Background/Purpose

The 4 Janus kinases (JAK1, JAK2, JAK3 and TYK2) are cytoplasmic tyrosine kinases that mediate intracellular signaling of cytokines (e.g. certain interleukins and interferons) and growth factors (e.g. erythropoietin). GLPG0634 is the first JAK inhibitor that displays a high JAK1 selectivity towards the 3 other JAK family members in functional assays. It showed a favorable safety and efficacy profile in two 4-week Phase 2a studies in rheumatoid arthritis (RA) patients. In order to further characterize GLPG0634, we compared the gene expression profile of circulating leukocytes of healthy volunteers and RA patients before and after 4 weeks of daily treatment with 200 mg of GLPG0634.

Methods

RA patients participated in the Phase 2a Proof of concept, a randomized, double-blind, placebo-controlled study enrolling 36 patients with insufficient response to MTX. They were orally treated with placebo or 200 mg QD GLPG0634 for 4 weeks. Blood was sampled in PAXgene tubes at pre-dose the first and the last days of treatment. Non-matched healthy volunteers were also sampled in PAXgene tubes. mRNA was extracted, labeled and profiled using Affymetrix U219 micro-arrays. Data analysis was performed in R/BioConductor using linear regression models (limma).

Results

The leukocyte gene signature of 12 healthy subjects was first compared to the one obtained from 24 RA patients prior to placebo or GLPG0634 treatment. As expected, genes showing differential expression compared to healthy subjects allowed for definition of a disease signature. Four weeks of treatment with GLPG0634 (200 mg QD) impacted the signal levels for 3120 probes in RA patient samples (adjusted p-value < 0.05 and absolute log2-fold change > 1 compared to the same subjects at pre-dose), while the signal levels of only 78 probes were impacted to the same extent in the placebo group. Remarkably, the highly GLPG0634-impacted genes matched with the disease-effect genes and displayed an inverse regulation (Spearman R=-0.85), showing that administration of GLPG0634 at 200 mg QD led to the restoration of a healthy-like gene expression profile (treatment-effect genes). Pathway analysis performed for the affected gene sets suggests an impact on immune-inflammation systems

Conclusion

Blood transcriptome analysis of healthy volunteers and patients recruited in the proof-of-concept study of GLPG0634 in RA identified a disease signature with many genes involved in RA-linked pathways. After 4 weeks of treatment with GLPG0634, transcriptome analysis showed that the compound was able to reverse strongly the disease effect, leading to a gene signature close to that of healthy volunteers. These data are in line with the good efficacy of the 200 mg QD administration of GLPG0634 in RA patients and further support the use of GLGP0634 in RA patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/treatment-of-rheumatoid-arthritis-patients-with-the-jak1-selective-inhibitor-glpg0634-reverses-an-arthritis-specific-blood-gene-signature-to-healthy-state/