Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose:
The 4 Janus kinases (JAK1, JAK2, JAK3 and TYK2) are cytoplasmic tyrosine kinases that transduce intracellular signaling for cytokines including interleukins and interferons, and for growth factors such as erythropoietin. GLPG0634 is a JAK inhibitor that has been shown to be selective for JAK1 over JAK2 in human whole blood and over JAK3 and TYK 2 in biochemical assays. GLPG0634 showed a favorable safety and efficacy profile in two 4-week Phase 2A studies in patients with rheumatoid arthritis (RA). Its activity is supported by an active metabolite that shows a high plasma exposure in humans. Here, we have evaluated the JAK1 selectivity of GLPG0634 and its main metabolite in animals, healthy volunteers and RA patients.
Methods:
JAK selectivity of GLPG0634 and its metabolite was evaluated by measuring STAT phosphorylation (pSTAT) in whole blood from humans, dogs and monkeys incubated with triggers that activate JAK-dependent pathways by flow cytometry. STAT phosphorylation measurement in cells transfected with JAK siRNA was performed using SureFire technology. Effects on JAK–dependent gene signatures in blood incubated with or without triggers were assessed by QRT-PCR. Sources of blood were from healthy volunteers (untreated or following 10 days of GLPG0634), RA patients (4-week GLPG0634 treatment), untreated animals and mice subjected to CIA (2-week treatment with GLPG0634).
Results:
An approximately 30-fold selective inhibition of JAK1 over JAK2 by parent GLPG0634 using the IL6/pSTAT1 assay for JAK1 and GM-CSF/pSTAT5 for JAK2 was similarly found with its metabolite. However, the metabolite displayed an >10 fold lower JAK inhibition potency. In cellular knock-down experiments with siRNA we confirmed IL-6-induced pSTAT1 to be an exclusive JAK1-driven event. The JAK1 selective inhibition by GLPG0634 and its metabolite was confirmed in complementary whole blood assays for alternative pathways: IL-2/pSTAT5 (JAK1/JAK3) and IFNα/pSTAT1 (JAK1/TYK2). In these pathways, where JAK1 partners with other JAKs, a 10-fold selectivity over the inhibition of JAK2-driven signalling was found in human, dog and monkey blood. Transcriptional profiling was applied to assess selectivity of GLPG0634 using genes such as MX1, MX2 and GBP1 (IFNα-induced) and HRH4 (GM-CSF-induced) in human whole blood. In samples from human healthy volunteers exposed to GLPG0634 (and its metabolite as formed), gene expression analysis showed that selectivity was conserved up to the highest dose (450 mg QD). In addition, JAK1 selectivity over JAK2 was confirmed in blood from mice with collagen-induced arthritis (CIA) treated with GLPG0634, as well as from RA patients administered GLPG0634 at the doses of 100 mg BID and 200 mg QD.
Conclusion:
These data demonstrate that GLPG0634 and its metabolite are highly selective JAK1 inhibitors in humans and animal species, using various technologies. The disease status did not alter selectivity, as a similar JAK inhibition profile was observed in blood from either healthy subjects or RA patients. Longer-term clinical studies are ongoing to confirm a favorable risk-benefit by selective inhibition of JAK1 and avoiding effects related to JAK2, such as anemia.
Disclosure:
R. Galien,
Galapagos SASU,
3;
B. Vayssière,
Galapagos SASU,
3;
S. de Vos,
Galapagos NV,
3;
M. Auberval,
Galapagos SASU,
3;
N. Vandeghinste,
Galapagos NV,
3;
S. Dupont,
Galapagos SASU,
3;
P. Clément-Lacroix,
Galapagos SASU,
3;
P. Delerive,
Galapagos SASU,
3;
F. Vanhoutte,
Galapagos NV,
3;
R. Brys,
Galapagos NV,
3;
A. Van der Aa,
Galapagos NV,
3;
L. Van Rompaey,
Galapagos NV,
3;
G. van ‘t Klooster,
Galapagos NV,
3.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/analysis-of-the-jak1-selectivity-of-glpg0634-and-its-main-metabolite-in-different-species-healthy-volunteers-and-rheumatoid-arthritis-patients/