©Copyright 2015 Galapagos NV

Favorable human safety, pharmacokinetics and pharmacodynamics of the autotaxin inhibitor GLPG1690, a potential new treatment in COPD

Ellen M. van der Aar, PhDGalapagos, Mechelen, Belgium

L. Fagard, J. Desrivot, S. Dupont, B. Heckmann, R. Blanqué, L. Gheyle, J. Ralic, F. Vanhoutte

ERS International Congress, Amsterdam27 September 2015

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Outline

• Target background

• GLPG1690 pharmacology

• GLPG1690 first-in-human data: safety, PK and PD

single ascending dose

multiple ascending dose

• Conclusions

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GT2645

ATXLysophosphatidylcholine (LPC)

Lysophosphatidic acid (LPA)

Autotaxin (ATX)Target background

• Also known as ENPP2, secreted enzyme

• Converts LPC to the bioactive lipid mediator LPA

• “LPA” covers a family of related molecules (i.e. LPA 18:2, LPA 20:4)

• 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)

• Studies with KO of LPA receptors indicate a role in

bone development

fertility/reproduction

neurogenesis

formation of blood- and lymphatic vessels

Stoddard and Chun, 2015

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‘1690 in vitro activity

LPA species‘1690

IC50 (nM)

C14:0 96

C16:0 117

C18:1 115

C18:2 112

C18:3 102

C20:4 93

C22:6 94

• Similar biochemical potency for mouse and human ATX

• Release of LPA species observed in plasma incubated at 37 ºC

• When co-incubated with ‘1690, inhibition of LPA release

similar IC50 for all LPA species

Ex vivo human plasma LPA assay (LC/MS)

SourceInhibition by

‘1690

mATX IC50=224 nM

hATX IC50=131 nM

hATXKi =14.7 nM (competitive)

In vitro LPC assay

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% LPA18:2 reduction GLPG1690 plasma concentration

‘1690 - 3 mg/kg

‘1690 - 10 mg/kg

‘1690 - 30 mg/kg

‘1690 - 3 mg/kg

‘1690 - 10 mg/kg

‘1690 - 30 mg/kg

0

5000

10000

15000

20000

25000

0

20

40

60

80

100

0 4 8 12 16 20 24

G4

51

99

0-5

(n

g/

ml)

PIN

Time (hour)

% r

ed

ucti

on

LP

A 1

8:2

‘1690 in vivo activityPK/PD model in mouse

‘1690 at ≥ 3 mg/kg in mice causes sustained reduction in plasma LPA levels

GLP

G1

69

0 (

ng

/m

L)

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‘1690 in vivo activity 11-day prophylactic mouse tobacco smoke model

‘1690 significantly reduced the total cells in BALF to a similar extent as roflumilast

Cell count in BALF

vehicle

TS + vehicle

TS + ‘1690 5 mg/kg bid

TS + ‘1690 10 mg/kg bid

TS + dexamethasone 0.3 mg/kg bid

TS + roflumilast 5 mg/kg qd

See poster discussion session PA2129Monday, Sept 28(Blanqué et al)

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‘1690 in vivo activity 21-day prophylactic mouse bleomycin model

‘1690 at 30 mg/kg bid significantly superior to pirfenidone on the Ashcroft fibrotic score and on collagen content

Ashcroft fibrotic score Collagen content

vehicle

BLM + vehicle

BLM + pirfenidone 50 mg/kg bid

BLM + ‘1690 10 mg/kg bid

BLM + ‘1690 30 mg/kg bid

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‘1690: First-in-HumanObjectives/design

• Randomized, double-blind, placebo-controlled, single center

• Healthy male subjects (18-50 years)

• In each dose group: 6 on active and 2 on placebo, oral suspension

• Part 1: single ascending dose (SAD)

20 up to 1500 mg

• Part 2: multiple ascending dose (MAD)

150 mg bid - 600 mg qd - 1000 mg qd for 14 days

• Objectives

safety and tolerability

pharmacokinetic profile

pharmacodynamics: effects on plasma LPA 18:2

10

0.1

1

10

100

1000

10000

100000

0 6 12 18 24 30 36 42 48

Pla

sm

a G

LP

G1

69

0 (

ng

/m

L)

Time (h)

20 mg 60 mg 150 mg 300 mg

600 mg 1000 mg 1500 mg

‘1690: SADPlasma profile (mean ±SEM)

• Safety: well-tolerated up to highest dose (1500 mg)

• PK: dose proportional; t½ ~5 h

• Plasma levels above ex vivo IC50 for LPA 18:2 reduction as of dose of 60 mg

Ex vivo IC50 = ~100 nM

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‘1690: SAD% reduction LPA 18:2 (mean ±SD)

Dose-dependent reduction observed in plasma LPA 18:2

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‘1690 SADPK/PD relationship

IC50=118 nM

In vivo IC50 for inhibition of LPA 18:2 is in accordance with ex vivo IC50

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‘1690: MADPlasma profile (mean ±SEM)

• Mild AEs reported: GI disturbances, dry mouth and headache

• No clinically relevant findings in ECGs, vital signs, physical exam, lab parameters

• Multiple dose PK profile and exposure consistent with single dose data

• Minor accumulation (ratio of ~1.7) to steady state

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‘1690: MADLPA18:2 – mean % reduction

• Dose/regimen-dependent reduction in plasma LPA 18:2

• Maximum inhibition of LPA 18:2 around 85-90%

• At steady state continuous inhibition of LPA of >60% from 0 to 24h

• Transient effect: LPA levels return to baseline 36 - 48h post-last dosing

-40

-20

0

20

40

60

80

100

0 0.5 1 2 4 6 8 12 24 48 0 0.5 1 2 4 6 8 12 24 48

D1 D14

% L

PA 1

8:2

re

du

ctio

n

Time (h)

150 mg b.i.d.

PlaceboGLPG1690

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ConclusionsGLPG1690

• Potent and selective inhibitor of autotaxin

• Reduces plasma LPA levels ex vivo and in vivo

• Favorable safety profile, good plasma PK and solid PD response indicating target engagement in healthy volunteers

• Galapagos is currently preparing for an exploratory Ph2a study in IPF patients

stronger validation of ATX/LPA pathway in IPF

ongoing collaboration with professor Hiemstra (LUMC, Leiden, NL) to strengthen the link with COPD

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Acknowledgment