FRI0539 A safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) study with increasing oral doses of glpg1972 administered daily for 29 days shows a strong biomarker effect in patients with KNEE and/or HIP OA
Authors: H.M. Deckx, S. Hatch, M. Robberechts, S. Dupont, J. Desrivot, H. Coleman, S. Larsson, A. Struglics, E.M. van der Aar, A. Fiew
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Osteoarthritis (OA) is characterised by structural changes of the joint, of which degradation of articular cartilage is one of the major signs<sup>1</sup>. The main proteoglycan component of the extracellular matrix of articular cartilage is aggrecan. GLPG1972 as a potent and selective inhibitor of ADAMTS-5, a key aggrecan-cleaving enzyme involved in cartilage degradation, is being developed as a potential disease-modifying OA drug (DMOAD). Aggrecan cleavage by ADAMTS-5 results in release of N-terminal ARGS neo-epitope fragments of which serum levels significantly decreased in healthy subjects treated with GLPG1972 during 14 days in a previous study². <h3>Objectives</h3> To assess safety, tolerability, PK and PD (serum ARGS-aggrecan levels) during and following administration of GLPG1972 in patients with knee and/or hip OA. <h3>Methods</h3> This was a single centre, randomised, double-blind, placebo-controlled, age and gender stratified, ascending dose Phase Ib study, with three semi-sequential cohorts of 10 patients each, randomised to active drug or placebo in a 4:1 ratio. Doses tested were once daily 100, 200 and 300 mg. Treatment duration was 29 days. Patients had follow-up visits 14 and 21 days after last dosing for additional PD assessments. Methods for PD have been described previously³. <h3>Results</h3> Thirty patients were included. Of these, 24 patients (M/F rate 8/16, 14 aged 50–64 and 10 aged 65–75) received active medication. All adverse events (AE) were mild and transient. No serious AEs were reported during the study; one female patient in the 300 mg group was discontinued after 15 days of treatment due to drug-related elevated transaminase values which returned to normal 9 days later while her bilirubin levels remained normal. There were no overall trends in lab abnormalities over time or significant changes in vital signs, ECG and Holter parameters. Steady state in plasma exposure was reached after 3 days of dosing. Exposure increased dose-proportionally. Mean serum ARGS levels (SEM) decreased steadily over time in all patients receiving GLPG1972: −40% (2.9),%–46% (4.5) and −53% (2.8) at day 15 compared to baseline in the 100, 200 and 300 mg group respectively. These levels remained stable until last dose on day 29, then consistently returned to pre-dose levels for all groups 14 and 21 days after last dose. Placebo group levels remained unchanged. <h3>Conclusions</h3> When administered daily for 29 days in patients with knee and/or hip OA, GLPG1972 at oral doses of 100, 200 and 300 mg q.d. was generally well tolerated and safe. Serum ARGS levels, as a marker for target engagement and potential proxy of cartilage degradation, showed a dose-dependent decrease over time up to 53% below baseline in the 300 mg group. These PK-PD findings are consistent with what we observed in a previous study in healthy subjects² and reinforce the rationale for developing GLPG1972 as a DMOAD. <h3>References</h3> [1] Hunter DJ, et al. Curr. Opin. Rheumatol. 2009;21:110–117. [2] van der Aar E, et al. <i>Arthritis Rheumatol</i>. 2017;69(suppl 10). [3] Larsson, et al. Osteoarthritis Cartilage2014;22(2):242–9. <h3>Disclosure of Interest</h3> H. Deckx Employee of: Galapagos NV, Belgium, S. Hatch Consultant for: Galapagos NV, Belgium, M. Robberechts Employee of: Galapagos NV, Belgium, S. Dupont Employee of: Galapagos SASU, France, J. Desrivot Employee of: has been employee of Galapagos SASU, France, H. Coleman Paid instructor for: Covance has been contracted by Galapagos NV to conduct the study, S. Larsson: None declared, A. Struglics: None declared, E. van der Aar Employee of: Galapagos NV, Belgium, A. Fiew Employee of: Galapagos NV, Belgium