Background/Purpose:

GLPG0634 is an orally-available, selective inhibitor of Janus kinase 1 (JAK1) with an IC₅₀ of 0.6 μM and a 30-fold selectivity over JAK2 in human whole blood. Non-selective JAK inhibitors have shown long-term efficacy in treating rheumatoid arthritis (RA). However, doses and thereby efficacy are limited by JAK2-driven side effects. Selective inhibition of JAK1 may result in a cleaner safety profile while maintaining clinical efficacy. Based on its pharmacokinetic (PK) half life, both once-daily (QD) and twice-daily (BID) dosing regimens have been explored. In patients with active RA on methotrexate, 4 weeks daily  dosing of 200 mg GLPG0634 has shown highly encouraging efficacy and safety.

Objectives:

Evaluate the safety, PK, JAK pharmacodynamics (PD) and -selectivity of GLPG0634 at high dose QD regimens in healthy volunteers.

Methods:

In a single-center Phase I study, 3 panels of 8 male healthy volunteers (2 on placebo) received QD dosing of 200 mg, 300 mg and 450 mg GLPG0634 for 10 days. Safety was monitored continuously and followed until 7 days after the last dose. Day profiles for PK and PD were evaluated on Days 1 and 10. GLPG0634 plasma concentrations were assessed by LC-MS/MS. Inhibition of JAK1 was measured by ex vivo IL-6 induced STAT1 phosphorylation (pSTAT1) in CD4⁺ cells, and JAK2 by GM-CSF induced pSTAT5 in CD33⁺cells.

Results:

GLPG0634 was safe and well-tolerated for 200 mg, 300 mg and 450 mg QD, following 10 days of dosing. Treatment-emergent adverse events over all dose groups were typical Phase I findings (mild and transient headache and abdominal discomfort), with a comparable incidence in GLPG0634- and placebo- treated subjects. There were no relevant findings regarding hematology (including reticulocytes), biochemistry (including LDL cholesterol, ALT/AST or creatinine) or other safety parameters (ECG and vital signs, including blood pressure). A maximal tolerated dose was not reached.

Steady state PK was dose proportional up to 450 mg QD, with an apparent mean half-life of 8 hours. The PK was similar in RA patients and healthy volunteers. There was no accumulation to steady state with low trough levels relative to GLPG0634’s IC₅₀. Still, JAK1 signaling remained suppressed up to 24 hours from drug intake, whereas JAK2 signaling was not influenced up to the high dose of 450 mg QD. 

 

Conclusion:

At high doses, exceeding those showing high level efficacy in a 4-week RA patient study, GLPG0634 was well tolerated and safe in healthy volunteers. No safety signals were found with GLPG0634; typical findings reported within 2 weeks of dosing of non-selective JAK inhibitors were not observed. Up to 450 mg QD, GLPG0634 was highly selective for inhibition of JAK1 over JAK2. The data suggest the PD half life to be longer than that for PK.
Ongoing studies in RA patients will determine the efficacy of low doses of GLPG0634 (30 mg QD) and the safety of high doses (300 mg QD).

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« Back to 2012 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/once-daily-high-dose-regimens-of-glpg0634-in-healthy-volunteers-are-safe-and-provide-continuous-inhibition-of-jak1-but-not-jak2/