Publications by authors named "Florence Namour"

18 Publications

  • Page 1 of 1

Filgotinib, a JAK1 Inhibitor, Has No Effect on QT Interval in Healthy Subjects.

Clin Pharmacol Drug Dev 2020 01 2;9(1):32-40. Epub 2019 Dec 2.

Gilead Sciences, Inc, Foster City, California, USA.

Filgotinib, a selective inhibitor of Janus kinase 1, is being developed for the treatment of chronic inflammatory diseases. Electrocardiograms evaluated the effect of filgotinib on the corrected QT (QTc) interval in 52 healthy subjects who received each of 4 treatments: filgotinib 200 mg (therapeutic dose), 450 mg (supratherapeutic dose), and placebo, each administered once daily for 7 days, and a single dose of moxifloxacin 400 mg (positive control). Plasma samples were collected for pharmacokinetic analysis. The QTc interval was calculated using Fridericia's correction factor (QTcF) or an individual correction factor (QTcI). The relationship between plasma concentrations of filgotinib and its major metabolite and time-matched, baseline-adjusted, placebo-corrected QTc (ΔΔQTc) was evaluated. Filgotinib did not prolong QTcF or QTcI and using an appropriate mixed-effect model, the upper limit of the 2-sided 90% confidence interval for ΔΔQTc for each filgotinib dose (200 and 450 mg) remained below 10 milliseconds at all postdose time points. There were no clinically relevant relationships between QTc interval and plasma concentrations of filgotinib or its major metabolite. Filgotinib, administered at 200 or 450 mg, was generally well tolerated. Results of this thorough QT study demonstrate that filgotinib and its major metabolite are not associated with QTc interval prolongation.
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January 2020

GLPG1837, a CFTR potentiator, in p.Gly551Asp (G551D)-CF patients: An open-label, single-arm, phase 2a study (SAPHIRA1).

J Cyst Fibros 2019 09 27;18(5):693-699. Epub 2019 May 27.

Galapagos NV, Mechelen, Belgium. Electronic address:

Background: Investigation of novel cystic fibrosis transmembrane conductance regulator (CFTR) potentiators, such as GLPG1837, for CF patients with gating mutations is challenging as trials require patients to withhold ivacaftor, the current standard of care. This study explored the feasibility of such a study and the impact of one-week ivacaftor withdrawal.

Methods: This open-label, single-arm study aimed to enrol 32 adults ≥18 years of age with CF and at least one p.Gly551Asp (G551D) mutation. Patients received three increasing GLPG1837 dosages twice-daily for two 7-day and one 14-day period following a one-week ivacaftor washout. The primary outcome was safety; secondary outcomes were changes in sweat chloride concentration, spirometry outcomes, and pharmacokinetics.

Results: Twenty-six patients enrolled; 24 completed the study. Adverse events were reported by 53.8-76.9% of patients (dosage-dependent), with respiratory adverse events most common. Mean sweat chloride concentrations decreased from 97.7 mmol/L (baseline) to 68.7 mmol/L (end of GLPG1837 treatment). In ivacaftor-pre-treated patients, mean sweat chloride concentrations rose from 42.5 mmol/L at screening to 98.5 mmol/L after ivacaftor washout. Levels were decreased following GLPG1837 treatment (to 68.8 mmol/L at treatment end). Percent predicted forced expiratory volume in 1 s declined from 73.3% at screening to 68.5% after ivacaftor washout but returned to screening level at treatment end (73.1%).

Conclusions: Patient willingness to participate in the study suggests that the need for a short period of ivacaftor withdrawal may not be a barrier to development of novel potentiators, such as GLPG1837. A one-week ivacaftor washout was generally well tolerated, but resulted in a decline in lung function, which was reversed with GLPG1837 treatment to pre-washout levels. Combined with the concentration-dependent decrease in sweat chloride concentration, results show that GLPG1837 increases CFTR activity in G551D-CF patients. FUND: This work was supported by Galapagos NV.

Clinical Trial Registration Numbers: NCT02707562; EudraCT 2015-003291-77.
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September 2019

Population Pharmacokinetic and Pharmacodynamic Analysis of GLPG1690, an Autotaxin Inhibitor, in Healthy Volunteers and Patients with Idiopathic Pulmonary Fibrosis.

Clin Pharmacokinet 2019 09;58(9):1175-1191

Galapagos SASU, 102 avenue Gaston Roussel, 93230, Romainville, France.

Background And Objectives: GLPG1690 is an autotaxin inhibitor in development for the treatment of idiopathic pulmonary fibrosis. Several publications suggested a role of autotaxin in the control of disease-affected lung function and of lysophosphatidic acid in lung remodeling processes. The aim of the current article was to describe the exposure-response relationship of GLPG1690 and further develop a rational basis to support dose selection for clinical trials in patients with idiopathic pulmonary fibrosis.

Methods: Two trials were conducted in healthy volunteers: in the first trial, GLPG1690 was administered as single doses from 20 mg up to 1500 mg, and subsequently in multiple daily doses of 300-1000 mg. In a second trial, the interaction of rifampin with 600 mg of GLPG1690 was evaluated. A third trial was conducted in patients with idiopathic pulmonary fibrosis administered 600 mg of GLPG1690 once daily for 12 weeks. The exposure-response (lysophosphatidic acid C18:2 reduction) relationship of GLPG1690 was first described using non-linear mixed-effects modeling and the model was subsequently deployed to simulate a lysophosphatidic acid C18:2 reduction as a biomarker of autotaxin inhibition in the dose range from 50 to 1000 mg once or twice daily.

Results: The population pharmacokinetics and lysophosphatidic acid C18:2 response of GLPG1690 were adequately described by a combined population pharmacokinetic and pharmacokinetic/pharmacodynamic model. Dose, formulation, rifampin co-administration, health status (healthy volunteer vs. patient with idiopathic pulmonary fibrosis), and baseline lysophosphatidic acid C18:2 were identified as covariates in the model. The effect of dose on systemic clearance indicated that GLPG1690 followed a more than dose-proportional increase in exposure over the simulated dose range of 50-1000 mg once daily. Model-based simulations showed reductions in lysophosphatidic acid C18:2 of at least 80% with doses greater or equal to 200 mg once daily.

Conclusion: Based on these results, 200 and 600 mg once-daily doses were selected for future clinical trials in patients with idiopathic pulmonary fibrosis.
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September 2019

The Relative Bioavailability and Effects of Food and Acid-Reducing Agents on Filgotinib Tablets in Healthy Subjects.

Clin Pharmacol Drug Dev 2019 07 15;8(5):585-594. Epub 2019 Feb 15.

Horizon Pharma, Brisbane, CA, USA.

Filgotinib is a potent, selective Janus kinase-1 inhibitor being developed to treat chronic inflammatory diseases. This phase 1 study in healthy subjects evaluated the relative bioavailability of filgotinib maleate tablets versus the reference tablet (filgotinib hydrochloride) and effects of food and acid-reducing agents (ARAs) on the pharmacokinetics of filgotinib and its major metabolite. Noncompartmental pharmacokinetic parameters of filgotinib and its major metabolite were compared between the 2 tablets at 100- and 200-mg doses and with or without food or ARAs. Filgotinib maleate tablets resulted in equivalent plasma exposures (area under concentration-time curve to infinity [AUC ] and maximum concentration [C ]) of filgotinib and its metabolite as the reference tablet (90%CIs of geometric least-squares mean ratios were within the prespecified no-effect boundary of 70% to 143%). Food intake had no effect on filgotinib AUC , but a high-fat meal reduced C by 20%. Coadministration of filgotinib with omeprazole or famotidine had no effect on filgotinib AUC , but omeprazole decreased C by 27%. Neither food nor ARAs affected metabolite exposure. Single-dose filgotinib 100 or 200 mg was well tolerated. This study supports evaluation of filgotinib maleate tablets, administered without regard to food or ARAs, in future clinical studies.
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July 2019

Influence of age and renal impairment on the steady state pharmacokinetics of filgotinib, a selective JAK1 inhibitor.

Br J Clin Pharmacol 2018 12 4;84(12):2779-2789. Epub 2018 Oct 4.

Galapagos NV, Generaal de Wittelaan L11 A3, 2800, Mechelen, Belgium.

Aims: Filgotinib (GS-6034, formerly GLPG0634) is an oral, selective Janus kinase 1 (JAK1) inhibitor that showed early response and sustained efficacy in patients with rheumatoid arthritis and with Crohn's disease. The aim of the present study was to investigate the impact of age and renal impairment (RI) on the pharmacokinetics (PK) of filgotinib and its main metabolite.

Methods: The effect of age was assessed in two groups of 10 elderly healthy subjects (65-74 and ≥75 years of age) and a control group of 10 younger healthy subjects (40-50 years of age). The impact of RI was investigated in three groups of subjects with mild (n = 6), moderate (n = 6) and severe (n = 3) RI [estimated glomerular filtration rate (eGFR) 60-89, 30-59 and 15-29 ml min 1.73 m , respectively] and a control group (n = 9) with normal renal function (eGFR ≥90 ml min 1.73 m ). The PK of filgotinib and its metabolite were evaluated following filgotinib 100 mg once-daily doses for 10 days.

Results: At steady state, the exposure [area under the concentration-time curve over the dosing interval (AUC )] of filgotinib and its metabolite was moderately higher (1.45- and 1.33-fold, respectively) in the elderly subjects (≥75 years) compared with younger subjects. Renal clearance for filgotinib and its metabolite decreased with the degree of RI, leading to a maximum increase in AUC of 1.54-fold for filgotinib and 2.74-fold for the metabolite in subjects with severe RI. Filgotinib was generally safe and well tolerated.

Conclusions: Age and mild to moderate impairment of renal function had limited impact on the PK of filgotinib. In subjects with severe RI, the exposure to the metabolite of filgotinib was elevated, consistent with its renal elimination pathway.
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December 2018

Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Filgotinib, a Selective JAK-1 Inhibitor, After Short-Term Treatment of Rheumatoid Arthritis: Results of Two Randomized Phase IIa Trials.

Arthritis Rheumatol 2017 10 31;69(10):1949-1959. Epub 2017 Aug 31.

Galápagos NV, Mechelen, Belgium.

Objective: JAK inhibitors have shown efficacy in rheumatoid arthritis (RA). We undertook this study to test our hypothesis that selective inhibition of JAK-1 would combine good efficacy with a better safety profile compared with less selective JAK inhibitors.

Methods: In two 4-week exploratory, double-blind, placebo-controlled phase IIa trials, 127 RA patients with an insufficient response to methotrexate (MTX) received filgotinib (GLPG0634, GS-6034) oral capsules (100 mg twice daily or 30, 75, 150, 200, or 300 mg once daily) or placebo, added onto a stable regimen of MTX, to evaluate safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of filgotinib. The primary efficacy end point was the number and percentage of patients in each treatment group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 4.

Results: Treatment with filgotinib at 75-300 mg met the primary end point and showed early onset of efficacy. ACR20 response rates progressively increased to week 4, and the Disease Activity Score in 28 joints using the C-reactive protein (CRP) level decreased. Marked and sustained improvements were observed in serum CRP level and other PD markers. The PK of filgotinib and its major metabolite was dose proportional over the 30-300 mg range. Early side effects seen with other less selective JAK inhibitors were not observed (e.g., there was no worsening of anemia [JAK-2 inhibition related], no effects on liver transaminases, and no increase in low-density lipoprotein or total cholesterol). A limited decrease in neutrophils without neutropenia was consistent with immunomodulatory effects through JAK-1 inhibition. There were no infections. Overall, filgotinib was well tolerated. Events related to study drug were mild or moderate and transient during therapy, and the most common such event was nausea.

Conclusion: Selective inhibition of JAK-1 with filgotinib shows initial efficacy in RA with an encouraging safety profile in these exploratory studies.
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October 2017

Safety, pharmacokinetics and pharmacodynamics of GLPG0974, a potent and selective FFA2 antagonist, in healthy male subjects.

Br J Clin Pharmacol 2016 07 1;82(1):139-48. Epub 2016 May 1.

Galapagos NV, 2800, Mechelen, Belgium.

Aims: Free fatty acids (FFA) can act as direct signalling molecules through activation of several membrane-bound G-protein coupled receptors. The FFA2 receptor (known as GPR43) is activated by short chain fatty acids (SCFA) such as acetate and has been shown to play a major role in SCFA-induced neutrophil activation and migration and to contribute in the development and control of inflammation. GLPG0974 is a potent and selective antagonist of the human FFA2. The main objectives of the two phase 1 trials were to characterize the safety, tolerability, pharmacokinetics and pharmacodynamics of GLPG0974.

Methods: Two consecutive randomized, double-blind, placebo-controlled, single centre trials in healthy subjects were performed. In the first, GLPG0974 was administered as single doses up to 250 mg and in the second, multiple daily doses up to 400 mg for 14 days were evaluated. Non-compartmental analysis was used to determine GLPG0974 pharmacokinetics while target engagement was investigated through the inhibition of neutrophils in acetate-simulated whole blood samples using surface expression of CD11b activated epitope as a marker of neutrophil activation.

Results: The investigation of safety/tolerability and pharmacokinetics in the early development phase showed that GLPG0974 was safe and well tolerated up to a daily dose of 400 mg. GLPG0974 showed good and dose proportional exposure up to 400 mg daily as well as a substantial and sustained inhibition of acetate-stimulated neutrophil activation.

Conclusion: Based on these results, a proof-of-concept study was initiated to evaluate the safety, tolerability and efficacy of GLPG0974 in patients with mild to moderate ulcerative colitis.
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July 2016

A dose escalating phase I study of GLPG0187, a broad spectrum integrin receptor antagonist, in adult patients with progressive high-grade glioma and other advanced solid malignancies.

Invest New Drugs 2016 Apr 20;34(2):184-92. Epub 2016 Jan 20.

Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584, CX Utrecht, The Netherlands.

Background: Integrin signaling is an attractive target for anti-cancer treatment. GLPG0187 is a broad spectrum integrin receptor antagonist (IRA). GLPG0187 inhibited tumor growth and metastasis in mouse models.

Methods: We aimed to determine the Recommended Phase II Dose (RP2D) and to assess safety and tolerability of continuous i.v. infusion in patients with advanced malignant solid tumors. Anticipated dose levels were 20, 40, 80, 160, 320, and 400 mg/day in a modified 3 + 3 design. Plasma concentrations of GLPG0187 were assessed to characterize the pharmacokinetics (PK). C-terminal telopeptide of type I collagen (CTX) was used as pharmacodynamics marker.

Results: Twenty patients received GLPG0187. No dose limiting toxicities (DLTs) were observed. The highest possible and tested dose was 400 mg/day. Fatigue was the most frequently reported side effect (25%). Recurrent Port-A-Cath-related infections and skin toxicity suggest cutaneous integrin inhibition. No dose-dependent toxicity could be established. PK analysis showed a short average distribution (0.16 h) and elimination (3.8 h) half-life. Continuous infusion resulted in dose proportional PK profiles. We observed decreases in serum CTX levels independent of the dose given, suggesting target engagement at the lowest dose level tested. Single agent treatment did not result in tumor responses.

Conclusions: GLPG0187 was well tolerated with a dose-proportional PK profile upon continuous infusion. No formal maximal tolerated dose could be established. GLPG0187 showed signs of target engagement with a favourable toxicity profile. However, continuous infusion of GLPG0187 failed to show signs of monotherapy efficacy.
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April 2016

Clinical Confirmation that the Selective JAK1 Inhibitor Filgotinib (GLPG0634) has a Low Liability for Drug-drug Interactions.

Drug Metab Lett 2016 ;10(1):38-48

Galapagos SASU, 102 avenue Gaston Roussel, 93230 Romainville, France.

Objective: The selective Janus kinase 1 inhibitor filgotinib (GLPG0634), which is currently in clinical development for the treatment of rheumatoid arthritis (RA) and Crohn's disease, demonstrated encouraging safety and efficacy profiles in RA patients after 4 weeks of daily dosing. As RA patients might be treated with multiple medications simultaneously, possible drug-drug interactions of filgotinib with cytochrome P450 enzymes and with key drug transporters were evaluated in vitro and in clinical studies.

Methods: The enzymes involved in filgotinib's metabolism and the potential interactions of the parent and its active major metabolite with drug-metabolizing enzymes and drug transporters, were identified using recombinant enzymes, human microsomes, and cell systems. Furthermore, filgotinib's interaction potential with CYP3A4 was examined in an open-label study in healthy volunteers, which evaluated the impact of filgotinib co-administration on the CYP3A4-sensitive substrate midazolam. The potential interaction with the common RA drug methotrexate was investigated in a clinical study in RA patients.

Results: In vitro, filgotinib and its active metabolite at clinically relevant concentrations did not interact with cytochrome P450 enzymes and uridine 5'-diphospho-glucuronosyltransferases, and did not inhibit key drug transporters. In the clinic, a lack of relevant pharmacokinetic drug interactions by filgotinib and its active metabolite with substrates of CYP3A4, as well as with organic anion transporters involved in methotrexate elimination were found.

Conclusion: the collective in vivo and in vitro data on drug-metabolizing enzymes and on key drug transporters, support co-administration of filgotinib with commonly used RA drugs to patients without the need for dose adjustments.
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December 2016

Effects of Nandrolone in the Counteraction of Skeletal Muscle Atrophy in a Mouse Model of Muscle Disuse: Molecular Biology and Functional Evaluation.

PLoS One 2015 11;10(6):e0129686. Epub 2015 Jun 11.

Section of Pharmacology, Dept. of Pharmacy & Drug Sciences, University of Bari "Aldo Moro", Bari, Italy.

Muscle disuse produces severe atrophy and a slow-to-fast phenotype transition in the postural Soleus (Sol) muscle of rodents. Antioxidants, amino-acids and growth factors were ineffective to ameliorate muscle atrophy. Here we evaluate the effects of nandrolone (ND), an anabolic steroid, on mouse skeletal muscle atrophy induced by hindlimb unloading (HU). Mice were pre-treated for 2-weeks before HU and during the 2-weeks of HU. Muscle weight and total protein content were reduced in HU mice and a restoration of these parameters was found in ND-treated HU mice. The analysis of gene expression by real-time PCR demonstrates an increase of MuRF-1 during HU but minor involvement of other catabolic pathways. However, ND did not affect MuRF-1 expression. The evaluation of anabolic pathways showed no change in mTOR and eIF2-kinase mRNA expression, but the protein expression of the eukaryotic initiation factor eIF2 was reduced during HU and restored by ND. Moreover we found an involvement of regenerative pathways, since the increase of MyoD observed after HU suggests the promotion of myogenic stem cell differentiation in response to atrophy. At the same time, Notch-1 expression was down-regulated. Interestingly, the ND treatment prevented changes in MyoD and Notch-1 expression. On the contrary, there was no evidence for an effect of ND on the change of muscle phenotype induced by HU, since no effect of treatment was observed on the resting gCl, restCa and contractile properties in Sol muscle. Accordingly, PGC1α and myosin heavy chain expression, indexes of the phenotype transition, were not restored in ND-treated HU mice. We hypothesize that ND is unable to directly affect the phenotype transition when the specialized motor unit firing pattern of stimulation is lacking. Nevertheless, through stimulation of protein synthesis, ND preserves protein content and muscle weight, which may result advantageous to the affected skeletal muscle for functional recovery.
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May 2016

Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Modeling of Filgotinib (GLPG0634), a Selective JAK1 Inhibitor, in Support of Phase IIB Dose Selection.

Clin Pharmacokinet 2015 Aug;54(8):859-74

Galapagos SASU, 102 Avenue Gaston Roussel, 93230, Romainville, France,

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.
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August 2015

Characterization of GLPG0492, a selective androgen receptor modulator, in a mouse model of hindlimb immobilization.

BMC Musculoskelet Disord 2014 Sep 3;15:291. Epub 2014 Sep 3.

GALAPAGOS SASU, 102 Avenue Gaston Roussel, 93230 Romainville, France.

Background: Muscle wasting is a hallmark of many chronic conditions but also of aging and results in a progressive functional decline leading ultimately to disability. Androgens, such as testosterone were proposed as therapy to counteract muscle atrophy. However, this treatment is associated with potential cardiovascular and prostate cancer risks and therefore not acceptable for long-term treatment. Selective Androgen receptor modulators (SARM) are androgen receptor ligands that induce muscle anabolism while having reduced effects in reproductive tissues. Therefore, they represent an alternative to testosterone therapy. Our objective was to demonstrate the activity of SARM molecule (GLPG0492) on a immobilization muscle atrophy mouse model as compared to testosterone propionate (TP) and to identify putative biomarkers in the plasma compartment that might be related to muscle function and potentially translated into the clinical space.

Methods: GLPG0492, a non-steroidal SARM, was evaluated and compared to TP in a mouse model of hindlimb immobilization.

Results: GLPG0492 treatment partially prevents immobilization-induced muscle atrophy with a trend to promote muscle fiber hypertrophy in a dose-dependent manner. Interestingly, GLPG0492 was found as efficacious as TP at reducing muscle loss while sparing reproductive tissues. Furthermore, gene expression studies performed on tibialis samples revealed that both GLPG0492 and TP were slowing down muscle loss by negatively interfering with major signaling pathways controlling muscle mass homeostasis. Finally, metabolomic profiling experiments using 1H-NMR led to the identification of a plasma GLPG0492 signature linked to the modulation of cellular bioenergetic processes.

Conclusions: Taken together, these results unveil the potential of GLPG0492, a non-steroidal SARM, as treatment for, at least, musculo-skeletal atrophy consecutive to coma, paralysis, or limb immobilization.
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September 2014

GLPG0492, a novel selective androgen receptor modulator, improves muscle performance in the exercised-mdx mouse model of muscular dystrophy.

Pharmacol Res 2013 Jun 22;72:9-24. Epub 2013 Mar 22.

Sezione di Farmacologia, Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, Bari, Italy.

Anabolic drugs may counteract muscle wasting and dysfunction in Duchenne muscular dystrophy (DMD); however, steroids have unwanted side effects. We focused on GLPG0492, a new non-steroidal selective androgen receptor modulator that is currently under development for musculo-skeletal diseases such as sarcopenia and cachexia. GLPG0492 was tested in the exercised mdx mouse model of DMD in a 4-week trial at a single high dose (30 mg/kg, 6 day/week s.c.), and the results were compared with those from the administration of α-methylprednisolone (PDN; 1 mg/kg, i.p.) and nandrolone (NAND, 5 mg/kg, s.c.). This assessment was followed by a 12-week dose-dependence study (0.3-30 mg/kg s.c.). The outcomes were evaluated in vivo and ex vivo on functional, histological and biochemical parameters. Similar to PDN and NAND, GLPG0492 significantly increased mouse strength. In acute exhaustion tests, a surrogate of the 6-min walking test used in DMD patients, GLPG0492 preserved running performance, whereas vehicle- or comparator-treated animals showed a significant increase in fatigue (30-50%). Ex vivo, all drugs resulted in a modest but significant increase of diaphragm force. In parallel, a decrease in the non-muscle area and markers of fibrosis was observed in GLPG0492- and NAND-treated mice. The drugs exerted minor effects on limb muscles; however, electrophysiological biomarkers were ameliorated in extensor digitorum longus muscle. The longer dose-dependence study confirmed the effect on mdx mouse strength and resistance to fatigue and demonstrated the efficacy of lower drug doses on in vivo and ex vivo functional parameters. These results support the interest of further studies of GLPG0492 as a potential treatment for DMD.
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June 2013

Oral administration of GLPG0259, an inhibitor of MAPKAPK5, a new target for the treatment of rheumatoid arthritis: a phase II, randomised, double-blind, placebo-controlled, multicentre trial.

Ann Rheum Dis 2013 May 17;72(5):741-4. Epub 2012 Nov 17.

Department of Rheumatology, University Hospital KU Leuven, Leuven, Belgium.

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.
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May 2013

Identification of a 4-(hydroxymethyl)diarylhydantoin as a selective androgen receptor modulator.

J Med Chem 2012 Oct 25;55(19):8236-47. Epub 2012 Sep 25.

GALAPAGOS, Parc Biocitech, 102 Avenue Gaston Roussel, 93230 Romainville, France.

Structural modification performed on a 4-methyl-4-(4-hydroxyphenyl)hydantoin series is described which resulted in the development of a new series of 4-(hydroxymethyl)diarylhydantoin analogues as potent, partial agonists of the human androgen receptor. This led to the identification of (S)-(-)-4-(4-(hydroxymethyl)-3-methyl-2,5-dioxo-4-phenylimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile ((S)-(-)-18a, GLPG0492) evaluated in vivo in a classical model of orchidectomized rat. In this model, (-)-18a exhibited anabolic activity on muscle, strongly dissociated from the androgenic activity on prostate after oral dosing. (-)-18a has very good pharmacokinetic properties, including bioavailability in rat (F > 50%), and is currently under evaluation in phase I clinical trials.
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October 2012

Pharmacokinetics, safety, and tolerability of GLPG0259, a mitogen-activated protein kinase-activated protein kinase 5 (MAPKAPK5) inhibitor, given as single and multiple doses to healthy male subjects.

Drugs R D 2012 Sep;12(3):141-63

Galapagos SASU, Romainville, France.

Background And Objectives: GLPG0259 is a small-molecule inhibitor of mitogen-activated protein kinase-activated protein kinase 5 (MAPKAPK5), a kinase enzyme that plays a role in important inflammatory pathways. The main objectives of the phase I clinical studies in early development were to characterize the pharmacokinetics, tolerability, and safety of GLPG0259 in healthy subjects, including the development of a solid dosage form (free-base pellets and fumarate salt capsules) and the potential for interaction of GLPG0259 with methotrexate.

Subjects And Methods: Four phase I studies were initiated. Study 1 was a randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of single ascending doses (1.5-150 mg) and multiple oral doses (20 and 50 mg once daily) of GLPG0259 in healthy male subjects (n = 34). Study 2 was a randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of oral multiple ascending doses of GLPG0259 (25-75 mg once daily) given for 14 days to healthy male subjects, and to get preliminary information on the potential pharmacokinetic interaction between GLPG0259 and methotrexate (n = 24). Studies 3 and 4 were open-label, randomized, crossover studies to compare the oral bioavailability of two solid dosage forms of GLPG0259 (a capsule) relative to an oral solution after a 100 mg or 50 mg single dose and to evaluate the effect of food on these formulations (n = 12 for each study).

Main Outcome Measures: The non-compartmental pharmacokinetic parameters for plasma concentrations of GLPG0259 were determined, and a population pharmacokinetic model of GLPG0259 was developed to support the planning of the number and timing of the sparse samples to be taken per patient in the phase II study. Safety and tolerability data are also summarized.

Results: The absorption of GLPG0259 was slow, with a decrease in the absorption rate with increasing dose, and there was decreased elimination, with an apparent terminal elimination half-life of 26.0 hours. On the basis of statistical analysis of variance, the exposure to GLPG0259 increased in proportion to the dose over a 30-150 mg single-dose range and a 25-75 mg repeated-dose range. Between- and within-subject variability in GLPG0259 pharmacokinetics was low/moderate (coefficient of variation [CV] 16-30%). After once-daily repeated dosing, steady-state plasma concentrations were reached at between 5 and 8 dosing days, which is consistent with the long apparent elimination half-life of GLPG0259. Food increased the bioavailability of GLPG0259 given in a solid dosage form. Co-administration of GLPG0259 with a single dose of methotrexate 7.5 mg did not result in any change in the pharmacokinetic profiles of either GLPG0259 or methotrexate.

Conclusion: In summary, the investigation of safety/tolerability and pharmacokinetics in the early development phase showed that single and repeated doses of GLPG0259 were safe and well tolerated. The most common adverse event reported was mild gastrointestinal discomfort. The pharmacokinetics characterized in healthy male subjects showed no major obstacles and supports a once-daily oral regimen in patients.
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September 2012

A single centre, open-label, cross-over study of pharmacokinetics comparing topical zinc/clindamycin gel (Zindaclin) and topical clindamycin lotion (Dalacin T) in subjects with mild to moderate acne.

J Dermatolog Treat 2006 ;17(3):154-7

Aster Cephac, Paris, FranceStrakan Ltd, Buckholm Mill, Galashiels, UK.

Zinc/clindamycin gel (Zindaclin 1%) gel, is a new once-daily topical acne treatment (Strakan Ltd) containing clindamycin phosphate equivalent to 1% clindamycin and zinc acetate in a formulation, which leads to a reduced systemic absorption of clindamycin through the skin. The objective of the study was to compare the systemic absorption of clindamycin from zinc/clindamycin gel and clindamycin lotion (Dalacin T topical lotion, Pharmacia Ltd) after repeated twice-daily topical administration for two periods of 5 days with an intervening gap of 2 weeks in 24 subjects with mild to moderate acne. Plasma Cmax, and AUC0-12 of clindamycin measured after single and multiple applications of zinc/clindamycin gel were between 30% and 50% lower than for clindamycin lotion. As zinc/clindamycin gel is a topical treatment for acne, the lower systemic bioavailability may be beneficial because there may be a correspondingly lower risk of systemic events in zinc/clindamycin gel-treated subjects.
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October 2006