A NEW ERA in IPF:

Trials and Treatments

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)

DPLD of known cause, eg, drugs or association, eg, collagen vascular disease Idiopathic pulmonary fibrosis Idiopathic interstitial pneumonias Granulomatous DPLD, eg, sarcoidosis IIP other than idiopathic pulmonary fibrosis Other forms of DPLD, eg, LAM, HX, etc Desquamative interstitial pneumonia Acute interstitial pneumonia Nonspecific interstitial pneumonia (provisional) Respiratory bronchiolitis interstitial lung disease Cryptogenic organizing pneumonia Lymphocytic interstitial pneumonia Pleuroparenchymal fibroelastosis Travis WD, et al; ATS/ERS Committee on Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med. 2013;188(6):733-748.

Major Idiopathic Interstitial Pneumonias

Category

Chronic fibrosing

Clinical-Radiologic-Pathologic Diagnosis

IPF Idiopathic nonspecific interstitial Pneumonia (iNSIP) Respiratory bronchiolitis-ILD (RB-ILD) Smoking related Desquamative interstitial pneumonia (DIP) Acute/ subacute Cryptogenic organizing pneumonia (COP) Acute interstitial pneumonia (AIP)

Associated Radiographic and/or Pathologic pattern

UIP NSIP Respiratory bronchiolitis Desquamative interstitial pneumonia Organizing pneumonia 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 Raghu G, et al. Am J Respir Crit Care Med. 2011;183:788-824.

IPF/Not IPF Not IPF

2011 ATS/ERS Diagnostic Criteria for IPF

Exclusion of known causes of ILD* AND UIP pattern on HRCT without surgical biopsy OR Definite/possible UIP pattern on HRCT with a surgical lung biopsy showing definite/probable UIP *also known as diffuse parenchymal lung disease, DPLD Raghu G, et al. Am J Respir Crit Care Med. 2011;183:788-824.

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) Clinical picture Pathologic pattern (lung biopsy) 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 Genetic predisposition Lung homeostasis Steele MP, Schwartz DA. Annu Rev Med. 2013;64:265-276.

Aberrant 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 Interferon-beta (1999) Interferon-gamma (GIPF-001) Interferon-gamma (Inspire) Pirfenidone (CAPACITY 1) Pirfenidone (CAPACITY 2)

167 330 826 344 Progression-free survival time Progression-free survival Survival time Change in FVC 435 Change in FVC

Pirfenidone (Ogura)

275 Change in FVC

Etanercept

100 Change in DL co , FVC Progression-free survival

Imatinib Mesylate

120

Bosentan (BUILD 1 and 2)

132 Change in 6MW

Bosentan (BUILD 3)

390 Progression-free survival time

Anticoagulation N-acetylcysteine (NAC) (IFIGENIA) Sildenafil (STEP)

56 184 29

Result

Negative Negative Negative Negative Positive Positive Negative Negative Negative Negative Positive and NAC/azathioprine/prednisone Change in FVC, DL co should not be used for IPF Change in 6MWD, Borg dyspnea index Positive Negative Noth I, et al. Am J Respir Crit Care Med. 2012 Jul 1;186(1):88-95.\

2011 Guidelines on Management of IPF

Treatment Strong For Weak For Weak Against

Corticosteroid Colchicine Cyclosporine A Interferon γ 1b Bosentan Etanercept NAC/Azathioprine/Prednisone NAC Anticoagulation Pirfenidone Mechanical ventilation Pulmonary rehab Long-term oxygen Lung transplantation X X X X X X X X

Strong Against

X X X X X 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)

TNF-α IL-6

Pirfenidone

TGF-β IL-6 MMPs Collagenases ROIs Collagen

Hilberg O, et al. Clin Respir J. 2012;6:131-143.

CAPACITY 2011

CAPACITY-2 Pre-2011 ATS 2011 2011-2013 2014 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.

CAPACITY Endpoints

Endpoint

FVC Overall survival Progression-free survival Six-minute walk distance DL CO Dyspnea Exertional desaturation

CAPACITY-2



X



X X X X CAPACITY-1 X X X



X X X

Noble P, et al. Lancet. 2011;377:1760-1769.

ASCEND 2014

Pre-2011 ATS 2011 2011-2013 2014

ASCEND Study Design

Inclusion Criteria

• • • • • • Age 40-80 Confirmed IPF 50 - 90% FVC pred 30 - 90% DL CO pred FEV 1 /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.

52 Weeks Oral Pirfenidone 2403 mg Daily Placebo

Endpoints

1 0 : Δ FVC or death 2 0 : 6-MWD PFS Dyspnea Death

Primary ASCEND Endpoint Achieved

Primary Endpoint

48% Relative Reduction

King TE, et al. N Engl J Med. 2014;370(22):2083-2092.

Week

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.

Pirfenidone Reduces Loss of FVC

Rank ANCOVA P-value < 0.00001 at each indicated time point King TE, et al. N Engl J Med. 2014;370(22):2083-2092.

Week

235 ml 428 ml <0.000001

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 … Dyspnea Cough IPF

Pirfenidone (%) (N = 278) Placebo (%) (N = 277)

36 28.1

17.6

15.8

13.4

8.7

6.1

6.5

11.9

12.6

11.2

17.6

12.9

6.5

7.9

6.5

13 8.7

… … 14.7

25.2

9.4

17.7

29.6

18.1

Δ (%)

22.6

19.4

11.5

9.3

5.4

4.7

4.7

4.6

4.2

… -3 -4.4

-8.7

King TE, et al. N Engl J Med. 2014;370(22):2083-2092.

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 33

• • • •

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.

34

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

VEGF

Nintedanib

PDGF FGF SHP-1 Pleiotropic Effects

Hilberg F, et al. Cancer Res. 2008;68(12):4774-4782.

Tai WT, et al. J Hepatol. 2014;61(1):89-97.

Nintedanib Showed Promise for FVC Endpoint

Pre-2011 ATS 2011 2011-2013 2014 Richeldi L, et al. N Engl J Med.2011:365;1079-1089.

INPULSIS 2014

Pre-2011 ATS 2011 2011-2013 2014

INPULSIS-1 and INPULSIS-2 Study Design

Inclusion Criteria

• • • • • Age > 40 IPF ≤ 5y ≥ 50% FVC pred 30 - 79% DL CO HRCT within 1y pred

3 2

52 Weeks Nintedanib 300 mg Daily Placebo

Endpoints

1 0 : ΔFVC 2 0 : Time to first AE Δ SGRQ 1066 Patients AE – Acute Exacerbation SGRQ – St. George’s Respiratory Questionnaire Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.

Primary INPULSIS Endpoint Achieved

Annual Rate of Change of FVC INPULSIS-1 INPULSIS-2

52% Relative Reduction 45% Relative Reduction

Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.

Nintedanib Placebo

Nintedanib Reduces Loss of FVC

INPULSIS-1 INPULSIS-2 Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.

Week

Mixed Findings for Time to First Acute Exacerbation

INPULSIS-1 INPULSIS-2 Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.

Days

Common Nintedanib Adverse Events

Event

Any (%) Diarrhea (%) Nausea(%)

INPULSIS-1

Nintedanib (n = 309) Placebo (n = 204) 96 89 62 23 19 6

INPULSIS-2

Nintedanib (n = 329) Placebo (n = 219) 94 90 63 26 18 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 • INPULSIS-2 Δ = 125.3 ml Δ = 93.7 ml P < 0.001

P < 0.001

Nintedanib had significant benefit in time to the first acute exacerbation in INPULSIS-2 • INPULSIS-1 HR = 1.15

• INPULSIS-2 HR = 0.38

P = 0.67

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.

48

• • • • • •

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.

49

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.

50

Current Phase 2 Trials for IPF

Next Generation Therapy?

Trial

Co-trimoxazole (Ph 3) FG-3019 Rituximab Simtuzumab GC-1008 QAX576 Tralokinumab STX-100 BMS-986020

Target

Pneumocystis jiroveci Anti-CTGF CD-20 Anti-LOXL2 TGF  Anti-IL-13 Anti-IL-13 αvβ6 LPA Receptor

N Primary Endpoint

56 Change in FVC or respir. Hospital’n 90 58 500 25 40 302 32 300 Change in FVC from baseline Titers of anti-HEp-2 autoantibodies PFS Safety, tolerability, PK Safety, tolerability, FVC Change in FVC from baseline Adverse events 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 2 500 Re-Tx 2 000

COPD

1 500 1 000 500

IPF 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 DL CO < 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

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

Early Evidence for a NAC Cocktail

ATS 2011 2011-2013 2014 Demedts M, et al. New Engl J Med. 2005;353:2229-2242.

PANTHER 2012

Pre-2011 ATS 2011 2011-2013 2014 Raghu G, et al. N Engl J Med. 2012;366:1968-1977.

• Pre-2011

PANTHER 2012 Interim Results

Primary

FVC (liters)

Triple Therapy

-0.24

Placebo

-0.23

ATS 2011 2011-2013 2014

P-value

0.85

Triple therapy has no benefit for FVC • Increased risk of death

Time to Death

Kaplan–Meier Analysis 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

PANTHER 2012 Adverse Events

• Triple therapy has higher incidence of adverse events than placebo 35 30 25 20 15 10 5 0 P-values < 0.05

ATS 2011 2011-2013 2014 P-value for each comparison < 0.05

Raghu G, et al. N Engl J Med. 2012;366:1968-1977.

Placebo Pred/Aza/NAC 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-to moderate 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.

PANTHER 2014

Pre-2011 ATS 2011 2011-2013 2014 Martinez FJ, et al. N Engl J Med. 2014;370(22):2093-2101.

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.