Update in ILD: Current Approaches to IPF Andrew M. Tager, M.D. MGH Research in IPF: Identifying New Targets for Effective Drug Therapies Andrew M. Tager, M.D. Interstitial Lung Disease Program Pulmonary and Critical Care Unit Massachusetts General Hospital Harvard Medical School

Unmet Need for Effective IPF Therapy US demographics: Incidence > 30,000 patients / year Prevalence > 80,000 current patients Poor prognosis: 35.2 mos

Conventional Treatment of IPF Recommendation of 2000 ATS / ERS consensus statement Prednisone + Azathrioprine or Cyclophosphamide 0.5 mg/kg/d x 4 wks then 0.25 mg/kg/d x 8 wks 0.125 mg/kg/d or 0.25 mg/kg QOD 2 - 3 mg/kg/d (150 mg/d max) Start at 25 - 50 mg/d  by 25 mg q 7 - 14 d 2 mg/kg/d (150 mg/d max) Start at 25 - 50 mg/d  by 25 mg q 7 - 14 d Recommendation based on hypothesis that IPF results from chronic inflammation There are lung diseases where chronic inflammation causes fibrosis, such as hypersensitivity pneumonitis

PANTHER Trial of Conventional Treatment of IPF (Prednisone / Azathioprine / NAC) Update in ILD: Current Approaches to IPF Andrew M. Tager, M.D. Treatment Arms: Pred / Aza / NAC - vs - NAC alone - vs - Placebo Prednisone/Azathioprine/NAC: PANTHER The IFIGENIA study suggested a positive effect of NAC in combination with prednisone and azathioprine. PANTHER is a 3-arm placebo-controlled study comparing the IFIGENIA NAC cocktail with NAC alone and placebo alone. This 1-year study is designed to address whether NAC is effective alone or in combination with the “conventional” drug cocktail of prednisone and azathioprine. This trial is part of the NIH IPF clinical research network. 4

Conventional IPF Treatment Lacks Efficacy

Injury / Abnormal Repair Hypothesis of IPF Pathogenesis IPF pathology suggests: repetitive / recurrent injury Restoration of normal structure and function Effective repair Pulmonary fibrosis and loss of function Ineffective repair What injures the lung in IPF? Unknown / may be different in different patients Why are repair responses ineffective in IPF? Recurrent nature of injury may overwhelm repair mechanisms Repair mechanisms may be abnormal / overly exuberant

Phases of Wound Healing Responses to Injury Epithelium Capillary Epithelial Cell Death Lung Injury Basement Membrane Re-epithelialization Fibrin Clot Vascular leak Extracellular Matrix Fibroblasts Fibroblast Accumulation and Matrix Deposition Abnormalities of any of these responses can contribute to fibrosis

BAL from IPF Patients Contains Signals that Attract Fibroblasts The amount of these signals present in BAL correlates with IPF severity and rate of progression These fibroblast-attracting signals are also present in mouse models of pulmonary fibrosis BAL from normal mouse BAL from mouse with pulmonary fibrosis

Discovery of LPA as the Signal that Attracts Fibroblasts to the Lung in IPF We discovered LPA by purifying the fibroblast attractant activity in BAL LPA exerts its effects through several molecules on the surface of cells called receptors We discovered that LPA exerts its pro-fibrotic effects through one of these receptors, called LPA1 We demonstrated the importance of the LPA-LPA1 pathway to lung fibrosis with mice genetically lacking LPA1 LPA1 knockout mice (LPA1 KOs)

Bleomycin-induced Fibrosis Requires LPA1 Normal mouse after bleomycin Bleomycin LPA1 KO mouse after bleomycin Bleomycin Mouse lung – normal appearance

Bleomycin-induced Fibrosis Requires LPA1 100 LPA1 KO 75 Percent survival 50 Normal mice 25 5 10 15 20 Days post challenge

Bringing LPA-LPA1 Pathway Inhibition to the Clinic

Bringing LPA-LPA1 Pathway Inhibition to the Clinic

LPA-LPA1 Pathway Inhibition: an Academic-Industry Collaboration Update in ILD: Current Approaches to IPF Andrew M. Tager, M.D. Target Discovery IPF Patients Drug Discovery Clinical Trials

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