A NEW ERA in IPF: Trials and Treatments

1. A NEW ERA in IPF:Trials and Treatments

2. 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

3. Outline • Diagnosis • Pathophysiology model • IPF drug trials • PANTHER (NAC) • ASCEND (pirfenidone) • INPULSIS (nintedanib) • Recent drug approvals! • Referral of patients with IPF

4. 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)

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

6. Major Idiopathic Interstitial Pneumonias Travis et al. Am J Respir Crit Care Med. 2013;188:733-748.

7. 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/Not IPF IPF Not IPF Raghu G, et al. Am J Respir Crit Care Med. 2011;183:788-824.

8. 2011 ATS/ERS Diagnostic Criteria for IPF UIP pattern on HRCT without surgical biopsy OR Definite/possible UIP pattern on HRCT with a surgical lung biopsy showing definite/probable UIP 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.

9. Idiopathic Pulmonary Fibrosis Normal Lungs Usual Interstitial Pneumonia

10. Idiopathic Pulmonary Fibrosis Normal Lung Usual Interstitial Pneumonia

11. Idiopathic Pulmonary Fibrosis Normal Lung Fibroblastic Focus in Usual Interstitial Pneumonia

12. Clinical-Radiologic-Pathologic Approach to ILD

13. 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 Aberrant Wound healing Genetic predisposition Lung homeostasis Interstitial lung disease Steele MP, Schwartz DA. AnnuRev Med.2013;64:265-276.

14. Eras of Care for IPF ATS Statement 2011 Pre-ATS Statement 2011 2011-2013 2014

15. Completed Trials for IPF: Prior to 2011 Consensus Statement Subsequent trials showed that warfarin and NAC/azathioprine/prednisone should not be used for IPF Noth I, et al. Am J RespirCrit Care Med. 2012 Jul 1;186(1):88-95.\

16. 2011 Guidelines on Management of IPF

17. ThreeRecent IPF Clinical Trials American Thoracic Society 2014 • PANTHER N-acetylcysteine (NAC) • ASCEND pirfenidone • INPULSIS nintedanib (BIBF1120)

18. PANTHERN-acetylcysteine (NAC)

19. 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.

20. ASCENDPirfenidone

21. Possible Mechanisms of Pirfenidone Action • Antifibrotic • Molecular target unclear • Active in several animal models of fibrosis (lung, liver, kidney) Pirfenidone • MMPs • Collagenases ROIs • TGF-β • IL-6 • TNF-α • IL-6 • Collagen Hilberg O, et al. Clin Respir J. 2012;6:131-143.

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

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

24. ATS 2011 ASCEND 2014 2014 2011-2013 Pre-2011

25. ASCEND Study Design 52 Weeks • Inclusion Criteria • Age 40-80 • Confirmed IPF • 50 - 90% FVC pred • 30 - 90% DLCOpred • FEV1/FVC ≥ 0.80 • 6-MWD ≥ 150 m Endpoints 10: Δ FVC or death 20: 6-MWD PFS Dyspnea Death Oral Pirfenidone 2403 mg Daily Placebo 555 Patients • PFS - Progression-free survival King TE, et al. N Engl J Med. 2014;370(22):2083-2092.

26. Primary ASCEND Endpoint Achieved Primary Endpoint Patients with ≥ 10% FVC Decline or Death (%) 48% Relative Reduction Week King TE, et al. N Engl J Med. 2014;370(22):2083-2092.

27. 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.

28. Pirfenidone Reduces Loss of FVC 235 ml Mean Change (ml) Rank ANCOVA P-value < 0.00001 at each indicated time point 428 ml Week <0.000001 King TE, et al. N Engl J Med. 2014;370(22):2083-2092.

29. More Pirfenidone Patients Maintain Walk Distance or Survive Proportion of Patients with ≥50 m Decline or Death (%) Week King TE, et al. N Engl J Med. 2014;370(22):2083-2092.

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

31. 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.

32. 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.

33. 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

34. FDA Approval of Pirfenidone (Esbriet) http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails/. Accessed October 2014. • 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.

35. Pirfenidone Warnings and PrecautionsTemporary 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.

36. 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.

37. INPULSISNintedanib

38. Possible Mechanisms of Nintedanib Action • Triple kinase inhibitor • Phosphatase activator • Antiangiogenic, antitumor activity Nintedanib • VEGF • PDGF • FGF SHP-1 Pleiotropic Effects HilbergF, et al. Cancer Res. 2008;68(12):4774-4782. Tai WT, et al. J Hepatol. 2014;61(1):89-97.

39. ATS 2011 Nintedanib Showed Promise for FVC Endpoint 2014 2011-2013 Pre-2011 Richeldi L, et al. N Engl J Med.2011:365;1079-1089.

40. ATS 2011 INPULSIS 2014 2014 2011-2013 Pre-2011

41. INPULSIS-1 and INPULSIS-2 Study Design 52 Weeks • Inclusion Criteria • Age > 40 • IPF ≤ 5y • ≥ 50% FVC pred • 30 - 79% DLCOpred • HRCT within 1y • Endpoints • 10: ΔFVC • 20: Time to first AE • ΔSGRQ Nintedanib 300 mg Daily 3 2 Placebo 1066 Patients AE – Acute Exacerbation SGRQ – St. George’s Respiratory Questionnaire Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.

42. Primary INPULSIS Endpoint Achieved Annual Rate of Change of FVC INPULSIS-2 INPULSIS-1 45% Relative Reduction 52% Relative Reduction Nintedanib Placebo Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.

43. Nintedanib Reduces Loss of FVC INPULSIS-1 Mean Observed Change from Baseline in FVC (mL) INPULSIS-2 Week Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.

44. Mixed Findings for Time to First Acute Exacerbation INPULSIS-1 Cumulative Incidence of First Acute Exacerbation (%) INPULSIS-2 Days Richeldi L, et al. N Engl J Med. 2014;370(22):2071-2082.

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

46. INPULSIS Summary • Nintedanib had significant benefit in adjusted annual rate of change in FVC • INPULSIS-1 Δ = 125.3 mlP < 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.

47. 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.

48. FDA Approval of Nintedanib (Ofev) http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails/. Accessed October 2014. • 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.

49. Nintedanib Warnings and Precautions http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails/. Accessed October 2014. 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. Embryofetaltoxicity: 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.

50. 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.