INTERSTITIAL LUNG DISEASE Faculty Disclosures The Changing - - PowerPoint PPT Presentation

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INTERSTITIAL LUNG DISEASE The Changing Landscape UCSF November 2016

CLINICAL TRIALS IN INTERSTITIAL LUNG DISEASE (ILD) Jeff Golden jeff.golden@ucsf.edu Clinical Trials - Fizaa Ahmed <Fizaa.Ahmed@ucsf.edu> 415 502-1958

Faculty Disclosures Research Funding: Clinical Trials

Bayer Biogen Boehringer Ingelheim Bristol-Myers Squibb Gilead Genentech/Roche

Outline

Challenge of Therapeutic IPF Trials

FDA Approved drugs have challenge

Heterogeneity of IPF

Progression of Disease : i.e. earlier versus later disease Pulmonary Hypertension

Novel Agents : Improving Understanding of Pathogenesis Trials of non-IPF Fibrosis: Scleroderma, Rheumatoid Arthritis

INTERSTITIAL LUNG DISEASE The Changing Landscape CLINICAL TRIALS IN INTERSTITIAL LUNG DISEASE (ILD)

Raghu ‘99 King ‘11 King ‘09 Raghu ‘04 Demedts ‘05 Azuma ‘05 Ziesche ‘99 Douglas ‘98 King ‘08 Noble ‘11 Noble ‘11 Taniguchi ‘10 Raghu ‘08 Kubo ‘05 STEP IPFnet ‘10 ACE-IPF ‘12 PANTHER ‘12 Raghu ‘12 Shulgina ’12 Daniels ‘10 INPULSIS 1 ‘14 INPULSIS 2 ‘14 PANTHER ‘14 Richeldi ‘11 ASCEND ‘14

IPF: Randomized Controlled Trials

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Heterogeneic Disease: Pathologic Dx: temporal & spatial heterogeneity Natural History Unknown Mechanism Animal models 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

CLINICAL TRIALS IN INTERSTITIAL LUNG DISEASE (ILD)

Challenge of Therapeutic trials

Heterogeneic Disease: Pathologic Dx: temporal & spatial heterogeneity Natural History Unknown Mechanism Animal models 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

CLINICAL TRIALS IN INTERSTITIAL LUNG DISEASE (ILD)

Challenge of Therapeutic trials IPF: FDA Approved drugs make future studies more challenging Combination of Novel Agents and FDA Drugs Unknown how approved drugs work Mechanism of study agents & standard Rx Pharmacokinetic Interactions Pharmacodynamic Interactions FVC as Outcome Measure: Limited by benefit of standard Rx

Kevin Brown Univ Colorado FDA: Approved Standard Rx Study Drug 12 Months Pre-FDA Placebo

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Outline

Challenge of Therapeutic IPF Trials

FDA Approved drugs have challenge

Heterogeneity of IPF

Progression of Disease : i.e. earlier versus later disease Pulmonary Hypertension

Novel Agents : Improving Understanding of Pathogenesis Trials of non-IPF Fibrosis: Scleroderma, Rheumatoid Arthritis

INTERSTITIAL LUNG DISEASE The Changing Landscape CLINICAL TRIALS IN INTERSTITIAL LUNG DISEASE (ILD)

IPF: Challenge of Therapeutic trials

Progression of Disease: Changing Pathogenetic Mechanism (s) Ultimately Combination RX Pulmonary Artery Hypertension

Progression of Disease

IPF: Challenge of Therapeutic trials

Progression of Disease: Changing Pathogenetic Mechanism (s) Ultimately Combination RX Pulmonary Artery Hypertension

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IPF: Pulmonary Artery Hypertension Increases with Time

Distributions of the RHC mPAPs at baseline and follow-up (n = 44)

• S. Nathan 2011

IPF: Pulmonary Artery Hypertension Opportunity for Intervension Therapeutic Trials :

FAILED

• Endothelin Receptor Angtagonists (3)

Bosentan Macitentan Ambrisentan *contraindicated

• Reociquat

NEW STUDY - Inhaled Treprostinil

Inhaled Treprostinil

Inclusion: lung fibrosis

Heterogeneic Disease: Pathologic Dx: temporal & spatial heterogeneity Natural History Unknown Mechanism Animal models 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 CLINICAL TRIALS IN INTERSTITIAL LUNG DISEASE (ILD)

Challenge of Therapeutic trials

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IPF Rx : Precision Medicine Genotype-stratified Trials

Challenge of Therapeutic 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”

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IPF: Novel Targets

Epithelial apoptosis/injury Injured epithelium

Transforming growth factor-β (TGF- β)

Via Integrins (αvβ6) Reactivate Development pathways

Hedgehog reactivated pathway in fibrosis Wnt\B-catenin

IPF: Novel Targets

Epithelial apoptosis/injury Injured epithelium

Transforming growth factor B (TGF- β)

Via Integrins (αvβ6) Reactivate Development pathways

Hedgehog reactivated pathway in fibrosis Wnt\ β-catenin

TGF-b (Transforming Growth Factor B) Integrins (avb6)

TGFβ EMT Tumor progression, invasion Epithelial carcinogenesis Adaptive Immunity Fibroblast activation and collagen production TGFβ has long been considered a therapeutic target, but pleiotropic effects are a major limitation

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αvβ6 integrin is highly induced in pulmonary fibrosis

Bleomycin Saline 250 150 50 Hydroxyproline content Anti-β6 antibody Control

β6 blocking antibody starting 14 days after bleomycin prevents pulmonary fibrosis in mice Horan, et al, Am J Respir Crit Care Med, 2008 Normal IPF

STX-100, a humanized monoclonal antibody blocking αvβ6 is in phase 2 trial for Idiopathic Pulmonary Fibrosis (Biogen/Idec)

Stromedix Humanized monoclonal antibody to αvβ6 integrin Phase 2 Study : Proof of Concept

Inhibition of pro-fibrotic activity (dose related)

• Down Regulated in BAL monkey fibrosis model:

TGF-B inducible proteins Tissue inhibitor of metalloproteinase 1 (TIMP-1) Plasminogen activator inhibitor-1 (PAI-1) Endothelin-1

• IPF Subjects : Pre and Post Therapy blood and lavage

IPF: Novel Targets

Epithelial apoptosis/injury Injured epithelium Inflammation Profibrotic (M2) Macrophages Fibroblast positive feedback mediators

“STIFFNESS”

IPF: Novel Targets

Inflammation

• Non-targeted: cellular & humoral Rx -HARM

insert screen shot

• Inflammation: Specific Targets

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IPF: Novel Targets

Inflammation

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

LEBRIKIZAMAB STUDY

PENTRAXIN STUDY Profibrotic (M2)Macrophages

Pentraxin Study

Profibrotic (M2)Macrophages

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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

ECM prestrain generated by myofibroblast contracton affects TGF-B1 activation

Fibroblast positive feedback mediators Mechanosensitive signaling itself regulates fibroblast activation --- STIFFNESS VIA COLLAGEN CROSSLINKING

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HOPE THESE CARTOONS COME TRUE

FDA APPROVED IPF RX Other Fibrotic Lung Diseases

• Rheumatoid Arthritis
• Scleroderma

Scleroderma Lung Study II Mycophenolate Mofetil: Limitations FUTURE: Treat Multiple Targets; anti-fibrotics

Before Cellcept After Cellcept

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SCLERODERMA LUNG DISEASE 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

Lung Translantation: Scleroderma Transplant Informs Lung Fibrosis

Lung Fibrosis in the Lung Allograft

• Chronic Lung Allograft Dysfunction (CLAD):

Bronchiolitis Obliterans (BOS) “Restrictive Allograft Dysfunction” (RAS)

Restrictive Allograft Syndrome (RAS)

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Transplant Informs Lung Fibrosis

Outline

Challenge of Therapeutic IPF Trials

FDA Approved drugs have challenge

Heterogeneity of IPF

Pulmonary Hypertension

Novel Agents Trials of non-IPF Fibrosis: Scleroderma, Rheumatoid Arthritis

INTERSTITIAL LUNG DISEASE The Changing Landscape CLINICAL TRIALS IN INTERSTITIAL LUNG DISEASE (ILD)

PHASE 1 PHASE 2 PHASE 3 REGISTRATION LAUNCHED

PIRFENIDONE BOSENTAN COTRIMOXAZOLE AMBRISENTAN OMEPRAZOLE WARFARIN SILDENAFIL TRIPLE THERAPY IFN-γ

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

IPF: Challenge of Therapeutic trials

• Coordinated IPF Clinical Trials Network

broad range of stakeholders patients, providers, scientists, professional societies, advocacy groups, industry and governments agencies

• Cystic Fibrosis Foundation
• National Cancer Institute : Lung Cancer Master Program

Public Private partnership

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THANKS TO OUR PATIENTS !!!

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IPF: Lung Transplantation

Outline

Challenge of Therapeutic IPF Trials

FDA Approved drugs have challenge

Heterogeneity of IPF

Progression of Disease : i.e. earlier versus later disease Pulmonary Hypertension

Novel Agents : Improving Understanding of Pathogenesis Trials of non-IPF Fibrosis: Scleroderma, Rheumatoid Arthritis

INTERSTITIAL LUNG DISEASE The Changing Landscape CLINICAL TRIALS IN INTERSTITIAL LUNG DISEASE (ILD)

INTERSTITIAL LUNG DISEASE The Changing Landscape CLINICAL TRIALS IN INTERSTITIAL LUNG DISEASE (ILD)

COMMUNITY COLLABORATION

BASIC SCIENCE & CLINCAL CARE PATIENT POPULATIONS GENERAL POPULATION TERTIARY CARE CENTER

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