Background/Purpose:

Increased aggrecanase activity is a well-known trigger factor for osteoarthritis (OA), initiating loss of cartilage aggrecan that precedes more severe cartilage degradation. A disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) is a key aggrecanase in humans and is a relevant target for the development of disease-modifying OA drugs (DMOADs).
GLPG1972 is a potent small molecule inhibitor of ADAMTS-5 displaying high selectivity versus a number of other zinc metalloproteases. The anti-catabolic activity of GLPG1972 was shown in murine and human cartilage explants, and its DMOAD activity was demonstrated in the destabilization of the medial meniscus (DMM) mouse model.
In the current study, the safety, tolerability, pharmacokinetics and pharmacodynamics of GLPG1972 in healthy male subjects were evaluated.

Methods:

GLPG1972 was administered as single oral doses (60 mg up to 2100 mg) or multiple doses (300 mg/day to 1050 mg/day for 14 days) formulated as a solution. Ascending single doses were evaluated in an alternating fashion between two panels of 8 male healthy subjects and multiple doses were evaluated sequentially in 3 groups of 8 male healthy subjects. In both parts, 6 subjects received GLPG1972 and 2 placebo. Plasma and urine were collected at several time points and intervals for the quantification of GLPG1972 by LC-MS/MS. Pharmacodynamics was assessed by measurement of the aggrecan ARGS neoepitope levels in plasma by an enzyme-linked immunosorbent assay.

Results:

Administration of single (up to 2100 mg) and multiple (up to 1050 mg q.d.) ascending oral doses of GLPG1972 in healthy subjects was well tolerated, with no clinically relevant effects on ECGs, vital signs or laboratory parameters.

GLPG1972 given as a single oral dose in fasted state was rapidly absorbed with a median t_max range of 1 to 4 h and eliminated with a terminal half-life of approximately 10 h. The rate of absorption decreased with higher doses, whereas the plasma exposure in terms of AUC increased dose-proportionally. After once-daily dosing for 14 days in fed state, GLPG1972 plasma exposure (both C_max and AUC) increased dose-proportionally over the entire dose range. Pharmacokinetic steady state was reached after 2 dosing days, with minimal accumulation. The excretion of unchanged GLPG1972 in urine over a 24 h period was low (<11% of the administered dose).

The aggrecan ARGS neoepitope levels decreased progressively over time during treatment with GLPG1972 but not with placebo. The extent of the pharmacodynamic effect was similar for the 3 tested doses. The maximal reduction in plasma concentrations of aggrecan ARGS neoepitope was about 60% at day 14 versus baseline. No plateau had been attained on day 14, suggesting that it may take longer to obtain the maximum effect.

Conclusion:

GLPG1972 was shown to be safe and well-tolerated in healthy male subjects with a suitable pharmacokinetic profile and a marked decrease of the aggrecan ARGS neoepitope biomarker, indicating target engagement. These data and the preclinical data package confirm the potential of GLPG1972 to be a potential DMOAD treatment. GLPG1972 will be progressed to a Phase 2 study in osteoarthritis.

« Back to 2017 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/favorable-human-safety-pharmacokinetics-and-pharmacodynamics-of-the-adamts-5-inhibitor-glpg1972-a-potential-new-treatment-in-osteoarthritis/