1. 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

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 / 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 mg/d
 by 25 mg q d
2 mg/kg/d
(150 mg/d max)
Start at mg/d
 by 25 mg q 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)
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

5. Conventional IPF Treatment Lacks Efficacy

6. 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

7. 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

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 normal mouse
BAL from mouse with pulmonary fibrosis

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
LPA1 KO mouse after bleomycin
Bleomycin
Mouse lung – normal appearance

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

12. Bringing LPA-LPA1 Pathway Inhibition to the Clinic

13. Bringing LPA-LPA1 Pathway Inhibition to the Clinic

14. 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

15. THANK YOU SECOND WIND FOUNDATION!!!!!