Safety, Pharmacokinetics, and Pharmacodynamics of the Autotaxin Inhibitor GLPG1690 in Healthy Subjects: Phase 1 Randomized Trials

Ellen van der Aar, Julie Desrivot, Sonia Dupont, Bertrand Heckmann, Ann Fieuw, Simone Stutvoet, Liesbeth Fagard, Karen Van de Wal, Eric Helmer, Ellen van der Aar, Julie Desrivot, Sonia Dupont, Bertrand Heckmann, Ann Fieuw, Simone Stutvoet, Liesbeth Fagard, Karen Van de Wal, Eric Helmer

Abstract

GLPG1690 is a novel autotaxin inhibitor in development for the treatment of idiopathic pulmonary fibrosis (IPF). We report phase 1 studies investigating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GLPG1690 in healthy subjects. We performed a first-in-human randomized, double-blind, placebo-controlled trial of single (20, 60, 150, 300, 600, 1000, 1500 mg) and multiple (14 days: 150 mg twice daily; 600 and 1000 mg once daily) ascending oral doses of GLPG1690 (NCT02179502), and a randomized, open-label, crossover relative bioavailability study to compare the PK of tablet and capsule formulations of GLPG1690 600 mg and to assess the effect of food on PK of the tablet formulation (NCT03143712). Forty and 13 subjects were randomized in the first-in-human and relative bioavailability studies, respectively. GLPG1690 was well tolerated, with no dose-limiting toxicity at all single and multiple doses. GLPG1690 was rapidly absorbed and eliminated, with a median tmax and mean t1/2 of approximately 2 and 5 hours, respectively. GLPG1690 exposure increased with increasing dose (mean Cmax , 0.09-19.01 µg/mL; mean AUC0-inf , 0.501-168 µg·h/mL, following single doses of GLPG1690 20-1500 mg). PD response, evidenced by rapid reduction in plasma lysophosphatidic acid (LPA) C18:2 levels, increased with increasing GLPG1690 plasma levels, plateauing at approximately 80% reduction in LPA C18:2 at around 0.6 µg/mL GLPG1690. Tablet and capsule formulations had similar PK profiles, and no clinically significant food effect was observed when comparing tablets taken in fed and fasted states. The safety, tolerability, and PK/PD profiles of GLPG1690 support continued clinical development for IPF.

Keywords: clinical pharmacology; clinical trials; drug-food interactions; pharmacodynamics; pharmacokinetics and drug metabolism; pulmonary.

Conflict of interest statement

Ellen van der Aar, Sonia Dupont, Bertrand Heckmann, Ann Fieuw, Simone Stutvoet, Liesbeth Fagard, Karen Van de Wal, and Eric Helmer are employees of Galapagos. Julie Desrivot is a former employee of Galapagos. Medical writing assistance in the preparation of this manuscript was provided by Jane Murphy (CircleScience, an Ashfield Company, part of UDG Healthcare plc), and funded by Galapagos.

© 2019 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
GLPG1690 plasma concentration‐time profiles for the (A) SAD and (B) MAD study populations following administration of GLPG1690 (oral suspension). For the MAD part of the study, the last dosing day was day 14 (1 dose for GLPG1690 600 mg and 1000 mg once daily; 2 doses 12 hours apart for GLPG1690 150 mg twice daily). Data are mean ± SD. h, hour; MAD, multiple ascending doses; SAD, single ascending doses; SD, standard deviation.
Figure 2
Figure 2
LPA C18:2 reduction from baseline for the (A) SAD population, (B) MAD population on day 1, and (C) MAD population on day 14 following administration of GLPG1690 (oral suspension) or placebo. Data are mean ± SD. h, hour; LPA, lysophosphatidic acid; MAD, multiple ascending doses; SAD, single ascending doses; SD, standard deviation.
Figure 3
Figure 3
Correlation between LPA C18:2 percentage reduction from baseline and GLPG1690 plasma concentration for the SAD population. The IC50 is estimated to be 118 nM (0.07 µg/mL). 1 µM GLPG1690 = 0.6 µg/mL. IC50, half maximal inhibitory concentration; SAD, single ascending doses.
Figure 4
Figure 4
GLPG1690 plasma concentration‐time profiles following (A) a single oral dose of GLPG1690 300 mg given as an oral suspension or capsule in a fed state (both n = 6; first‐in‐human study) and (B) a single oral dose of GLPG1690 600 mg given as a capsule or tablet in a fed state or a tablet in a fasted state (all n = 12; relative bioavailability study). Data are mean ± SD. h, hour; SD, standard deviation.

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