THU0236 Once-Daily Dosing of GLPG0634, a Selective JAK1 Inhibitor, is Supported by Its Active Metabolite
Authors: F. Namour, R. Galien, F. P. Vanhoutte, P. Wigerinck, G. van ’t Klooster
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> GLPG0634 is an orally-available, selective, inhibitor of Janus kinase 1 (JAK1). Through inhibition of signaling pathways for cytokines involved in rheumatoid arthritis (RA), non-selective JAK inhibitors have shown long-term efficacy in treating RA but also dose-limiting side effects. Selective inhibition of JAK1 may result in an acceptable safety profile while maintaining clinical efficacy and a rapid onset of action. Both once-daily (QD) and twice-daily (BID) dosing regimens have been explored in humans. QD dosing of GLPG0634 in humans has shown highly encouraging pharmacodynamic (PD) properties, and efficacy in RA as demonstrated in a 4-week Proof of Concept study. <h3>Objectives</h3> Evaluate the PK, PD and efficacy of GLPG0634 and its main metabolite(s) in healthy volunteers and patients with active RA. <h3>Methods</h3> GLPG0634 was dosed in healthy volunteers (N=36) at doses of 25, 50 and 100 mg BID, and 200, 300 and 450 mg QD for 10 days, and in RA patients (N=24) at 100 mg BID and 200 mg QD for 28 days added on to a background therapy of methotrexate. The clinical PK of GLPG0634 and its active major metabolite was evaluated, and PD in whole blood from healthy volunteers through <i>ex vivo</i> IL-6 induced phosphorylation of STAT1 (pSTAT1) in CD4+ cells was evaluated for JAK1 activity. For JAK2 activity, GM-CSF induced pSTAT5 was measured in CD33+ cells. JAK inhibition and selectivity of the metabolite were evaluated <i>in vitro</i>. <h3>Results</h3> The PK for GLPG0634 following BID and QD dosing was predictable from prior single dose data, showing dose-proportionality and a half-life of 7 h. Its major active metabolite showed plasma levels in humans well exceeding those of GLPG0634 and a half-life of 22 h. The PK profile in healthy volunteers and RA patients was similar. IL-6 induced pSTAT1 was inhibited for the entire 24 h dosing period, including at 24 h after the last dose for dose regimens of 200 mg QD. No relevant inhibition of JAK2 activity was observed at any dose level. While plasma levels of GLPG0634 were low at these time points, those for the major metabolite remained high. QD dosing showed a high level of efficacy within 4 weeks with 75% of patients achieving ACR20, a decrease in DAS28 (CRP) of 2.2, and normalization within 7 days of the high baseline CRP levels. While the major metabolite was found to be a 10 to 20-fold less potent kinase inhibitor generally, its selectivity forJAK1 was similar to that of GLPG0634. <h3>Conclusions</h3> The results of these studies indicate that an active metabolite supports the activity of GLPG0634. The long half-life of this metabolite provides a lasting effect, though at a lower level of JAK1 inhibition than GLPG0634. The lower potency for inhibition of JAK1 is, at least in part, compensated by the high exposure in humans. These findings may explain the sustained efficacy results observed with QD dosing of GLPG0634, and the 24-hour suppression of JAK1 in whole blood from healthy volunteers on GLPG0634, in spite of its moderate half-life. These data indicate that a major active metabolite supports longer lasting effects of GLPG0634 and reduces fluctuations in JAK1 inhibition. This may allow for QD dosing in a therapeutic setting, adding to dosing convenience for patients. <h3>Disclosure of Interest</h3> F. Namour Employee of: Galapagos SASU, R. Galien Employee of: Galapagos SASU, F. Vanhoutte Employee of: Galapagos NV, P. Wigerinck Employee of: Galapagos NV, G. van 't Klooster Employee of: Galapagos NV