Slide Title

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Therapies for Idiopathic Pulmonary Fibrosis –Pharmacologic, Non-Pharmacologic

Amy Olson, MD, MSPHAssociate Professor, Division of Pulmonary and Critical Care MedicineNational Jewish Health, Denver, CO

Slide TitleLearning Objectives

• Describe best practices for diagnosing IPF based on the most recent evidence-based guidelines

• Develop a comprehensive assessment and diagnosis strategy to differentiate IPF from other interstitial lung diseases

• Develop a comprehensive approach to management of IPF based on the most recent clinical data to include pharmacologic and non-pharmacologic therapies

• Determine appropriate strategies for the multidisciplinary healthcare team to effectively educate patients with IPF about their disease and address quality of life issues

Slide TitleLearning Objectives

• Review Guidelines for the Treatment of IPF• Overview of IPF Pathophysiology• Review the two FDA-approved anti-fibrotic therapies for IPF

– Proposed mechanism of action– Outcomes from the clinical trials– Management

• Expectations• Side Effects

• Review recommended non-pharmacologic therapies– Lung Transplant– Oxygen therapy– Pulmonary Rehabilitation– Co-morbidities (?)

Slide TitleGuidelines for the Treatment of IPF

Raghu G, et al. Am J Respir Crit Care Med. 2015;192:238-248.

Slide TitleStrong vs. Conditional Recommendations

Raghu G, et al. Am J Respir Crit Care Med. 2015;192:238-248.

Slide TitleConventional Pharmacological Therapies

Treatment Strong For

Conditional For

Weak Against

Strong Against

Lung Transplantation XLong-term oxygen for hypoxemia XPulmonary Rehabilitation X

Comorbidity Therapy – GERD X

Pirfenidone XNintedanib (TKI – multiple targets) XSildenafil (PDE-5 inhibitor) XMacitentan/Bosentan (Dual ERA) XNAC alone XNAC/Azathioprine/Prednisone XCorticosteroids XWarfarin (Anticoagulation) XAmbrisentan (Selective ERA) XImatinib (TKI – one target) X

Raghu G, et al. Am J Respir Crit Care Med. 2011;183:788-824.Raghu G, et al. Am J Respir Crit Care Med. 2015;192:238-248.

Slide TitlePathophysiology of IPF

This image has been adapted and reprinted with permission of the American Thoracic Society. Copyright © 2017 American Thoracic Society.Ahluwalia N, et al./2014/New Therapeutic Targets in Idiopathic Pulmonary Fibrosis/Am J Respir Crit Care Med/190/867-878.

The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

Slide TitleIPF Histopathology

Courtesy of Steve Groshong, MD, NJH.

Slide TitleAnti-Fibrotic TherapiesTreatment Strong

ForConditional

ForWeak

AgainstStrong

AgainstLung Transplantation XLong-term oxygen for hypoxemia XPulmonary Rehabilitation X

Comorbidity Therapy – GERD X

Pirfenidone XNintedanib (TKI – multiple targets) XSildenafil (PDE-5 inhibitor) XMacitentan/Bosentan (Dual ERA) XNAC alone XNAC/Azathioprine/Prednisone XCorticosteroids XWarfarin (Anticoagulation) XAmbrisentan (Selective ERA) XImatinib (TKI – one target) X

Raghu G, et al. Am J Respir Crit Care Med. 2011;183:788-824.Raghu G, et al. Am J Respir Crit Care Med. 2015;192:238-248.

Slide TitlePharmacologic Therapies - Pirfenidone

• Anti-fibrotic• Anti-inflammatory• Anti-oxidant

Slide TitlePathophysiology of IPF

This image has been adapted and reprinted with permission of the American Thoracic Society. Copyright © 2017 American Thoracic Society.Ahluwalia N, et al./2014/New Therapeutic Targets in Idiopathic Pulmonary Fibrosis/Am J Respir Crit Care Med/190/867-878.

The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

Slide TitleCapacity I & II: Pirfenidone

Reprinted from The Lancet, 377, Nobel PW, et al., Pirfenidone in patients with Idiopathic Pulmonary Fibrosis (CAPACITY): two randomised trials, 1760-1769, Copyright 2011, with permission from Elsevier.

Based on this data, the FDA did not approve Pirfenidone and a 3rd study was required (Ascend)

Mean change from baseline in percentage predicted FVC in study 004 (A), study 006 (B), and the pooled population (C)FVC=forced vital capacity. *Pirfenidone 2403 mg/day versus placebo. †Rank ANCOVA (pirfenidone 2403 mg/day vs placebo). 95% CIs were only calculated for absolute differences for the week 72 timepoint in study 004 (0·7 to 9·1) and study 006 (−3·5 to 4·7).

Slide TitleAscend: Pirfenidone Primary Endpoint Was Achieved

.* For deaths, FVC = 0.

Patie

nts w

ith ≥ 10%

 FVC

 De

cline or Death (%

)

48% Relative Reduction

Mean Ch

ange in FVC

 from

 Baseline

235 ml vs. 428 ml*

From The New England Journal of Medicine, King TE, et al., A Phase 3 Trial of Pirfenidone in Patients with Idiopathic Pulmonary Fibrosis, 370, 2083-2092. Copyright © 2014 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society

Slide TitleSide EffectsAdverse Event Pirfenidone (N=278) Placebo (N=277)Nausea 36% 13.4%Rash 28.1% 8.7%Dyspepsia + 17.6% 6.1%GERD 11.9% 6.5%

• In addition to nausea and dyspepsia, subjects on therapy also had an increased incidence of anorexia, vomiting, and decrease in weight

• The rash is typically a photosensitivity rash that results in a macular-type exanthema with flaking plaques, and can be extremely pruritic

• Discontinuation due to side effects was 14.4%King TE, et al. N Engl J Med. 2014;370:2083-2092.

Koulelidis A, et al. http://www.pneumon.org/assets/files/844/file501_383.pdf.

Slide TitlePharmacologic Therapies - Nintedanib

• Triple Tyrosine Kinase Inhibitor– Vascular Endothelial Growth Factor (VEGF)– Platelet Derived Growth Factor (PDGF)– Fibroblast Growth Factor (FGF)

Slide TitlePathophysiology of IPF

This image has been adapted and reprinted with permission of the American Thoracic Society. Copyright © 2017 American Thoracic Society.Ahluwalia N, et al./2014/New Therapeutic Targets in Idiopathic Pulmonary Fibrosis/Am J Respir Crit Care Med/190/867-878.

The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

Slide TitleINPULSIS 1 & 2: NintedanibPrimary Endpoint Was Achieved

From The New England Journal of Medicine, Richeldi, et al., Efficacy and Safety of Nintedanib in Idiopathic  Pulmonary Fibrosis, 370, 2071‐2082. Copyright © 2014 Massachusetts Medical Society.  Reprinted with permission from Massachusetts Medical Society

52% Relative Reduction

45% Relative Reduction

Slide TitleSide Effects: Gastrointestinal

Discontinuation due to side effects was 21%.

Adverse Event * Nintedanib (N=309) Placebo (N=204)

Any 96% 89%Diarrhea 62% 19%Nausea 23% 6%

* Adverse event data from INPULSIS 1; similar to INPULSIS 2. Richeldi L , et al. N Engl J Med. 2014 ;370:2071-2082.

Slide TitleSide Effects: Bleeding

• Theoretical risk with nintedanib given inhibition of PDGF and VEGF

• Patients on anticoagulation were excluded from INPULSIS studies

Bleeding Events

Epistaxis Contusion Serious Bleeding

Nintedanib 10.3% 4.1% 1.6% 1.3%

Placebo 7.8% 3.1% 0.9% 1.4%

Corte T , et al. Respiratory Research. 2015; 16:116.

Slide TitleSide Effects: Additional

• Myocardial Infarction

• Fatal adverse cardiac events

– Other cardiovascular events were similar between the treatment and placebo groups.

INPULSIS I INPULSIS IINintedanib 0.3% (n=1) 0.6% (n=2)Placebo 1% (n=2) 1.8% (n=4)

Richeldi L , et al. N Engl J Med. 2014 ;370:2071-2082.

Slide Title

Pirfenidone• Pirfenidone vs. Placebo

– ↑AST/ALT > 3 x upper limits of normal

• (2.9% vs. 0.7%)– All elevations were reversible– Lead to discontinuation in 1% of

patients• Monitoring

– LFTs q month x 6 months – LFTs q 3 months

Nintedanib• Nintedanib vs. Placebo

– ↑AST/ALT > 3 x upper limits of normal

– INPULSIS 1• (4.9% vs. 0.5%)

– INPULSIS 2• (5.2% vs. 0.9%)

• Monitoring– LFTs q month x 3 months – LFTs q 3 months

Side Effects - Liver Toxicity

Slide TitleManagement of Side Effects

• Patient Education• Adjunctive Medications/Food

– Diarrhea with Nintedanib Loperamide– Nausea with Pirfenidone Ensure medications taken within the

meal• If a side effect occurs, adjust dose• If it persists, temporary interrupt therapy• Once resolved, slow re-escalation• Permanent discontinuation for recurrent or severe side

effects

Slide TitleManagement of Expectations

• These anti-fibrotics MAY– Slow down progression of disease– Cause significant side-effects

• These anti-fibrotics WON’T– Make a patient feel better

• May or may not make a patient live longer• Thus, the “conditional” recommendation

Slide TitleMr. H Has Been Newly Diagnosed With IPF. What Is His Likely Response?

1. Mr. H may not want to take pirfenidone due to the phototoxocity.

2. Mr. H may not want to take pirfenidone due to the number of pills/frequency of dosing.

3. Mr. H may not want to take nintedanib due to his cardiac history.

4. Mr. H may not want to take nintedanib due to concerns for diarrhea.

5. All of the above.

Slide TitleMr. H Has Been Newly Diagnosed With IPF. What Is His Likely Response?

1. Mr. H may not want to take pirfenidone due to the phototoxocity.

2. Mr. H may not want to take pirfenidone due to the number of pills/frequency of dosing.

3. Mr. H may not want to take nintedanib due to his cardiac history.

4. Mr. H may not want to take nintedanib due to concerns for diarrhea.

5. All of the above.

Slide TitleConventional Non-Pharmacological Therapies

Treatment Strong For

Conditional For

Weak Against

Strong Against

Lung Transplantation XLong-term oxygen for hypoxemia XPulmonary Rehabilitation X

Comorbidity Therapy – GERD X

Pirfenidone XNintedanib (TKI – multiple targets) XSildenafil (PDE-5 inhibitor) XMacitentan/Bosentan (Dual ERA) XNAC alone XNAC/Azathioprine/Prednisone XCorticosteroids XWarfarin (Anticoagulation) XAmbrisentan (Selective ERA) XImatinib (TKI – one target) X

Raghu G, et al. Am J Respir Crit Care Med. 2011;183:788-824.Raghu G, et al. Am J Respir Crit Care Med. 2015;192:238-248.

Slide TitleLung Transplantation

• The only therapy that prolongs survival in IPF

• IPF is now the number one diagnosis for transplant

• Five-year survival is ~ 50%• Many centers are

transplanting older patients (>65) Chambers DC, et al. J Heart Lung Transplant. 2017 Oct;36(10):1047-1059.

King TE Jr, et al. Lancet. 2011;378:1949-1961.

Slide TitleLung Transplantation: When To Refer

• At the time of diagnosis – Evaluation (due to

unpredictable course)• As disease progresses

– Listing (based on Lung Allocation Score)

Chambers DC, et al. J Heart Lung Transplant. 2017 Oct;36(10):1047-1059.Reprinted from The Lancet, 378, King TE Jr, et al., Idiopathic Pulmonary Fibrosis, 1949-1961, Copyright 2011, with permission from Elsevier.

Slide TitleOxygen Therapy

• “Ensure oxygen saturations are > 90% at all times”– Rest, Ambulation, Exercise, Sleep

• Obstructive Sleep Apnea (OSA) is common in IPF• Patients may not present with typical symptoms• Untreated OSA may be associated with worse prognosis

– Mortality & Clinical Progression– While this is a “Strong Recommendation,” limited data

• No proven survival benefit• Evidence does exist that it may improve exercise capacity/reduces

dyspnea• At present,

– Ongoing studies – Calls for more research

Raghu G, et al. Am J Respir Crit Care Med. 2011;183:788-824.Bosi M, et al. Lung. 2017 Jul 3. [Epub ahead of print].

Dowman LM, et al. Respirology. 2017;22:957-964.

Slide TitlePulmonary Rehabilitation

• Most programs meet 2-3 times per week for 4 to 12 weeks or more...– Improves quality of life– Increases walk distance– Decreases breathlessness– Decreases depression

• Duration of benefit?Image from: www.thoracic.org. ATS Patient Information Series.

Dowman L, et al. Cochrane Database Sys Rev. 2014 Oct 6;(10). Olson AL, et al. Patient Relat Outcome Meas. 2016 May 17;29-35.

Raghu G, et al. Am J Respir Crit Care Med. 2011;183:788-824.

Slide TitleComorbidities: Gastroesophageal Reflux Disease (GERD) • Higher prevalence in IPF

– Distal GER reported as high as 88% of patients– Proximal GER reported as high as 71% of patients– May be silent

• Hypothesized to play a role in progressive lung fibrosis

• IPF treatment recommendations – Conditional for the treatment of reflux

Lee JS, et al. Am J Respir Crit Care. 2011;184:1390-1394.

Slide TitlePathophysiology of IPF

This image has been adapted and reprinted with permission of the American Thoracic Society. Copyright © 2017 American Thoracic Society.Ahluwalia N, et al./2014/New Therapeutic Targets in Idiopathic Pulmonary Fibrosis/Am J Respir Crit Care Med/190/867-878.

The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.

Slide TitleOther Comorbidities

Comorbidities Relative Risk (95% CI)Pulmonary Hypertension 15.56 (9.39-25.80)*Pulmonary Embolism 6.97 (4.92-9.89)*Pulmonary Infections 4.20 (3.86-4.57)*Heart Failure 3.83 (3.47-4.23)*Sleep Apnea 3.65 (3.05-4.37)*Lung Cancer 2.83 (2.25-3.55)*Myocardial Infarction 2.13 (1.74-2.60)*Coronary Artery Disease 1.86 (1.74-1.99)*Depression 1.40 (1.18-1.66)*

Collard H, et al. J Med Econ. 2012;15:829-835.

Slide TitleIPF Future

• We have no known pharmacologic therapy to halt disease

• Still much work to be done• Consider discussing with patients a referral

for a clinical trial

Slide TitleSummary

• For patients with IPF– Two FDA approved anti-fibrotic therapies are available

• Equipoise on the efficacy• Shared decision making between the physician and patient

regarding treatment/agent• Keeping patients on therapy requires

– Expectation management– Side effect management

– Remember the non-pharmacologic therapies & to identify and treat comorbidities

– Always consider ongoing clinical trials in IPF

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For additional resources and IPF patient education materials, please visit www.nationaljewish.org/IPF