MGH Research in IPF: Identifying New Targets for Effective Drug Therapies Andrew M. Tager, M.D. Interstitial Lung Disease Program Pulmonary and Critical.

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:

35.2mos

• 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

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

Conventional Treatment of IPF

• 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)

Treatment Arms: Pred / Aza / NAC - vs - NAC alone - vs - Placebo

Conventional IPF Treatment Lacks Efficacy

Injury / Abnormal RepairHypothesis of IPF Pathogenesis

• Why are repair responses ineffective in IPF?– Recurrent nature of injury may overwhelm repair mechanisms– Repair mechanisms may be abnormal / overly exuberant

• 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

BasementMembrane

Epithelium

Re-epithelialization

ExtracellularMatrix

Fibroblasts

Fibroblast Accumulation

and Matrix Deposition

Fibrin Clot

Vascular leak

Capillary

EpithelialCell Death

Lung Injury

Phases of Wound Healing Responses to Injury

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 mouse with pulmonary fibrosis

BAL from normal mouse

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

Mouse lung – normal appearance

LPA1 KO mouse after bleomycin

Bleomycin

Normal mouse after bleomycin

Bleomycin

Pe

rce

nt s

urvi

val

0 5 10 15 20

Normal mice

Days post challenge

0

50

75

25

LPA1 KO100

Bleomycin-induced Fibrosis Requires LPA1

Bringing LPA-LPA1 Pathway Inhibitionto the Clinic

Bringing LPA-LPA1 Pathway Inhibitionto the Clinic

LPA-LPA1 Pathway Inhibition:an Academic-Industry Collaboration

Drug Discovery

Target Discovery IPF Patients

Clinical Trials

THANK YOUSECOND WIND

FOUNDATION!!!!!