1. PFF Teal = 0+160+175 MAIN COLORS PFF Green = 120+162+47 Light Green = 193+216+47 Red = 242+102+73 HIGHLIGHT COLORS Light Grey = 220+220+210 Dark Grey = 100+98+76 Black = 0+0+0 CLINICAL CARE: NEW AND EVOLVING TREATMENT STRATEGIES SESSION LEADERS: GANESH RAGHU, MD LUCA RICHELDI, MD, PHD

4. PHASE 1 PHASE 2 PHASE 3 REGISTRATION LAUNCHED PIRFENIDONE BOSENTAN COTRIMOXAZOLE AMBRISENTAN OMEPRAZOLE WARFARIN SILDENAFIL TRIPLE THERAPY IFN-  www.clinicaltrials.gov NEGATIVE RESULTS POSITIVE RESULTS PENDING RESULTS ON GOING THALIDOMIDE MACITENTAN TRALOKINUMAB CC-930 IMATINIB SIMTUZUMAB LEBRIKIZUMAB BMS-986020 ETANERCEPT QAX576 CNTO 888 STX-100 hMSC IW001 PRM-151 GSK2126458 SAR156597 NINTEDANIB NAC OCTREOTIDE GC1008 TETRATHIOMOLYBDATE ILOPROST ZILEUTON TREPROSTINIL FG-3019 LOSARTAN GLPG1690 TD139

6. PFF Teal = 0+160+175 MAIN COLORS PFF Green = 120+162+47 Light Green = 193+216+47 Red = 242+102+73 HIGHLIGHT COLORS Light Grey = 220+220+210 Dark Grey = 100+98+76 Black = 0+0+0 COMBINATION THERAPY: A WAY TO CURE IPF LUCA RICHELDI, MD, PHD PAUL NOBLE, MD, PHD CLINICAL CARE: NEW AND EVOLVING TREATMENT STRATEGIES NOVEMBER 14, 2015

7. Noble et al, JCI 2012 Epithelial Dysfunction in the Pathobiology of Progressive Fibrosis

9. Reduced Type II alveolar epithelial cells in IPF lungs Normal IPF EPCAM HTII-280 Percent of AEC2 in R2 Normal IPF 68.8% 8.6% Liang et al, unpublished

10. Self renewal and differentiation of AEC2 stem cells in 3D organoid culture Barkauskas et al. JCI. 2013 Sftpc-CreER;Rosa-Tomato mice Pdgfra-GFP mice Sftpc-CreER;Rosa-Tomato mice

11. Reduced stem cell renewal of AEC2 cells from IPF lung Liang et al, unpublished

12. Why is fibrosis progressive and destructive in IPF?

13. Cell suspension placed in upper chamber Invasive cells pass through Matrigel layer and cling to the bottom of the Boyden chamber membrane. Non- invasive cells stay in the upper chamber After removal of non-invasive cells, invasive cells are stained and quantified Invasive Capacity= #cells invaded matrigel/20x hpf Schematic of invasion assay

14. NHF IPF HAS2 mRNA level (arbitrary units) P = 0.025 Fibroblasts from IPF patients spontaneously invade Matrigel and express HAS2 during invasion Yi et al. J Exp Med. 2011

15. Noble et al, JCI 2012 Paradigm for the development of severe pulmonary fibrosis

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

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

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

19. 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 45% Relative Reduction 52% Relative Reduction Nintedanib Placebo

20. Linking IPF Pathogenesis to Potential Therapies Ahluwalia N, et al. Am J Respir Crit Care Med. 2014:Aug 4. [Epub ahead of print].

21. PFF Teal = 0+160+175 MAIN COLORS PFF Green = 120+162+47 Light Green = 193+216+47 Red = 242+102+73 HIGHLIGHT COLORS Light Grey = 220+220+210 Dark Grey = 100+98+76 Black = 0+0+0 Lancet Resp Med 2014; 11: 933-42

22. PFF Teal = 0+160+175 MAIN COLORS PFF Green = 120+162+47 Light Green = 193+216+47 Red = 242+102+73 HIGHLIGHT COLORS Light Grey = 220+220+210 Dark Grey = 100+98+76 Black = 0+0+0 Lancet Resp Med 2014; 11: 933-42

23. PFF Teal = 0+160+175 MAIN COLORS PFF Green = 120+162+47 Light Green = 193+216+47 Red = 242+102+73 HIGHLIGHT COLORS Light Grey = 220+220+210 Dark Grey = 100+98+76 Black = 0+0+0 Eur Respir J 2015; 45: 1382-1392

24. PFF Teal = 0+160+175 MAIN COLORS PFF Green = 120+162+47 Light Green = 193+216+47 Red = 242+102+73 HIGHLIGHT COLORS Light Grey = 220+220+210 Dark Grey = 100+98+76 Black = 0+0+0 Eur Respir J 2015; 45: 1382-1392

25. PFF Teal = 0+160+175 MAIN COLORS PFF Green = 120+162+47 Light Green = 193+216+47 Red = 242+102+73 HIGHLIGHT COLORS Light Grey = 220+220+210 Dark Grey = 100+98+76 Black = 0+0+0 Eur Respir J 2015; 45: 1208-1210

26. PFF Teal = 0+160+175 MAIN COLORS PFF Green = 120+162+47 Light Green = 193+216+47 Red = 242+102+73 HIGHLIGHT COLORS Light Grey = 220+220+210 Dark Grey = 100+98+76 Black = 0+0+0 Investigation of drug-drug interaction between nintedanib and pirfenidone in patients with IPF (an open-label, multiple dose, two group study) EudraCT: 2015-000732-15

27. PFF Teal = 0+160+175 MAIN COLORS PFF Green = 120+162+47 Light Green = 193+216+47 Red = 242+102+73 HIGHLIGHT COLORS Light Grey = 220+220+210 Dark Grey = 100+98+76 Black = 0+0+0 2012201320142015201620172018 ONGOING PHASE 2 PHARMACOLOGICAL TRIALS BG00011 (N=40) Tralokinumab (N=186) BMS-986020 (N=135) Simtuzumab (N=500) FG-3019 (N=136) Lebrikizumab (N=300) SAR156597 (N=300) TD139 (N=60) THESE WILL PROBABLY ALL BE COMBINATION TRIALS

28. PFF Teal = 0+160+175 MAIN COLORS PFF Green = 120+162+47 Light Green = 193+216+47 Red = 242+102+73 HIGHLIGHT COLORS Light Grey = 220+220+210 Dark Grey = 100+98+76 Black = 0+0+0 Science Transl Med 2015 Aug 12; 7(300): 300ps17

29. PFF Teal = 0+160+175 MAIN COLORS PFF Green = 120+162+47 Light Green = 193+216+47 Red = 242+102+73 HIGHLIGHT COLORS Light Grey = 220+220+210 Dark Grey = 100+98+76 Black = 0+0+0 Science Transl Med 2015 Aug 12; 7(300): 300ps17

30. PFF Teal = 0+160+175 MAIN COLORS PFF Green = 120+162+47 Light Green = 193+216+47 Red = 242+102+73 HIGHLIGHT COLORS Light Grey = 220+220+210 Dark Grey = 100+98+76 Black = 0+0+0 CLINICAL TESTS GENOMICS MATRIX TELOMERES SENESCENCE INNATE IMMUNITY AIRWAY MUCINS SURFACTANT PROTEINS MICROBIOME ADAPTIVE IMMUNITY EPIGENETICS

31. PFF Teal = 0+160+175 MAIN COLORS PFF Green = 120+162+47 Light Green = 193+216+47 Red = 242+102+73 HIGHLIGHT COLORS Light Grey = 220+220+210 Dark Grey = 100+98+76 Black = 0+0+0 COMBINATION THERAPY and / or PRECISION THERAPY ?

33. Carol Liang Dianhua Jiang Yanli Zhang Stan Ningshan Yu Yamaguchi (Burnham Institute) Christina Barkauskas/Brigid Hogan (Duke) Barry Stripp (Cedars-Sinai) Collaborators NIH, HL060539, AI052201, HL77291 NIH PO1 HL108793, HL060539, AI052201, HL77291 Women’s Guild Lung Institute Guerin Family Pulmonary Research Fund Cedars-Sinai Medical Center Beverly Hills, CA