Favorable human safety, pharmacokinetics and pharmacodynamics of the autotaxin inhibitor GLPG1690, a potential new treatment in COPD Ellen M. van der Aar, PhD Galapagos, Mechelen, Belgium L. Fagard, J. Desrivot, S. Dupont, B. Heckmann, R. Blanqué, L. Gheyle, J. Ralic, F. Vanhoutte ERS International Congress, Amsterdam 27 September 2015 Copyright 2015 Galapagos NV
Outline Target background GLPG1690 pharmacology GLPG1690 first-in-human data: safety, PK and PD single ascending dose multiple ascending dose Conclusions 2
Autotaxin (ATX) Target background GT2645 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 Lysophosphatidylcholine (LPC) ATX Lysophosphatidic acid (LPA) 3
LPA signalling LPA acts through at least six distinct G-protein-coupled receptors (LPA 1 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 4
1690 in vitro activity In vitro LPC assay Ex vivo human plasma LPA assay (LC/MS) Source matx hatx hatx Inhibition by 1690 IC 50 =224 nm IC 50 =131 nm K i =14.7 nm (competitive) LPA species 1690 IC 50 (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 º C When co-incubated with 1690, inhibition of LPA release similar IC 50 for all LPA species 5
% reduction LPA 18:2 PIN GLPG1690 G451990-5 (ng/ml) (ng/ml) 1690 in vivo activity PK/PD model in mouse 100 25000 80 20000 60 15000 40 10000 20 5000 0 0 0 4 8 12 16 20 24 Time (hour) % 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 1690 at 3 mg/kg in mice causes sustained reduction in plasma LPA levels 6
1690 in vivo activity 11-day prophylactic mouse tobacco smoke model Cell count in BALF See poster discussion session PA2129 Monday, Sept 28 (Blanqué et al) 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 1690 significantly reduced the total cells in BALF to a similar extent as roflumilast 7
1690 in vivo activity 21-day prophylactic mouse bleomycin model 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 1690 at 30 mg/kg bid significantly superior to pirfenidone on the Ashcroft fibrotic score and on collagen content 8
1690: First-in-Human Objectives/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 9
Plasma GLPG1690 (ng/ml) 1690: SAD Plasma profile (mean ±SEM) 100000 10000 Ex vivo IC 50 = ~100 nm 1000 100 10 1 0.1 0 6 12 18 24 30 36 42 48 Time (h) 20 mg 60 mg 150 mg 300 mg 600 mg 1000 mg 1500 mg Safety: well-tolerated up to highest dose (1500 mg) PK: dose proportional; t½ ~5 h Plasma levels above ex vivo IC 50 for LPA 18:2 reduction as of dose of 60 mg 10
1690: SAD % reduction LPA 18:2 (mean ±SD) Dose-dependent reduction observed in plasma LPA 18:2 11
1690 SAD PK/PD relationship IC 50 =118 nm In vivo IC 50 for inhibition of LPA 18:2 is in accordance with ex vivo IC 50 12
1690: MAD Plasma 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 13
% LPA 18:2 reduction 1690: MAD LPA18:2 mean % reduction Placebo GLPG1690 100 150 mg b.i.d. 80 60 40 20 0-20 -40 0 0.5 1 2 4 6 8 12 24 48 0 0.5 1 2 4 6 8 12 24 48 D1 D14 Time (h) 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 14
Conclusions GLPG1690 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 15
Acknowledgment 16