IPF
50 - 90% FVC pred
30 - 90% DLCO pred
FEV1/FVC ≥ 0.80
6-MWD ≥ 150 m
555 Patients
PFS - Progression-free survival
King TE, et al. N Engl J Med. 2014;370(22):2083-2092.
Endpoints
Oral Pirfenidone
2403 mg Daily
Placebo
10: Δ FVC or death
20: 6-MWD
PFS
Dyspnea
Death
Primary ASCEND Endpoint Achieved
Patients with ≥ 10% FVC
Decline or Death (%)
Primary
Endpoint
48% Relative
Reduction
Week
King TE, et al. N Engl J Med. 2014;370(22):2083-2092.
Pirfenidone Increased
Progression-Free Survival*
*Progression is first occurrence of death,
10% ↓ FVC, or 50 m ↓ 6MWD
King TE, et al. N Engl J Med. 2014;370(22):2083-2092.
Mean Change (ml)
Pirfenidone Reduces Loss of FVC
235 ml
Rank ANCOVA P-value < 0.00001
at each indicated time point
428 ml
Week
King TE, et al. N Engl J Med. 2014;370(22):2083-2092.
<0.000001
Proportion of Patients with
≥50 m Decline or Death (%)
More Pirfenidone Patients Maintain Walk
Distance or Survive
King TE, et al. N Engl J Med. 2014;370(22):2083-2092.
Week
ASCEND Adverse Events
Adverse Event
Nausea
Rash
Dyspepsia
Anorexia
GERD
Weight Loss
Insomnia
Dizziness
Vomiting
Pirfenidone (%) Placebo (%)
(N = 278)
(N = 277)
36
13.4
28.1
8.7
17.6
6.1
15.8
6.5
11.9
6.5
12.6
7.9
11.2
6.5
17.6
13
12.9
8.7
…
Dyspnea
Cough
IPF
King TE, et al. N Engl J Med. 2014;370(22):2083-2092.
Δ (%)
22.6
19.4
11.5
9.3
5.4
4.7
4.7
4.6
4.2
…
…
…
14.7
25.2
9.4
17.7
29.6
18.1
-3
-4.4
-8.7
Pirfenidone Associated with Less Mortality
ASCEND and CAPACITY data
From randomization to 28 days after last dose
Cox proportional hazard model
Log-rank test
King TE, et al. N Engl J Med. 2014;370(22):2083-2092.
ASCEND Summary
• Treatment with pirfenidone for 52 weeks significantly
reduced disease progression, as measured by
– Changes in % predicted FVC (P < 0.001)
– Changes in 6-minute walk distance (P = 0.04)
– Progression-free survival (P < 0.001)
• Treatment with pirfenidone reduced all-cause
mortality and treatment emergent IPF-related
mortality in pooled analyses at week 52
• Pirfenidone was generally safe and well tolerated
King TE, et al. N Engl J Med. 2014;370(22):2083-2092.
ASCEND Conclusions
• Pirfenidone, as compared with placebo, reduced
disease progression in patients with IPF
• Treatment was generally safe, had an
acceptable side effect profile, and was
associated with fewer deaths
37
FDA Approval of Pirfenidone (Esbriet)
• Approved October 15, 2014
• Indicated for the treatment of IPF
• Dosage and administration
– 801 mg (three 267 mg capsules) three times daily with food
– Doses should be taken at the same time each day
– Initiate with titration
• Days 1 through 7: 1 capsule 3x per day
• Days 8 through 14: 2 capsules 3x per day
• Days 15 onward: 3 capsules 3x per day
– Consider temporary dosage reduction, treatment
•
interruption, or discontinuation for management of
adverse reactions.
Prior to treatment, conduct liver function tests.
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.
DrugDetails/. Accessed October 2014.
38
Pirfenidone Warnings and Precautions
Temporary dosage reductions or discontinuations may be required
• Elevated liver enzymes: ALT, AST, and bilirubin
elevations have occurred with pirfenidone. Monitor
ALT, AST, and bilirubin before and during treatment.
• Photosensitivity and rash: Photosensitivity and rash
have been noted with pirfenidone. Avoid exposure to
sunlight and sunlamps. Wear sunscreen and protective
clothing daily.
• Gastrointestinal disorders: Nausea, vomiting, diarrhea,
dyspepsia, gastro-esophageal reflux disease, and
abdominal pain have occurred with pirfenidone.
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.
DrugDetails/. Accessed October 2014.
Pirfenidone: Other Considerations
• Post-marketing experience (reactions of unknown frequency)
– Agranulocytosis
– Angioedema
– Bilirubin increased in combination with increases of ALT and AST
• Drug interactions
– Metabolized primarily via CYP1A2
– Activators and inhibitors of CYP1A2 should be used with caution with
pirfenidone
• Use with caution with mild/moderate hepatic impairment, not
•
•
recommended for patients with severe impairment
Use with caution with mild/moderate/severe renal impairment, not
recommended for patients with ESRD requiring dialysis
Smoking causes decreased exposure to pirfenidone. Instruct patients to
stop smoking prior to treatment with pirfenidone and to avoid smoking
when using pirfenidone.
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.
DrugDetails/. Accessed October 2014.
INPULSIS
Nintedanib
Possible Mechanisms of Nintedanib Action
• Triple kinase inhibitor
• Phosphatase activator
• Antiangiogenic,
antitumor activity
Nintedanib
VEGF
PDGF
FGF
Pleiotropic Effects
Hilberg F, et al. Cancer Res. 2008;68(12):4774-4782.
Tai WT, et al. J Hepatol. 2014;61(1):89-97.
SHP-1
Nintedanib Showed Promise
for FVC Endpoint
Richeldi L, et al. N Engl J Med.2011:365;1079-1089.
Pre-2011
ATS
2011
2011-2013
2014
Pre-2011
INPULSIS 2014
ATS
2011
2011-2013
2014
INPULSIS-1 and INPULSIS-2 Study Design
52 Weeks
Inclusion Criteria
•
•
•
•
•
Age > 40
IPF ≤ 5y
≥ 50% FVC pred
30 - 79% DLCO pred
HRCT within 1y
3
Nintedanib
300 mg Daily
2
1066 Patients
AE – Acute Exacerbation
SGRQ – St. George’s Respiratory Questionnaire
Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.
Placebo
Endpoints
10: ΔFVC
20: Time to first AE
Δ SGRQ
Primary INPULSIS Endpoint Achieved
Annual Rate of Change of FVC
INPULSIS-1
INPULSIS-2
45% Relative
Reduction
52% Relative
Reduction
Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.
Nintedanib
Placebo
Mean Observed Change from Baseline in FVC (mL)
Nintedanib Reduces Loss of FVC
Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.
INPULSIS-1
INPULSIS-2
Week
Cumulative Incidence of First Acute Exacerbation (%)
Mixed Findings for Time to First Acute Exacerbation
Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.
INPULSIS-1
INPULSIS-2
Days
Common Nintedanib Adverse Events
INPULSIS-1
Event
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.
INPULSIS Summary
• Nintedanib had significant benefit in adjusted annual rate of
•
•
change in FVC
• INPULSIS-1
Δ = 125.3 ml
P < 0.001
• INPULSIS-2
Δ = 93.7 ml
P < 0.001
Nintedanib had significant benefit in time to the first acute
exacerbation in INPULSIS-2
• INPULSIS-1
HR = 1.15
P = 0.67
• INPULSIS-2
HR = 0.38
P = 0.005
Significant difference in favor of nintedanib for the change
from baseline in the total SGRQ score in INPULSIS-2 but not
INPULSIS-1
Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.
INPULSIS Conclusions
• Nintedanib reduced the decline in FVC, which is
consistent with a slowing of disease progression
• Nintedanib was frequently associated with
diarrhea, which led to discontinuation of the
study medication in less than 5% of patients
Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.
FDA Approval of Nintedanib (Ofev)
• Approved October 15, 2014
• Indicated for the treatment of IPF
• Dosage and administration
– 150 mg twice daily approximately 12 hours apart
taken with food
– Consider temporary dose reduction to 100 mg,
temporary interruption, or discontinuation for
management of adverse reactions.
– Prior to treatment, conduct liver function tests.
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.
DrugDetails/. Accessed October 2014.
52
Nintedanib Warnings and Precautions
• Elevated liver enzymes: ALT, AST, and bilirubin elevations have occurred with
•
•
•
•
•
nintedanib. Monitor ALT, AST, and bilirubin before and during treatment. Temporary
dosage reductions or discontinuations may be required.
GI disorders: Diarrhea, nausea, and vomiting have occurred with nintedanib. Treat
patients at first signs with adequate hydration and antidiarrheal medicine (e.g.,
loperamide) or anti-emetics. Discontinue nintedanib if severe diarrhea, nausea, or
vomiting persists despite symptomatic treatment.
Embryofetal toxicity: Women of childbearing potential should be advised of the
potential hazard to the fetus and to avoid becoming pregnant.
Arterial thromboembolic events have been reported. Use caution when treating
patients at higher cardiovascular risk including known CAD.
Bleeding events have been reported. Use nintedanib in patients with known bleeding
risk only if anticipated benefit outweighs the potential risk.
GI perforation has been reported. Use nintedanib with caution when treating patients
with recent abdominal surgery. Discontinue nintedanib in patients who develop GI
perforation. Only use nintedanib in patients with known risk of GI perforation if the
anticipated benefit outweighs the potential risk.
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails/.
Accessed October 2014.
53
Nintedanib: Other Considerations
• Drug interactions
– Nintedanib is a substrate of P-glycoprotein (P-gp) and CYP3A4
– Concomitant use of P-gp and CYP3A4 inducers with nintedanib should
–
be avoided
Patients treated with P-gp and CYP3A4 inhibitors and nintedanib
should be monitored closely for adverse reactions
• Nintedanib is a VEGFR inhibitor, and may increase the risk of
•
•
bleeding. Monitor patients on full anticoagulation therapy
closely for bleeding and adjust anticoagulation treatment as
necessary.
Nintedanib not recommended for patients with moderate or
severe hepatic impairment
< 1% excreted via the kidney; no data on patients with severe
renal impairment and ESRD
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails/.
Accessed October 2014.
54
Current Phase 2 Trials for IPF
Next Generation Therapy?
Trial
Target
N
Primary Endpoint
Co-trimoxazole (Ph 3)
Pneumocystis
jiroveci
56
Change in FVC or respir. Hospital’n
FG-3019
Anti-CTGF
90
Change in FVC from baseline
Rituximab
CD-20
58
Titers of anti-HEp-2 autoantibodies
Simtuzumab
Anti-LOXL2
500
PFS
GC-1008
TGF-
25
Safety, tolerability, PK
QAX576
Anti-IL-13
40
Safety, tolerability, FVC
Tralokinumab
Anti-IL-13
302
Change in FVC from baseline
STX-100
αvβ6
32
Adverse events
BMS-986020
LPA Receptor
300
Rate of change in FVC
Clinical Trial Conclusions
• 2014 is a watershed year in IPF
– NAC did not show efficacy (PANTHER)
– Pirfenidone (ASCEND) and nintedanib (INPULSIS) showed
efficacy in mild/moderate IPF
– Pirfenidone and nintedanib approved 10/15/14 for the
treatment of IPF
– Still need data on advanced disease, combination
therapy, long-term safety, adherence
• Implications of having approved drug(s)
– Need early and accurate diagnosis
– Role of IPF and ILD Centers of Excellence is evolving
EARLY REFERRAL for
SPECIALTY CARE
Why refer early to an ILD Center?
• Diagnostic expertise
– Standardized assessment
– Confirmation of diagnosis
• Management expertise
– Choice of an appropriate therapy
– Oxygen prescription
– Pulmonary rehabilitation
– Attention to obesity and sarcopenia/frailty
– Potential enrollment in a clinical trial
– Transplant evaluation
Flaherty et al. Am J Respir Crit Care Med 2004;170:904-10.
Flaherty et al. Am J Respir Crit Care Med 2007;175:1054-60.
Lamas et al. Am J Respir Crit Care Med 2011;184:842-7.
ILD Checklist
•
•
•
•
•
•
•
•
•
•
Therapeutic options
Supplemental oxygen
Age-appropriate vaccinations
Risk factor reduction
Pulmonary rehabilitation
Clinical trials
Lung transplant evaluation
Patient education
Advocacy group involvement
Mental health needs
Referral
Opportunity?
x
x
x
x
x
x
x
Delayed Care Associated with
Higher Mortality
P for trend = 0.04
Lamas et al. Am J Respir Crit Care Med. 2011;184:842-847.
Lung Transplantation is Increasing
3,000
CF
IPF
COPD
Alpha-1
IPAH
Re-Tx
Number of Transplants
2,500
2,000
COPD
1,500
1,000
IPF
500
CF
0
http://www.ishlt.org/registries/slides.asp?slides=heartLungRegistry. Accessed August 2014.
Lung Transplantation for IPF:
2014 Referral Guidelines
• Histopathologic or radiographic evidence of usual
•
•
•
interstitial pneumonitis (UIP)
Abnormal lung function: FVC < 80% predicted or
DLCO < 40% predicted
Any dyspnea or functional limitation attributable to
lung disease
Any oxygen requirement, even if only during exertion
Weill D, et al. J Heart Lung Transplant.2014 Jun 26. [Epub ahead of print].
Conclusions
• Pirfenidone and nintedanib are FDA approved
for treatment of IPF
• Diagnosis of IPF requires a patient history,
physical exam, lab tests, HRCT, and sometimes
a biopsy
• Patients should be referred early
– Pulmonary rehabilitation
– ILD center
– Lung transplantation evaluation
To Receive Credit for this Activity:
Please Complete the Evaluation and Posttest
at www.pilotforipf.org/credit/##
Supplemental Slides
Possible NAC Mechanisms of Action
• Increase glutathione antioxidation
• Downregulate lysyl oxidase (LOX) activity,
(essential for collagen deposition)
Li S, et al. Respiration. 2012;84(6):509-517.
Rushworth GF, et al. Pharmacol Ther. 2014;141(2):150-159.
Pre-2011
ATS
2011
2011-2013
2014
Early Evidence for a NAC Cocktail
+ azathioprine
+ steroids
Acetylcysteine + azathioprine
+ steroids
Placebo ++azathioprine
azathioprine++steroids
steroids
Demedts M, et al. New Engl J Med. 2005;353:2229-2242.
Pre-2011
PANTHER 2012
Raghu G, et al. N Engl J Med. 2012;366:1968-1977.
ATS
2011
2011-2013
2014
Pre-2011
ATS
2011
2011-2013
2014
PANTHER 2012 Interim Results
Primary
Triple Therapy
Placebo
P-value
FVC (liters)
-0.24
-0.23
0.85
Time to Death
Kaplan–Meier Analysis
no benefit for FVC
• Increased risk of
death
Probability
• Triple therapy has
HR 9.26
(95% CI 1.16-74.1)
P = 0.01
Weeks Since Randomization
Raghu G, et al. N Engl J Med. 2012;366:1968-1977.
Pre-2011
ATS
2011
2011-2013
2014
• Triple therapy has
higher incidence of
adverse events than
placebo
Percentage
PANTHER 2012 Adverse Events
35
30
25
20
15
10
5
0
P-values < 0.05
Placebo
Pred/Aza/NAC
P-value for each comparison < 0.05
Raghu G, et al. N Engl J Med. 2012;366:1968-1977.
IPFNet writing committee. N Engl J Med 2012;366;1968-77.
PANTHER 2012 Conclusions
• Compelling evidence against the use of the
triple combination for patients with mild-tomoderate IPF
• Next steps
– Combination arm terminated
– Two arms of study continued (NAC vs placebo)
Raghu G, et al. N Engl J Med. 2012;366:1968-1977.
Pre-2011
PANTHER 2014
Martinez FJ, et al. N Engl J Med. 2014;370(22):2093-2101.
ATS
2011
2011-2013
2014
PANTHER Study Design
• Subjects: 264 patients with IPF (2 arm
•
•
•
•
continuation of PANTHER-IPF)
Treatment: acetylcysteine (600 mg) or placebo 3
times daily
Duration: 60 weeks
Primary end point: change in FVC
Secondary end points
– Time to the first acute exacerbation
– Change from baseline in the total score on the
St. George’s Respiratory Questionnaire
Martinez FJ, et al. N Engl J Med. 2014;370(22):2093-2101.
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Complete the Evaluation and Posttest:
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