MGH Research in IPF: Identifying New Targets for Effective Drug Therapies

1. 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

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

3. Conventional Treatment of IPF • Recommendation of 2000 ATS / ERSconsensus statement Prednisone + Azathrioprine or Cyclophosphamide 0.5 mg/kg/d x 4 wks then 0.25 mg/kg/d x 8 wks then 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

4. PANTHER Trial of Conventional Treatment of IPF(Prednisone / Azathioprine / NAC) Treatment Arms:Pred / Aza / NAC - vs - NAC alone - vs - Placebo

5. Conventional IPF TreatmentLacks Efficacy

6. Injury / Abnormal Repair Hypothesis of IPF Pathogenesis Effective repair Ineffective repair Pulmonary fibrosis and loss of function Restoration of normal structure and function • IPF pathology suggests: repetitive / recurrent injury • 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

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

8. 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 mouse with pulmonary fibrosis BAL from normal mouse

9. 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)

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

11. Bleomycin-induced Fibrosis Requires LPA1 100 LPA1 KO 75 Percent survival 50 Normal mice 25 0 0 5 10 15 20 Days post challenge

12. Bringing LPA-LPA1 Pathway Inhibitionto the Clinic

13. Bringing LPA-LPA1 Pathway Inhibitionto the Clinic

14. LPA-LPA1 Pathway Inhibition:an Academic-Industry Collaboration Target Discovery IPF Patients Drug Discovery Clinical Trials

15. THANK YOUSECOND WIND FOUNDATION!!!!!