©Copyright 2016 Galapagos NV

Strong reversal of the lung fibrosis disease signature by autotaxin inhibitor GLPG1690 in a mouse model for IPFMaté Ongenaert, PhDSenior Scientist Bioinformatics

Sonia Dupont, Roland Blanqué, Reginald Brys, Ellen van der Aar, Bertrand Heckmann

ERS London, UKSeptember 6th 2016

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Disclosure

• I and other authors have the following real or percieved conflicts of interest that relate to this presentation: All employees of Galapagos NV (Mechelen, Belgium) or Galapagos SASU

(Romainville, France)

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Outline

Autotaxin/LPA pathway background

Transcriptomics studies in BLM model

Mouse bleomycin (BLM) model - GLPG1690 performance and target engagement

Summary and outlook

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GT2645

ATXLysophosphatidylcholine (LPC)

Lysophosphatidic acid (LPA)

Autotaxin (ATX)Target background • Also known as ENPP2, secreted enzyme• Widely expressed (highest in brain, lymph nodes, kidney and

testis)• Converts LPC to the bioactive lipid mediator LPA • “LPA” covers a family of related molecules (i.e. LPA18:2, LPA20:4)• ATX is main source of LPA in blood

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LPA signalling• LPA acts through at least six

distinct G-protein-coupled receptors (LPA1–6)

• LPA controls activities like migration, contraction & survival

• Studies with KO of LPA receptors indicate a role in bone development fertility/reproduction neurogenesis formation of blood- and

lymphatic vesselsStoddard and Chun, 2015

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ATX/LPA pathway and IPFPreclinical and translational validation

• In modeled disease: bleomycin-exposed mice increased LPA in BALF (Tager et al, 2008) ATX levels increased in lungs (Oikonomou, 2012) inhibition of ATX attenuated lung fibrosis in mice (Oikonomou, 2012) genetic or pharmacological inhibition of LPAR1 attenuates

development of pulmonary fibrosis (Tager et al, 2008; Swaney et al, 2010)

• In patients with idiopathic pulmonary fibrosis (IPF) LPA levels increased in BALF (Tager et al, 2008) ATX levels elevated in lung (Oikonomou et al, 2012) LPA increased in exhaled breath condensate (Montesi et al, 2014)

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GLPG1690 reduces fibrosis in BLM models, reduces LPA levels in BALF

Mouse bleomycin model for lung fibrosis (prophylactic)

Relative levels of LPA species in BALF of mice subjected to BLM treatment

GLPG1690 in vivo activity

LPA

peak

are

a /

LPA

17:0

pea

k ar

eavehicleBLM + vehicle

BLM + pirfenidone 50 mg/kg bidBLM + ‘1690  30 mg/kg bid

Group

Ashc

roft

scor

e

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GLPG1690 - bleomycin modelGlobal transcriptomics (PCA)

vehicle

bleomycinGLPG1690

Lung microarray profiling: GLPG1690 protects for BLM induced effects on a global transcriptome level

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GLPG1690 - bleomycin modelMost affected genes

vehicleBLM ‘1690

• Top-40 most differentially expressed genes

perfect separation of the BLM cluster from sham

GLPG1690 partially reverses the BLM effect

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GLPG1690 - bleomycin modelRelevance in model

‘1690 (log2 Fold Change)

BLM

(lo

g2 F

old

chan

ge)

Strong negative correlation (Spearman R=-0.74) between BLM effect and GLPG1690 effects

‘1690(DOWN)

BLM(UP)

1088probes 259 18

^ Probes with both:- |log2(FC)|>1- FDR< 1%

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GLPG1690 - bleomycin modelFunctions

Color: log2 FCArea: log2 FC * -log10(p-value)

TncTn

c

Cxcl12

Smad6Smad6

Col5a1

Serpine2

Col1a2 Serpine2

Ednrb

Ccl2

immune response cytokines, Jak-Stat, TGFb

Extracellular matrix – focal adhesion

Col1a2

• Affected functions and pathways by BLM and counteracted by GLPG1690 relevant in BLM model and IPF biology:

extracellular matrix (Tnc, Spp1)

several collagens (Col3a1, Col5a1)

cytokines / chemokines (Cxcl12, Ccl2)

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GLPG1690 - bleomycin modelBLM/GLPG1690 – IPF relevance

• Many of the genes identified are relevant in IPF and/or altered in expression in IPF patients (assessed in 4 public transcriptomics studies)

• 52 genes upregulated in BLM and at least in ¾ IPF vs. normal studies and strongly counteracted by ‘1690

• BLM: log2(FC)>1• counteracted by ‘1690: log2(FC)< -1• IPF studies: log2(FC)>0.5 in at least ¾ studies

Gene Symbols BLM mouse models GLPG1690 Human IPF (public data)

Mouse Human BLMthis study

BLMGSE40151

GLPG1690this study GSE32537 GSE1066

7GSE5384

5Yang et

al.Cxcl12 CXCL12 3.09 1.11 -1.4 1.17 2.21 1.96 1.5Col3a1 COL3A1 2.51 1.15 -0.71 1.4 2.82 1.71 2.19Spp1 SPP1 4.19 1.59 -1.56 1.61 3.67 3.49 1.77Tnc TNC 4.6 2.54 -2.22 1.13 0.86 1.89 1.49

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GLPG1690: potent and selective inhibitor of autotaxin

Summary and outlook

Pharmacological and literature data support positioning in IPF

Strong anti-fibrotic effects in the mouse bleomycin modelIPF-related gene expression signature clearly affected after GLPG1690 administration

Exploratory phase IIa study in IPF patients ongoing (FLORA)

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Many thanks to all involved Galapagos colleagues