11/5/2016 INTERSTITIAL LUNG DISEASE Faculty Disclosures The Changing Landscape Research Funding: Clinical Trials UCSF November 2016 Bayer CLINICAL TRIALS IN INTERSTITIAL LUNG DISEASE (ILD ) Biogen Jeff Golden Boehringer Ingelheim jeff.golden@ucsf.edu Bristol-Myers Squibb Clinical Trials - Fizaa Ahmed Gilead <Fizaa.Ahmed@ucsf.edu> Genentech/Roche 415 502-1958 INTERSTITIAL LUNG DISEASE ASCEND ‘14 The Changing Landscape IPF: Randomized Controlled Trials INPULSIS 2 ‘14 INPULSIS 1 ‘14 CLINICAL TRIALS IN INTERSTITIAL LUNG DISEASE (ILD) PANTHER ‘12 Outline Shulgina ’12 Raghu ‘12 Richeldi ‘11 King ‘11 PANTHER ‘14 � Challenge of Therapeutic IPF Trials Noble ‘11 Noble ‘11 � FDA Approved drugs have challenge Taniguchi ‘10 Raghu ‘08 � Heterogeneity of IPF Daniels ‘10 Kubo ‘05 � Progression of Disease : i.e. earlier versus later disease ACE-IPF ‘12 Azuma ‘05 � Pulmonary Hypertension STEP IPFnet ‘10 King ‘08 Demedts ‘05 � Novel Agents : Improving Understanding of Pathogenesis King ‘09 Ziesche ‘99 Raghu ‘99 Douglas ‘98 Raghu ‘04 � Trials of non-IPF Fibrosis: Scleroderma, Rheumatoid Arthritis 1
11/5/2016 CLINICAL TRIALS IN INTERSTITIAL LUNG DISEASE (ILD) CLINICAL TRIALS IN INTERSTITIAL LUNG DISEASE (ILD) Challenge of Therapeutic trials Challenge of Therapeutic trials Heterogeneic Disease: Heterogeneic Disease: Pathologic Dx: temporal & spatial heterogeneity Pathologic Dx: temporal & spatial heterogeneity Natural History Natural History Unknown Mechanism Unknown Mechanism Animal models Animal models Biomarkers – likely vary with early and progressive disease biomarkers – likely vary with early and progressive disease Pulmonary Artery Hypertension Pulmonary Artery Hypertension Outcome markers – surrogates Outcome markers – surrogates FDA Approved drugs make future studies more difficult FDA Approved drugs make future studies more difficult FVC – regulatory precedent FVC – regulatory precedent Precision Medicine – lose subset benefit in unselected populations – Asthma Story Precision Medicine – lose subset benefit in unselected populations – Asthma Story IPF: FDA Approved drugs make future studies more challenging Combination of Novel Agents and FDA Drugs Kevin Brown Unknown how approved drugs work Univ Colorado Mechanism of study agents & standard Rx Pharmacokinetic Interactions Study Drug Pharmacodynamic Interactions FDA: Approved Standard Rx Pre-FDA Placebo FVC as Outcome Measure: Limited by benefit of standard Rx 12 Months 2
11/5/2016 INTERSTITIAL LUNG DISEASE The Changing Landscape IPF: Challenge of Therapeutic trials CLINICAL TRIALS IN INTERSTITIAL LUNG DISEASE (ILD) Outline Progression of Disease: � Challenge of Therapeutic IPF Trials Changing Pathogenetic Mechanism (s) � FDA Approved drugs have challenge Ultimately Combination RX � Heterogeneity of IPF � Progression of Disease : i.e. earlier versus later disease Pulmonary Artery Hypertension � Pulmonary Hypertension � Novel Agents : Improving Understanding of Pathogenesis � Trials of non-IPF Fibrosis: Scleroderma, Rheumatoid Arthritis Progression of Disease IPF: Challenge of Therapeutic trials Progression of Disease: Changing Pathogenetic Mechanism (s) Ultimately Combination RX Pulmonary Artery Hypertension 3
11/5/2016 IPF: Pulmonary Artery Hypertension IPF: Pulmonary Artery Hypertension Increases with Time Opportunity for Intervension Therapeutic Trials : FAILED -Endothelin Receptor Angtagonists (3) Bosentan Macitentan Ambrisentan *contraindicated -Reociquat Distributions of the RHC mPAPs at baseline and follow-up (n = 44) NEW STUDY - Inhaled Treprostinil S. Nathan 2011 CLINICAL TRIALS IN INTERSTITIAL LUNG DISEASE (ILD) Challenge of Therapeutic trials Heterogeneic Disease: Pathologic Dx: temporal & spatial heterogeneity Natural History Inhaled Treprostinil Unknown Mechanism Animal models Inclusion: lung fibrosis biomarkers – likely vary with early and progressive disease Pulmonary Artery Hypertension Outcome markers – surrogates FDA Approved drugs make future studies more difficult FVC – regulatory precedent Precision Medicine – lose subset benefit in unselected populations – Asthma Story 4
11/5/2016 IPF Rx : Precision Medicine Challenge of Therapeutic trials Genotype-stratified Trials � Where to Direct Therapeutic Intervention ? � KEY: Understand Mechanism (s) INTERSTITIAL PULMONARY FIBROSIS ( IPF) Challenge of Therapeutic trials : Mechanism of Disease IPF: Novel Targets � Epithelial apoptosis/injury � Injured epithelium � TELOMERES � Inflammation � Profibrotic (M2) Macrophages � Fibroblast positive feedback mediators � “STIFFNESS” 5
11/5/2016 IPF: Novel Targets IPF: Novel Targets � Epithelial apoptosis/injury � Epithelial apoptosis/injury � Injured epithelium � Injured epithelium � Transforming growth factor- β (TGF- β ) � Transforming growth factor B (TGF- β ) � Via Integrins ( α v β 6 ) � Via Integrins ( α v β 6 ) � Reactivate Development pathways � Reactivate Development pathways � Hedgehog reactivated pathway in fibrosis � Hedgehog reactivated pathway in fibrosis � Wnt\B-catenin � Wnt\ β -catenin TGF β has long been considered a therapeutic target, TGF-b (Transforming Growth Factor B) but pleiotropic effects are a major limitation Fibroblast activation Integrins (avb6) EMT and collagen production TGF β Adaptive Immunity Tumor progression, invasion Epithelial carcinogenesis 6
11/5/2016 α v β 6 integrin is highly induced in pulmonary fibrosis Stromedix Humanized monoclonal antibody to α v β 6 integrin β 6 blocking antibody starting 14 days Normal Phase 2 Study : Proof of Concept after bleomycin prevents pulmonary fibrosis in mice 250 Hydroxyproline content Bleomycin Inhibition of pro-fibrotic activity (dose related) Saline 150 IPF - Down Regulated in BAL monkey fibrosis model: TGF-B inducible proteins 50 Tissue inhibitor of metalloproteinase 1 (TIMP-1) Plasminogen activator inhibitor-1 (PAI-1) Anti- β 6 antibody Control Endothelin-1 Horan, et al, Am J Respir Crit Care Med, 2008 STX-100, a humanized monoclonal antibody blocking α v β 6 is in phase 2 trial - IPF Subjects : Pre and Post Therapy blood and lavage for Idiopathic Pulmonary Fibrosis (Biogen/Idec) IPF: Novel Targets IPF: Novel Targets � Epithelial apoptosis/injury � Inflammation � Injured epithelium - Non-targeted: cellular & humoral Rx - HARM � Inflammation insert screen shot � Profibrotic (M2) Macrophages � Fibroblast positive feedback mediators � “STIFFNESS” - Inflammation: Specific Targets 7
11/5/2016 � Inflammation IPF: Novel Targets LEBRIKIZAMAB STUDY Non-targeted: Harm--cellular & humoral Specific Target of Inflammation Intedanib lysophophotidic acid (LPA) T helper cell (TH2)inflammatory Periostin driven by TH2 inflammation Lebrikizamab study- IL-13 Profibrotic (M2) macrophages Pentraxin study PENTRAXIN STUDY Pentraxin Study Profibrotic (M2)Macrophages Profibrotic (M2)Macrophages 8
11/5/2016 IPF: Novel Targets � Epithelial apoptosis/injury � Injured epithelium � Inflammation � Profibrotic (M2) Macrophages � Fibroblast positive feedback mediators � Mechanosensitive signaling itself regulates fibroblast activation --- STIFFNESS � Lysloxidase like 2 (LOXL2) cross linking collagen fibrils Fibroblast positive feedback mediators ECM prestrain generated by myofibroblast Mechanosensitive signaling itself regulates fibroblast activation --- contracton affects TGF-B1 activation STIFFNESS VIA COLLAGEN CROSSLINKING 9
11/5/2016 HOPE THESE CARTOONS COME TRUE Scleroderma Lung Study II Mycophenolate Mofetil: Limitations FUTURE: Treat Multiple Targets; anti-fibrotics After Cellcept Before Cellcept FDA APPROVED IPF RX Other Fibrotic Lung Diseases • Rheumatoid Arthritis • Scleroderma 10
11/5/2016 Lung Translantation: SCLERODERMA LUNG DISEASE Scleroderma Cellcept and Nintedanib Dear Colleague, The Interstitial Lung Disease group at UCSF is participating in a very exciting trial with a therapy for patients with Scleroderma related pulmonary fibrosis. Boehringer-Ingelheim is looking for eligible subjects for a new Phase III study. This study will determine the efficacy and safety of Nintedanib in patients with Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD). This is a randomized, double-blind, placebo-controlled trial and the duration of treatment will be 52 weeks. FLYERS AVAILABLE from Fizaa Ahmed Restrictive Allograft Syndrome (RAS) Transplant Informs Lung Fibrosis � Lung Fibrosis in the Lung Allograft Chronic Lung Allograft Dysfunction (CLAD): � � Bronchiolitis Obliterans (BOS) � “Restrictive Allograft Dysfunction” (RAS) 11
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