Frédéric Vanhoutte

Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1)

Objectives To evaluate the efficacy and safety of different doses and regimens of filgotinib, an oral Janus kinase 1 inhibitor, as add-on treatment to methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and inadequate response to MTX. Methods In this 24-week phase IIb study, patients with moderate-to-severe active RA receiving a stable dose of MTX were randomised (1:1:1:1:1:1:1) to receive placebo or 50, 100 or 200 mg filgotinib, administered once daily or twice daily. Primary end point was the percentage of patients achieving a week 12 American College of Rheumatology (ACR)20 response. Results Overall, 594 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib 100 mg once daily or 200 mg daily (both regimens) achieved an ACR20 response versus placebo. For other key end points at week 12 (ACR50, ACR-N, Disease Activity Score based on 28 joints and C reactive protein value, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index), differences in favour of 100  or 200 mg filgotinib daily were seen versus placebo; responses were maintained or improved through to week 24. Rapid onset of action and dose-dependent responses were observed for most efficacy end points and were associated with an increased haemoglobin concentration. No significant differences between once-daily and twice-daily regimens were seen. Treatment-emergent adverse event rates were similar in placebo and filgotinib groups. Serious infections occurred in one and five patients in the placebo and filgotinib groups, respectively. No tuberculosis or opportunistic infections were reported. Conclusions Filgotinib as add-on to MTX improved the signs and symptoms of active RA over 24 weeks and was associated with a rapid onset of action. Filgotinib was generally well tolerated. Trial registration number: NCT01888874.

Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2)

Objectives To evaluate the efficacy and safety of different doses of filgotinib, an oral Janus kinase 1 inhibitor, as monotherapy in patients with active rheumatoid arthritis (RA) and previous inadequate response to methotrexate (MTX). Methods In this 24-week phase IIb study, patients with moderately to severely active RA were randomised (1:1:1:1) to receive 50, 100 or 200 mg filgotinib once daily, or placebo, after a ≥4-week washout from MTX. The primary end point was the percentage of patients achieving an American College of Rheumatology (ACR)20 response at week 12. Results Overall, 283 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib at any dose achieved ACR20 responses versus placebo (≥65% vs 29%, p<0.001). For other key end points at week 12 (ACR50, ACR70, ACR-N, Disease Activity Score based on 28 joints and C reactive protein, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index) significant differences from baseline in favour of filgotinib 100 and 200 mg versus placebo were seen; responses were maintained or improved through week 24. Rapid onset of action was observed for most efficacy end points. Dose-dependent increases in haemoglobin were observed. The percentage of patients with treatment-emergent adverse events (TEAE) was similar in the placebo and filgotinib groups (∼40%). Eight patients on filgotinib and one on placebo had a serious TEAE, and four patients, all of whom received filgotinib, experienced a serious infection. No tuberculosis or opportunistic infections were reported. Conclusions Over 24 weeks, filgotinib as monotherapy was efficacious in treating the signs and symptoms of active RA, with a rapid onset of action. Filgotinib was generally well tolerated. Trial registration number NCT01894516.

Correlations between Factors Determining the Pharmacokinetics and Antiviral Activity of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors of the Diaryltriazine and Diarylpyrimidine Classes of Compounds

AbstractObjective: To investigate the important factors that determine the bioavailability and the antiviral activity of the diaryltriazine (DATA) and diarylpyrimidine (DAPY) non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1 in animal species and humans using cell-based assays, physicochemical and comput ed parameters. Methods: This naturalistic study included 15 parameters ranging from molecular mechanics calculations to phase I clinical trials. The calculated parameters were solvent-accessible surface area (SASA), polar surface area and Gibbs free energy of solvation. Physicochemical parameters comprised lipophilicity (octanol/water partition coefficient [cLogP]), ionisation constant (pKa), solubility and aggregate radius. Cell-based assays included human colonic adenocarcinoma cell (Caco-2) permeability (transepithelial transport), drug metabolism and antiviral activity (negative logarithm of the molar effective concentration inhibiting viral replica tion by 50% [pEC50]). Exposure was tested in rats, dogs and human volunteers. Results: Of the 15 parameters, eight correlated consistently among one another. Exposure (area under the plasma concentration-time curve [AUC]) in humans correlated positively with that in rats (r = 1.00), with transepithelial transport (r = 0.83), lipophilicity (r = 0.60), ionisability (r = 0.89), hydrodynamic radius of aggregates (r = 0.66) and with antiviral activity (r = 0.61). Exposure in humans was also seen to correlate negatively with SASA (r = −0.89). No consistent correlation was found between exposure in dogs and the eight parameters. Of the 14 DATA/DAPY molecules, 11 form aggregates with radii between 34 and 100nm. Conclusions: We observed correlations between exposure in humans with expo sure in rats, transepithelial transport (Caco-2 cells), ionisability, lipophilicity, aggregate radius and SASA in the class of DATA/DAPY NNRTI compounds. The lipophilic DATA/DAPY compounds form aggregates. It can be assumed that absorption in the intestinal tract and endocytosis in infected cells of these lipophilic compounds are governed by the common phenomenon of aggregate formation. As the lymphatic system offers a pathway for intestinal uptake of aggregates, this may offer a therapeutic advantage in the treatment of HIV-1 infection. Although it was not the objective of the study, we found that the rat was a better in vivo model than the dog for the prediction of systemic exposure in this particular set of compounds.

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

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.

OP0263 Efficacy and safety of GLPG0634, a selective JAK1 inhibitor, after short-term treatment of rheumatoid arthritis; results of a phase IIA trial

Background GLPG0634 is an orally-available, selective inhibitor of Janus kinase 1 (JAK1). JAKs are critical components in signaling pathways for a number of cytokines and growth factors, including those involved in the disease process of rheumatoid arthritis (RA). Other non-selective JAK inhibitors have shown long-term efficacy in RA trials with an early onset of action, but doses and thereby efficacy are limited by side effects. By specifically targeting JAK1, treatment with GLPG0634 is expected to result in a cleaner safety profile while maintaining the rapid onset of clinical efficacy. Objectives Evaluate the short-term efficacy and safety of GLPG0634 in RA patients with insufficient response to methotrexate (MTX) alone. Methods A double-blind, placebo-controlled Proof-of-Concept trial in patients with active RA, showing an insufficient response to MTX, was conducted. Twenty-four patients with moderate to severe disease received GLPG0634 200 mg daily, half as once-daily regimen (200 mg q.d.) and half as twice-daily regimen (100 mg b.i.d.), and 12 patients received a matching placebo for a period of four weeks, while continuing to take their stable background therapy of MTX. Results Patient and disease characteristics were comparable for all three dose groups, with DAS28 (CRP) disease activity scores between 6.3 and 6.6. In each dose group, 11 out of 12 patients were female. The patients were well exposed to GLPG0634, with the same pharmacokinetics as previously observed in healthy volunteers. GLPG0634 was found well tolerated and safe with a rapid onset and high level of efficacy. Considering the small sample size, no clinically relevant differences were observed among the 100 mg b.i.d. and the 200 mg q.d. dose regimens. GLPG0634 met the primary endpoint of significant improvement in ACR20 response rate. Overall ACR20 responses were observed in 83% of patients receiving GLPG0634 vs. 33% of patients receiving placebo (p<0.01). GLPG0634 showed impressive results in secondary efficacy endpoints, such as the DAS28 (-2.5), and in reductions of serum C-reactive protein levels (-24.4 mg/L), both significant changes vs. placebo (p<0.0001). All patients completed the trial and no treatment-emergent safety signals were reported. No severe adverse events were reported in patients receiving GLPG0634. Instead of anemia, a modest improvement in hemoglobin was observed. In contrast to observations with JAK inhibitors with other selectivity profiles, no increases in LDL/cholesterol and no liver effects (ALT/AST) were observed in this trial. Conclusions These early clinical results are the first to demonstrate that selective inhibition of JAK1 is efficacious and safe for the treatment of RA. Consistent with the lack of inhibition of JAK2, no anemia was observed. Remarkable results include the high level of response within 4 weeks and the absence of effects on LDL/lipid. An extended GLPG0634 dose-range finding trial is now being conducted to further define the optimal doses for efficacy and safety for longer term studies. Disclosure of Interest F. Vanhoutte Employee of: Galapagos, M. Mazur: None Declared, F. Namour Employee of: Galapagos, A. van der Aa Employee of: Galapagos, P. Wigerinck Employee of: Galapagos, G. Van ’t Klooster Employee of: Galapagos

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

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.

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

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.

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

Background and ObjectivesGLPG0259 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 MethodsFour 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 MeasuresThe 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.ResultsThe 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.ConclusionIn 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.

Abstract 1568: GLPG0187, a small molecule integrin antagonist, shows good safety and decrease in CTX levels in single ascending dose study

Introduction : GLPG0187, a small molecule integrin antagonist with nanomolar affinity for the RGD-integrin receptors αvβ1, αvβ3, αvβ5, αvβ6 and α5β1, shows potent anti-angiogenic, anti-metastatic, anti-bone-resorption and anti-tumor activity in vitro and in vivo. Therefore GLPG0187 may offer a promising therapeutic approach for the treatment of integrin receptor expressing tumors and/or metastases. Methods: Based on promising preclinical data, a first-in-human study was performed with GLPG0187 to assess the safety and tolerability as well as pharmacokinetic and pharmacodynamic behavior of single ascending doses of the compound. GLPG0187 was administered subcutaneously in a dose range of 17.5 to 315 mg and orally in a dose range of 50 to 1200 mg. Results: GLPG0187 was systemically well tolerated with no adverse effects on ECG, vital signs or laboratory parameters. GLPG0187 showed a dose proportional pharmacokinetic profile over the dose range tested. Moreover, GLPG0187 dose proportionally decreased osteoclast activity as measured by plasma CTX (carboxy-terminal collagen crosslinks) levels. Conclusions: GLPG0187 was shown to be safe and well tolerated, to have a dose proportional pharmacokinetics and to inhibit osteoclast activity. These results provide further evidence that GLPG0187 could be an effective therapeutic for the treatment of cancer. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1568.

DOP070 The FFA2 antagonist GLPG0974: opportunity to treat neutrophil-driven inflammation

Background: KdPT is a tripeptide with broad anti-inflammatory activity. Pre-clinical data indicated that KdPT is safe and efficacy was shown in different murine models of intestinal inflammation. KdPT given orally proved to be safe and well tolerated in previous clinical studies. Methods: We performed a multi-centre, randomised, doubleblind, placebo-controlled prospective phase II trial (2011 002462 20) to evaluate efficacy and safety of KdPT in patients with mild to moderate ulcerative colitis (UC). As add-on therapy to aminosalicylates, azathioprine, and/or corticosteroids placebo or KdPT in three different doses (20, 50, 100mg BID) was administered. 168 patients were randomized (ITT: n = 162; PP: n = 116) in 6 countries. The primary objective was to determine time to response to KdPT, defined as time from Day 0 to earliest treatment visit at which sustained improvement in colitis activity index (CAI) of 50% was determined. Improvement in CAI was to be 50% at Week 8, irrespective of any interim decline, for improvement to be classified as sustained. Due to an unusually high placebo rate from week 6 on assumptions for the statistical evaluation of the primary endpoint were violated, thus appropriate statistical tests were run to compare treatment groups. Results: The primary endpoint for pooled KdPT (PP) approached significance using Log rank (Renyi family) test (p = 0.0525, onesided) and showed statistical significance for the Wilcoxon (Renyi family) test (p = 0.0368, one-sided). At Week 2 and Week 4, remission rates were approximately twice as high for pooled KdPT compared to placebo (2 weeks: p = 0.0361; 4 weeks: p = 0.0178). For 20mg KdPT remission occurred earlier compared to 50mg or 100mg K(D)PT. CAI response rates lost significance at later time points due to unexpected high placebo rates from week 6 on. Patients with active and more severe disease (CAI 9; baseline medication: aminosalicylates + corticosteroids and/or azathioprine) showed earlier and more pronounced response to KdPT compared to placebo (p = 0.0156). KdPT was safe and tolerated well at the investigated doses with no difference between placebo and KdPT groups.