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Namour F.,Galapagos SASU | Diderichsen P.M.,Quantitative Solutions BV | Cox E.,Quantitative Solutions BV | Vayssiere B.,Galapagos SASU | And 3 more authors.
Clinical Pharmacokinetics | Year: 2015

Background and Objectives: Filgotinib (GLPG0634) is a selective inhibitor of Janus kinase 1 (JAK1) currently in development for the treatment of rheumatoid arthritis and Crohn’s disease. While less selective JAK inhibitors have shown long-term efficacy in treating inflammatory conditions, this was accompanied by dose-limiting side effects. Here, we describe the pharmacokinetics of filgotinib and its active metabolite in healthy volunteers and the use of pharmacokinetic–pharmacodynamic modeling and simulation to support dose selection for phase IIB in patients with rheumatoid arthritis. Methods: Two trials were conducted in healthy male volunteers. In the first trial, filgotinib was administered as single doses from 10 mg up to multiple daily doses of 200 mg. In the second trial, daily doses of 300 and 450 mg for 10 days were evaluated. Non-compartmental analysis was used to determine individual pharmacokinetic parameters for filgotinib and its metabolite. The overall pharmacodynamic activity for the two moieties was assessed in whole blood using interleukin-6-induced phosphorylation of signal-transducer and activator of transcription 1 as a biomarker for JAK1 activity. These data were used to conduct non-linear mixed-effects modeling to investigate a pharmacokinetic/pharmacodynamic relationship. Results: Modeling and simulation on the basis of early clinical data suggest that the pharmacokinetics of filgotinib are dose proportional up to 200 mg, in agreement with observed data, and support that both filgotinib and its metabolite contribute to its pharmacodynamic effects. Simulation of biomarker response supports that the maximum pharmacodynamic effect is reached at a daily dose of 200 mg filgotinib. Conclusion: Based on these results, a daily dose range up to 200 mg has been selected for phase IIB dose-finding studies in patients with rheumatoid arthritis. © 2015, The Author(s).


Blanc J.,Galapagos | Geney R.,Galapagos SASU | Menet C.,Galapagos
Anti-Cancer Agents in Medicinal Chemistry | Year: 2013

With the advent of the Type II kinase inhibitor imatinib (Gleevec) for treatment against cancer, rational design of tailored molecules has brought a revolution in medicinal chemistry for treating tumours caused by kinase malfunctioning. Among different types of kinase inhibitors, the design of Type II inhibitors has been rationalized for maximizing the benefits and reducing drawbacks. Here we highlight the development made in Type II inhibitors, discussing the advantages and disadvantages of these types of molecules. Furthermore, we present the strategies for designing druggable molecules that either selectively inhibit target kinases or overcome drug resistance. © 2013 Bentham Science Publishers.


Menet C.J.,Galapagos | Rompaey L.V.,Galapagos | Geney R.,Galapagos SASU
Progress in Medicinal Chemistry | Year: 2013

In this review, we describe the current knowledge of the biology of the JAKs. The JAK family comprises the four nonreceptor tyrosine kinases JAK1, JAK2, JAK3, and Tyk2, all key players in the signal transduction from cytokine receptors to transcription factor activation. We also review the progresses made towards the optimization of JAK inhibitors and the importance of their selectivity profile. Indeed, the full array of many medicinal chemistry enabling tools (HTS, X-ray crystallography, scaffold morphing, etc.) has been deployed to successfully design molecules that discriminate among JAK family and other kinases. While the first JAK inhibitor was launched in 2011, this review also summarizes the status of several other small-molecule JAK inhibitors currently in development to treat arthritis, psoriasis, organ rejection, and multiple cancer types. © 2013 Elsevier B.V.


Westhovens R.,Catholic University of Leuven | De Keyser F.,Ghent University | Rekalov D.,Zaporizhzhia Regional Hospital | Nasonov E.L.,Institute of Rheumatology | And 6 more authors.
Annals of the Rheumatic Diseases | Year: 2013

Background: Mitogen-activated protein (MAP) kinases are key regulators of cytokine production, and are therefore potential targets for treatment of rheumatoid arthritis (RA). Objective: This two-part phase II study investigated the efficacy and safety of a once-daily 50 mg GLPG0259 (an inhibitor of MAP kinase-activated protein kinase 5) dose vs placebo ( part A). An interim analysis after part A would determine whether the dose-finding part ( part B) would be performed. Methods: In part A, eligible methotrexate (MTX)- refractory patients with RA were randomised to receive either a once-daily 50 mg dose of GLPG0259 or placebo, in addition to a stable dose of MTX, for 12 weeks. The primary efficacy end point was the percentage of patients achieving an American College of Rheumatology 20% improvement (ACR20) response after 12 weeks. Results: The interim analysis showed no difference between the percentage of subjects achieving the primary efficacy variable of ACR20 or the secondary efficacy variables (ACR50, ACR70 and Disease Activity Score 28) at week 12 in the GLPG0259-treated (n=19) and placebo-treated (n=11) groups. Owing to lack of efficacy, the study was terminated, and part B was not initiated. Conclusions: This innovative study design quickly provided conclusive results on the lack of efficacy of GLPG0259 in patients with RA.


Coste E.,University of Edinburgh | Greig I.R.,University of Aberdeen | Mollat P.,Galapagos SASU | Rose L.,University of Edinburgh | And 3 more authors.
Annals of the Rheumatic Diseases | Year: 2014

Introduction: Inflammatory joint diseases such as rheumatoid arthritis are associated with local bone erosions and systemic bone loss, mediated by increased osteoclastic activity. The receptor activator of nuclear factor (NF) κB ligand (RANKL) plays a key role in mediating inflammation-induced bone loss, whereas tumour necrosis factor (TNF) plays a central role in the inflammatory process. Here we tested whether a recently identified class of small molecule inhibitors of RANKL signalling (ABD compounds) also affect TNF signalling and whether these compounds inhibit inflammation in an animal model of rheumatoid arthritis.Methods: The inhibitory effects of the ABD compounds on TNF-induced signalling were tested in mouse macrophage cultures by western blotting and in an NFκB luciferase-reporter cell line. The anti-inflammatory effects of the compounds were tested in the mouse collagen-induced arthritis model of rheumatoid arthritis. Results The ABD compounds ABD328 and ABD345 both inhibited TNF-induced activation of the NFêB pathway and the extracellular signal-regulated kinase (ERK) and Jun kinase (JNK) mitogen activated protein kinases (MAPKs). When tested in the mouse collageninduced arthritis model of rheumatoid arthritis, the compounds suppressed inflammatory arthritis, inhibited joint destruction and prevented systemic bone loss. Furthermore, one of the compounds (ABD328) showed oral activity.Conclusions: Here we describe a novel class of small molecule compounds that inhibit both RANKL- and TNFinduced NFêB and MAPK signalling in osteoclasts and macrophages, and inflammation and bone destruction in a mouse model of rheumatoid arthritis. These novel compounds therefore represent a promising new class of treatments for inflammatory diseases, such as rheumatoid arthritis.


Patent
Galapagos Sasu and German Cancer Research Center | Date: 2010-04-13

The present invention relates to uses of antagonists of Rspondin-3 (Rspo3) polypeptides or Rspondin-3 nucleic acids. The invention is based on the demonstration that partial deficiency of Rspo3 leads to a significant increase of bone mass. These results indicate a major role for Rspo3 as a bone anabolic marker or target. Thus, the invention also relates to the use of Rspo3 antagonists in the treatment of osteopenia disorders, particularly in conditions associated with increased bone resorption.


Menet C.J.,Generaal de Wittelaan L | Mammoliti O.,Generaal de Wittelaan L | Lopez-Ramos M.,Galapagos SASU
Future Medicinal Chemistry | Year: 2015

The discovery of the JAK-STAT pathway was a landmark in cell biology. The identification of these pathways has changed the landscape of treatment of rheumatoid arthritis and other autoimmune diseases. The two first (unselective) JAK inhibitors have recently been approved by the US FDA for the treatment of myelofibrosis and rheumatoid arthritis and many other JAK inhibitors are currently in clinical development or at the discovery stage. Research groups have demonstrated the different roles of JAK member and the therapeutic potential of targeting them selectively. JAK1 plays a critical and potentially dominant role in the transduction of γc cytokine (γc = common γ chain) and in IL-6 signaling. In this review, we will discuss the state-of-the-art research that evokes JAK1 selective inhibition. © 2015 Future Science Ltd.


Bidet M.,University of Nice Sophia Antipolis | Tomico A.,University of Nice Sophia Antipolis | Martin P.,University of Nice Sophia Antipolis | Guizouarn H.,University of Nice Sophia Antipolis | And 2 more authors.
Molecular Cancer Research | Year: 2012

Most anticancer drugs fail to eradicate tumors, leading to the development of drug resistance and disease recurrence. The Hedgehog signaling plays a crucial role during embryonic development, but is also involved in cancer development, progression, and metastasis. The Hedgehog receptor Patched (Ptc) is a Hedgehog signaling target gene that is overexpressed in many cancer cells. Here, we show a link between Ptc and resistance to chemotherapy, and provide new insight into Ptc function. Ptc is cleared from the plasma membrane upon interaction with its ligand Hedgehog, or upon treatment of cells with the Hedgehog signaling antagonist cyclopamine. In both cases, after incubation of cells with doxorubicin, a chemotherapeutic agent that is used for the clinical management of recurrent cancers, we observed an inhibition of the efflux of doxorubicin from Hedgehog-responding fibroblasts, and an increase of doxorubicin accumulation in two different cancer cell lines that are known to express aberrant levels of Hedgehog signaling components. Using heterologous expression system, we stringently showed that the expression of human Ptc conferred resistance to growth inhibition by several drugs from which chemotherapeutic agents such as doxorubicin, methotrexate, temozolomide, and 5-fluorouracil. Resistance to doxorubicin correlated with Ptc function, as shown using mutations from Gorlin's syndrome patients in which the Ptc-mediated effect on Hedgehog signaling is lost. Our results show that Ptc is involved in drug efflux and multidrug resistance, and suggest that Ptc contributes to chemotherapy resistance of cancer cells. ©2012 AACR.


van der Horst G.,Leiden University | van den Hoogen C.,Leiden University | Buijs J.T.,Leiden University | Cheung H.,Leiden University | And 9 more authors.
Neoplasia | Year: 2011

Acquisition of an invasive phenotype by cancer cells is a requirement for bone metastasis. Transformed epithelial cells can switch to a motile, mesenchymal phenotype by epithelial-mesenchymal transition (EMT). Recently, it has been shown that EMT is functionally linked to prostate cancer stem cells, which are not only critically involved in prostate cancer maintenance but also in bone metastasis. We showed that treatment with the nonpeptide αv-integrin antagonist GLPG0187 dose-dependently increased the E-cadherin/vimentin ratio, rendering the cells a more epithelial, sessile phenotype. In addition, GLPG0187 dose-dependently diminished the size of the aldehyde dehydrogenase high subpopulation of prostate cancer cells, suggesting that αv-integrin plays an important role in maintaining the prostate cancer stem/progenitor pool. Our data show that GLPG0187 is a potent inhibitor of osteoclastic bone resorption and angiogenesis in vitro and in vivo. Real-time bioluminescent imaging in preclinical models of prostate cancer demonstrated that blocking αv-integrins by GLPG0187 markedly reduced their metastatic tumor growth according to preventive and curative protocols. Bone tumor burden was significantly lower in the preventive protocol. In addition, the number of bone metastases/mouse was significantly inhibited. In the curative protocol, the progression of bone metastases and the formation of new bone metastases during the treatment period was significantly inhibited. In conclusion, we demonstrate that targeting of integrins by GLPG0187 can inhibit the de novo formation and progression of bone metastases in prostate cancer by antitumor (including inhibition of EMT and the size of the prostate cancer stem cell population), antiresorptive, and antiangiogenic mechanisms. © 2011 Neoplasia Press, Inc.


Philippe C.-L.,Galapagos SASU
Current Drug Targets | Year: 2016

In recent decades we have seen an exponential interest in the implications of integrin receptors in cancer biology and especially in prostate tumour development. Integrins has been reported to control multiple mechanisms, such as cell survival, proliferation, differentiation, and migration. Here, we report the current understanding of the integrin signalling mechanisms in metastatic prostate tumour development, cross-talks between the primary and metastatic sites on tumour growth, interactions between tumour cells and tissue microenvironment, and epithelial-mesenchymal transition (EMT). Finally, this review presents the integrin-based chemotherapeutic agents currently under clinically consideration and provides an insight into cancer drug development using integrin as a target. © 2016 Bentham Science Publishers.

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