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Update on Therapies for Idiopathic Pulmonary Fibrosis
Paul WoltersAssociate Professor
University of California, San Francisco
Outline
• Classification of Interstitial lung disease
– Clinical classification
– Importance of establishing diagnosis of a specific ILD
• Review of 3 randomized trials for IPF
– PANTHER (prednisone, azathioprine, NAC)
– ASCEND (Pirfenidone)
– IMPULSIS (Nintedinib)
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Clinical Classification
Exposure-related:- Occupational- Environmental- Avocational- Medication- Desquamative
interstitial pneumonia (DIP)
- RBILD
Idiopathic interstitial
pneumonia (IIP)
Connective tissue disease:- Scleroderma- Rheum. arthritis- Sjogrens- UCTD
Other:- Sarcoidosis- Vasculitis/Diffuse alveolar
hemorrhage (DAH)- Langherhans cell histiocytosis
(LCH)- Lymphagioleiomyomatosis
(LAM)- Pulmonary alveolar
proteinosis (PAP)- Eosinophilic pneumonias- Neurofibromatosis- Inherited disorders- Chronic aspiration- Inflammatory bowel disease
Idiopathic pulmonary
fibrosis (IPF)
Acute interstitial pneumonia (AIP)
Nonspecific interstitial pneumonia (NSIP)
Cryptogenic organizing pneumonia (COP)
Lymphocytic interstitial pneumonia (LIP)
Why it is Important to be Aware of IPF
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And, the rate of death from pulmonary fibrosis is increasing
Olson et al, AJRCCM, 2007
Why This Matters
Bjoraker et al, Am J Resp Crit Care Med ‘98
DIP
/IPF
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IPF Treatment: 2010
• “Triple therapy”
– Variant of historical approach of combined prednisone and immunomodulator(azathioprine or cyclophosphamide)
RX
• Prednisone, azathioprine and acetylcysteine
Paul Wolters, MD
IPF Treatment: 2010
Acetylcysteine with prednisone and azathioprine
Demedts NEJM 2005;353:2229
Rx
placebo
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IPF Clinical Trials
PANTHER
• Prednisone, Azathioprine and N‐acetylcysteine: A Study That Evaluates Response in IPF
• Designed and funded by the NIH IPFnet
– Rationale: Test whether the “standard of care” IPF therapy is effective
– Address the use of NAC alone and in combination with prednisone/azathioprine against placebo
IPFnet NEJM 2012;366:1968 and IPFnet NEJM 2014;370:2093
PANTHER
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PANTHER
• Enrolled 341 patients with FVC ≥ 50%, DLCO ≥ 30%
• Randomized to NAC, NAC plus prednisone/azathioprine, or placebo for 60 weeks
• Primary endpoint: Change in FVC
IPFn = 341
NAC alonen =133
Placebon = 131
60 wks
1°: FVC
2°: death, acute exacerbation,
disease progression
NAC pus P/An =77*
IPFnet NEJM 2012;366:1968 and IPFnet NEJM 2014;370:2093
* Stopped early
PANTHER
Baseline NAC alone(n=133)
NAC + P/A(n=77)
Placebo (n=131)
Age, years 68 69 67
Male sex 74% 77% 67%
FVC 72% 69% 73%
DLCO 45% 42% 46%
6MWT distance 371 362 375
Dyspnea (UCSD) 26 30 27
QOL (SGRQ) 40 39 38
IPFnet NEJM 2012;366:1968 and IPFnet NEJM 2014;370:2093
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PANTHER Part A
• NAC plus prednisone/azathioprine stopped early for evidence of harm
IPFnet NEJM 2012;366:1968
Death or hospitalization
PANTHER Part B
• No difference in rate of FVC decline with NAC monotherapy
• Also no difference in:– Death
– Acute exacerbation
– Disease progression
– Hospitalization
– Dyspnea
– 6MWT distance
– Overall QOL
IPFnet NEJM 2014;370:2093
6/2/2015
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PANTHER: Conclusions
• Prednisone/azathioprine/N‐acetyl therapy does not slow progression of IPF.
– If anything, it may be harmful to patients.
• N‐acetyl therapy alone does not slow progression of IPF.
May 2014
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Pirfenidone: Rationale
• Pirfenidone limited development of lung fibrosis in animal models.
• Reduces production of TGF‐• Attenuates the activation of MAP kinases
• 2 phase 3 studies in IPF patients had mixed results
• One slowed progression of IPF, one did not
• Approved in Japan, Canada, Europe
• Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis
– Two previous phase 3 trials had mixed results
– Performed in response to an FDA request for an additional trial to support approval
– Designed to enrich subjects for disease progression (as measured by change in FVC)
King. NEJM 2014;370:2083
ASCEND
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ASCEND: Study design
• Enrolled 555 highly‐selected (1562 screened) patients with IPF
• Randomized to pirfenidone or placebo for 52 weeks
– Primary endpoint: Change in FVC
– Secondary endpoints: 50 meter decline in 6MWT; 20 point increase in UCSD dyspnea score; PFS (10% FVC decline, 50 meter 6MWT decline, or death); death (any cause and related to IPF)
IPFn = 555
Pirfenidonen = 278
Placebon = 277
52 wks
1°: FVC
2°: 6MWT distance; PFS; dyspnea; death
King. NEJM 2014;370:2083
ASCEND: Subjects
Baseline Pirfenidone (n=278) Placebo (n=277)
Age, years 68 68
Male sex 80% 77%
FVC 68% 69%
DLCO 44% 44%
6MWT distance 415 421
Dyspnea (UCSD) 34 37
Definite UIP HRCT 96% 95%
King. NEJM 2014;370:2083
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ASCEND: 1° Endpoint
King. NEJM 2014;370:2083
Relative difference = 45%P value < 0.001
ASCEND: 1° Endpoint
King. NEJM 2014;370:2083
10% or greater absolute decline
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ASCEND: Safety and tolerability
King. NEJM 2014;370:2083
• No difference in SAEs (3x LFT increase 2.9% vs 0.7%)
• Treatment discontinuation in 14.4% vs 10.8%
Adverse event Pirfenidone Placebo
Nausea 36.0% 13.4%
Rash 28.1% 8.7%
Dizziness 17.6% 13.0%
Dyspepsia 17.6% 6.1%
Anorexia 15.8% 6.5%
Vomiting 12.9% 8.7%
Decrease in weight 12.6% 7.9%
Gastroesophageal reflux 11.9% 6.5%
Insomnia 11.2% 6.5%
Nintedanib
• Intracellular tyrosine kinase inhibitor with multiple targets
• Lck• VEGF• PDGF• FGF• Src
• Phase 2 study suggested it slowed progression (loss of FVC) of IPF
Richeldi. NEJM 2011; 365: 1079
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• Rationale: Test whether nintedanib slows progression of IPF.
• INPULSIS I and II
– Two identical RCTs designed to further develop nintedanib after promising phase II results.
– 2 trials are required for approval by FDA.
Richeldi NEJM 2014;370:2071
INPULSIS
INPULSIS: Study design
• Enrolled 1066 patients with IPF/likely IPF
• Randomized (3:2) to nintedanib/placebo for 52 wks
– Primary endpoint: Change in FVC
– Secondary endpoints: time to acute exacerbation; quality of life (SGRQ); categorical change in FVC; death (any cause, respiratory)
IPFn = 1066
nintedanibn = 638
Placebon = 423
52 wks
1°: FVC
2°: acute exacerbation; QOL; death
Richeldi NEJM 2014;370:2071
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INPULSIS: Study design
• Enrolled 1066 patients with IPF/likely IPF
HRCT required A/B/C, A/C, or B/C for enrollment:
– A. Definite honeycombing, basal/peripheral predominance
– B. Reticulation and traction bronchiectasis
– C. Atypical features are absent
Richeldi Resp Med 2014;108:1023Raghu. AJRCCM 2011;183:788
INPULSIS: Subjects
Baseline INPULSIS 1 INPULSIS II
Nintedanib Placebo Nintedanib placebo
N= 309 204 329 214
Age, years 67 67 66 67
Male sex 81% 80% 78% 78%
FVC 80% 81% 80% 82%
DLCO 48% 48% 47% 46%
Oxygen saturation 96% 96% 96% 96%
SGRQ score 40 40 40 39
Richeldi NEJM 2014;370:2071
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INPULSIS: 1° Endpoint
Richeldi NEJM 2014;370:2071
Relative difference = 45%P value < 0.001
Relative difference = 52%P value < 0.001
INPULSIS: 1° Endpoint
Richeldi NEJM 2014;370:2071
Mean difference 109.9 (71.3, 148.6)P value < 0.001
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INPULSIS: 2° Endpoints
INPULSIS I INPULSIS II
Nintedanib Placebo Nintedanib Placebo
Change in SGRQ 4.34 4.39 2.80 * 5.48
Any death POOLED 5.5% 7.8%
Respiratory death POOLED 3.8% 5.0%
Richeldi NEJM 2014;370:2071
Hazard ratio 1.15 (0.54, 2.42)P value = 0.67
* Statistically significant difference
Acute exacerbation
INPULSIS: 2° Endpoints
Richeldi NEJM 2014;370:2071
Hazard ratio 0.38 (0.19, 0.77)P value = 0.005
INPULSIS I INPULSIS II
Nintedanib Placebo Nintedanib Placebo
Change in SGRQ 4.34 4.39 2.80 * 5.48
Any death POOLED 5.5% 7.8%
Respiratory death POOLED 3.8% 5.0%
Acute exacerbation
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INPULSIS: Safety and tolerability
• No difference in SAEs (3x LFT increase 5.1% vs 0.7%)
• Treatment discontinuation 23.7‐25.2% vs 17.6‐20.1%
Adverse event Nintedanib Placebo
Diarrhea 62%, 63% 19%, 18%
Nausea 23%, 26% 6%, 7%
Decreased appetite 8%, 13% 7%, 5%
Vomiting 13%, 10% 2%, 3%
Weight loss 8%, 11% 6%, 1%
Richeldi NEJM 2014;370:2071
October 15, 2014
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/default.htm
Pirfenidone = Esbriet
Nintedanib = Ofev
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Conclusions
• 2 medications are now approved that slow progression of Idiopathic Pulmonary Fibrosis – Pirfenidone: Markets as Esbriet
– Nintedinib: Marketed as OFEV
• Therapies appear equally efficacious
• Select a therapy based on perceived impact of side effect profile for a patient– Pirfenidone: Rash, dyspepsia, fatigue
– Nintedinib: Loose stool, rash
• Great advance, but improvements are needed…. Meds only slow progression, they do not stop progression or improve lung function.
Case
• 65 y/o man presents with a 5‐6 month history of progressive dyspnea on exertion, dry cough
• He uses a treadmill regularly
– Cut down from 40 to 30 minutes
– Decreased speed from 3.6 mph to 2.8 mph
• ROS: Right knee pain for many years, otherwise negative
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PMH / Meds
• PMH
– HTN
– Seizure disorder
– Hyperlipidemia
• Allergies
– Sulfa
• Medications
– Fenofibrate
– Lamictal
– Amlodipine
– Ibuprofen prn
Social & Family History
• Social history
– ½ ppd x 20 years, quit 15 years ago
– Denies EtOH, drug use
• Family history
– No lung or autoimmune disease
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Exposure History
• Occupational exposures
– Works as carpenter
• Environmental exposures
– No mold in the home, pets, birds, humidifier or hot tub use, swamp coolers, down
– Golfs 3x/week
Physical Examination
• Saturation 97% on room air
• Crackles at bilateral bases
• R knee is slightly swollen,not warm or tender
• Otherwise normal exam
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Data
• CBC, chem 7, LFTs within normal limits
• FVC 70% predicted
• DLCO 40% predicted
• Walk test in clinic– 97% on RA at rest
– 92% on RA at 3 min
• PFTs
– FEV1 2.56 (81%)
– FVC 2.83 (67%)
– FEV1/FVC 0.90
– TLC 5.13 (76%)
– DLco 12.37 (65%)
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What additional testing would you perform next in this patient?
1. Bronchoalveolar lavage (BAL)
2. BAL and transbronchial biopsy
3. High resolution CT of the chest
4. Surgical lung biopsy
5. No additional testing; diagnosis is clear
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What is the next step for this patient?
1. Bronchoalveolar lavage (BAL)
2. BAL and transbronchial biopsy
3. Surgical lung biopsy
4. No additional testing; diagnosis is clear
VATS