Nick Vandeghinste

Preclinical Characterization of GLPG0634, a Selective Inhibitor of JAK1, for the Treatment of Inflammatory Diseases

The JAKs receive continued interest as therapeutic targets for autoimmune, inflammatory, and oncological diseases. JAKs play critical roles in the development and biology of the hematopoietic system, as evidenced by mouse and human genetics. JAK1 is critical for the signal transduction of many type I and type II inflammatory cytokine receptors. In a search for JAK small molecule inhibitors, GLPG0634 was identified as a lead compound belonging to a novel class of JAK inhibitors. It displayed a JAK1/JAK2 inhibitor profile in biochemical assays, but subsequent studies in cellular and whole blood assays revealed a selectivity of ∼30-fold for JAK1- over JAK2-dependent signaling. GLPG0634 dose-dependently inhibited Th1 and Th2 differentiation and to a lesser extent the differentiation of Th17 cells in vitro. GLPG0634 was well exposed in rodents upon oral dosing, and exposure levels correlated with repression of Mx2 expression in leukocytes. Oral dosing of GLPG0634 in a therapeutic set-up in a collagen-induced arthritis model in rodents resulted in a significant dose-dependent reduction of the disease progression. Paw swelling, bone and cartilage degradation, and levels of inflammatory cytokines were reduced by GLPG0634 treatment. Efficacy of GLPG0634 in the collagen-induced arthritis models was comparable to the results obtained with etanercept. In conclusion, the JAK1 selective inhibitor GLPG0634 is a promising novel therapeutic with potential for oral treatment of rheumatoid arthritis and possibly other immune-inflammatory diseases.

Discovery and Optimization of an Azetidine Chemical Series As a Free Fatty Acid Receptor 2 (FFA2) Antagonist: From Hit to Clinic

FFA2, also called GPR43, is a G-protein coupled receptor for short chain fatty acids which is involved in the mediation of inflammatory responses. A class of azetidines was developed as potent FFA2 antagonists. Multiparametric optimization of early hits with moderate potency and suboptimal ADME properties led to the identification of several compounds with nanomolar potency on the receptor combined with excellent pharmacokinetic (PK) parameters. The most advanced compound, 4-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid 99 (GLPG0974), is able to inhibit acetate-induced neutrophil migration strongly in vitro and demonstrated ability to inhibit a neutrophil-based pharmacodynamic (PD) marker, CD11b activation-specific epitope [AE], in a human whole blood assay. All together, these data supported the progression of 99 toward next phases, becoming the first FFA2 antagonist to reach the clinic.

Acitretin as cancer chemoprophylaxis in a renal transplant recipient

The use of acitretin in a renal transplant recipient who had been treated for several premalignant and malignant skin lesions is the subject of this case report. During the treatment period no new dysplastic lesions developed.

THU0116 Biological Effects of the JAK1 Selective Inhibitor GLPG0634 on Inflammation Markers in Arthritic Mice

Background Non-selective Janus kinase (JAK) inhibitors have shown long-term efficacy in treating rheumatoid arthritis (RA). However, tolerated doses and thereby efficacy are limited due to JAK2-driven side effects. Selective inhibition of JAK1 may be associated with an improved safety profile while maintaining clinical efficacy. Currently available information for JAK1 inhibitors is limited. GLPG0634 is a JAK inhibitor which displays a high selectivity for JAK1 over JAK2 in human whole blood assays. It is currently being developed for RA treatment and displayed good efficacy and tolerability in a 4-week Phase 2a study. Objectives Characterize the mode of action of a JAK1-selective inhibitor by measuring the impact of GLPG0634 on JAK pathway activity and inflammation parameters in blood and paws in the mouse CIA model. Methods Mice with established collagen-induced arthritis (CIA) were treated with GLPG0634 (50 mg/kg po, bid) or etanercept (10 mg/kg ip, 3 times a week). Disease progression was evaluated using clinical score and histological parameters. Expression of genes related to JAK pathways and markers of inflammation were measured in hind paws as well as in circulating leukocytes (WBC) using qRT-PCR. Luminex technology was used to measure a panel of 35 cytokines and chemokines in mouse serum. Results Oral treatment with GLPG0634 decreased inflammation in CIA in mice as measured by clinical scores and paw histology, with the same efficacy as etanercept. In paws of arthritic mice, an increase of 20- to more than 200-fold in the expression of inflammation markers (IL-6, IL-1β, TNFα, CXCL1) was found. A 30% to 45% decrease of their expression was observed in GLPG0634-treated arthritic mice. A similar expression pattern was observed for the osteoclast differentiation factor RANKL and for proteases linked to inflammation (MMP3, MMP13). These findings corroborate the bone and cartilage protective effects of GLPG0634 observed by histological analysis of paws. In addition, decreases from 30 to 70% in serum levels of cytokines and chemokines (IL-6, IP-10/CXCL10, MCP-1) in GLPG0634-treated arthritic mice confirmed the immunomodulation and anti-inflammatory effects. Of interest, the increased expression of JAK1-induced genes Mx1 and Mx2 in arthritic mice both in WBC and hind paws was abolished after treatment of animals with GLPG0634, whereas expression of the JAK2-dependent gene HRH4 was not altered by GLPG0634 treatment. These findings show that the decrease in inflammation markers was associated with inhibition of JAK1 but not JAK2. Conclusions These data show that oral GLPG0634 administration reduces inflammation in the mouse CIA model to the same extent as parenteral etanercept. Effects on several inflammation markers in paws and serum demonstrate the anti-inflammatory activity of GLPG0634. These effects were achieved through selective JAK1 inhibition. These data establish that selective JAK1 inhibition by GLPG0634 is sufficient to mediate strong efficacy in an established arthritis model and provide some useful potential markers to follow pathology progression in arthritic mice and humans. Disclosure of Interest B. Vayssiere Employee of: Galapagos SASU, S. de Vos Employee of: Galapagos NV, D. Merciris Employee of: Galapagos SASU, M. Auberval Employee of: Galapagos SASU, S. Dupont Employee of: Galapagos SASU, N. Vandeghinste Employee of: Galapagos NV, L. Lepescheux Employee of: Galapagos SASU, P. Clement-Lacroix Employee of: Galapagos SASU, P. Delerive Employee of: Galapagos SASU, L. van Rompaey Employee of: Galapagos NV, R. Brys Employee of: Galapagos NV, R. Galien Employee of: Galapagos SASU

A multiparameter approach to monitor disease activity in collagen-induced arthritis

Introduction Disease severity in collagen-induced arthritis (CIA) is commonly assessed by clinical scoring of paw swelling and histological examination of joints. Although this is an accurate approach, it is also labour-intensive and the application of less invasive and less time-consuming methods is of great interest. However, it is still unclear which of these methods represents the most discriminating measure of disease activity.