Background/Purpose: 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. Based on GLPG0634’s moderate pharmacokinetic (PK) half-life, 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 early efficacy in RA in two 4-week Phase 2a studies/ Evaluate the PK, PD and efficacy of GLPG0634 and its main metabolite in healthy volunteers and patients with active RA

Methods: GLPG0634 was dosed in healthy volunteers (N=30) at doses of 50 and 100 mg BID and 200, 300 and 450 mg QD for 10 days. In Phase 2a studies, RA patients (n=98) received doses of 100 mg BID and  from 30 to 300 mg QD for 28 days, added on to a background therapy of methotrexate. The PK of GLPG0634 and its active major metabolite was evaluated. The PD was evaluated in whole blood from healthy volunteers using ex vivo IL-6 induced phosphorylation of STAT1 (pSTAT1) in CD4+ cells for JAK1 activity and GM-CSF induced pSTAT5 in CD33+ cells for JAK2. JAK inhibition and selectivity of the metabolite were evaluated in vitro

Results: The PK for GLPG0634 following BID and QD dosing showed dose-proportionality and a mean half-life of 7 h. A major metabolite was found that showed plasma levels in humans well exceeding those of GLPG0634 and a half-life ranging from 21 to 27 h. This metabolite was found to be active with a similar selectivity for JAK1 inhibition in human whole blood as parent GLPG0634. Its overall potency as a kinase inhibitor was 10 to 20-fold lower. In healthy volunteers, IL-6 induced pSTAT1 was inhibited for the entire 24 h dosing period, including at 24 h after the last dose for QD dose regimens. No relevant inhibition of JAK2 activity was observed at any dose level. While plasma levels of parent GLPG0634 were low beyond 12 hours from the last intake, those for its active metabolite remained high. The PK profile in RA patients for GLPG0634 and its metabolite were similar to that in healthy volunteers. A QD and BID regimen for a 200 mg daily dose showed a similar high level of efficacy following 4-week treatment in RA. QD dosing was found efficacious for doses of 75 mg onwards, with mean decreases in DAS28(CRP) ranging from 1.7 to 2.8 (placebo 0.3 to 1.2), and high baseline CRP levels normalizing within 7 to 14 days

Conclusion: The results of these studies suggest that the 24-hour maintained JAK1 inhibition and the observed clinical efficacy of QD dosing of GLPG0634 is supported by an active metabolite. The long half-life of this metabolite provides a lasting effect, though at a lower level of JAK1 inhibition than GLPG0634. The lower potency may be compensated by the high exposure. The 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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/an-active-metabolite-contributes-to-the-pharmacodynamics-and-efficacy-of-glpg0634-a-selective-jak1-inhibitor/