scholarly journals THU0216 PERIPHERAL PROTEIN BIOMARKER CHANGES FOLLOWING SELECTIVE INHIBITION OF JANUS KINASE 1 (JAK1) BY FILGOTINIB IN METHOTREXATE NAÏVE ADULTS WITH MODERATELY-TO-SEVERELY ACTIVE RHEUMATOID ARTHRITIS (FINCH3)

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 333.2-334
Author(s):  
P. C. Taylor ◽  
A. M. Mirza ◽  
B. Downie ◽  
J. Liu ◽  
R. E. Hawtin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Migration ◽  
Active Rheumatoid Arthritis ◽  
Immune Cell ◽  
Selective Inhibition ◽  
Rapid Onset ◽  
Janus Kinase ◽  
Bone Biology ◽  
Protein Biomarkers ◽  
Immune Cell Migration

Background:Filgotinib (FIL), an oral selective JAK1 inhibitor, has shown efficacy and safety in multiple phase 3 studies in adults with moderately-to-severely active rheumatoid arthritis (RA), including those who are naïve to methotrexate (MTX) therapy (FINCH3;NCT02886728).Objectives:A longitudinal study of protein biomarkers related to JAK signaling1, bone biology2, immune cell migration2, and inflammation2was conducted in FINCH3 pts to identify disease relevant biomarkers that are altered by FIL vs MTX.Methods:MTX-naive RA pts enrolled in FINCH3 received a stable dose of MTX (MTX mono), FIL200mg monotherapy (FIL200mg mono) or one of two doses of FIL once daily with MTX (FIL100mg+MTX, FIL200mg+MTX). Up to 27 disease relevant biomarkers were evaluated. Baseline (BL) correlation between biomarkers and clinical response measures were analyzed by Spearman Rank. Multiscale bootstrap resampling was used to evaluate significant intra-cluster biomarker membership. Mean changes in biomarker levels from BL to wks 4, 12 and 24 were compared between arms using MTX-adjusted estimates from a linear mixed effects model, adjusted for age, sex, race and BL biomarker level. A false discovery rate of 5% was applied for all analyses.Results:At BL, distinct clusters (CL) of biomarkers differentiated by JAK signaling were identified. The strongest intra-group correlations were in biomarkers upstream of JAK2 signaling (CL1; Rho range 0.88–0.98) and cytokines associated with JAK1 signaling (CL2; Rho range 0.72–0.77). Within MTX-naïve RA pts, there were significant BL correlations between 15 biomarkers and clinical measures. The strongest associations observed were between DAS28CRP and IL6, CXCL10, TNFRI, YKL-40, and CXCL13 (Rho >0.3).Relative to MTX mono, 23 biomarkers exhibited significantearly responsesto treatment (any arm, wk 4). The strongest treatment effect observed at wk 4 was a reduction by FIL+MTX (regardless of dose) and FIL200mg mono for CXCL13 (FIL100mg+MTX: -28.2%; FIL200mg+MTX: -40%; FIL200mg: -34%). This reduction was sustained in each arm through 24 wks, with the greatest reduction by FIL200mg+MTX (-37.8%). Dose differences were observed relative to FIL100mg+MTX, where FIL200mg+MTX led to anearly(wk 4) and significantly greater reduction of 9 biomarkers. There was a significant dose difference as adelayedresponse (wk 24) with a greater reduction by FIL200mg+MTX for 8 biomarkers.FIL200mg mono produced a greater effect on 18 biomarkers vs MTX mono, remaining significant through wk 24. The greatest effect in FIL200mg mono were reductions by wk 24 in CTX1 (-29.1%), CXCL13 (-33.2%), and IL6 (-29.5%), all of which were biomarkers associated with DAS28CRP at BL. Effects observed at any time point were largely similar between FIL200mg as a mono or in combination with MTX. Four biomarkers were uniquely different between FIL200mg mono and FIL200mg+MTX arms by wk 24: greater increase of MMP7 and decrease of GMCSF in FIL200mg+MTX; greater decrease of TRACP5B and ICAM1 in FIL200mg alone.Conclusion:Treatment through 24 weeks with FIL200mg (mono or with MTX) reduced many of the disease-relevant biomarkers tested; markers related to JAK signaling1, bone biology2, inflammation2, and immune cell migration2in the MTX-naïve RA setting. Changes were significantly reduced relative to MTX mono at wk 4, supporting the rapid onset of FIL clinical efficacy. The current study identified significant reductions of RA-associated disease markers that were unique to FIL mono, supporting the FIL mechanisms of action in the treatment of RA.References:[1]Majoros A, et al. Front Immunol. 2017;8:29[2]Brennan F, and McInnes I. J Clin Invest. 2008;118:3537-45Acknowledgments :This study was funded by Gilead Sciences, Inc. Editorial support was provided by Fishawack Communications Inc and funded by Gilead Sciences, Inc.Disclosure of Interests: :Peter C. Taylor Grant/research support from: Celgene, Eli Lilly and Company, Galapagos, and Gilead, Consultant of: AbbVie, Biogen, Eli Lilly and Company, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Roche, and UCB, Amer M. Mirza Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Bryan Downie Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Jinfeng Liu Shareholder of: Gilead Sciences Inc., Roche, Employee of: Gilead Sciences Inc., Rachael E. Hawtin Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Emon Elboudwarej Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc.

scholarly journals FRI0136 PERIPHERAL PROTEIN BIOMARKER CHANGES FOLLOWING SELECTIVE INHIBITION OF JANUS KINASE 1 (JAK1) BY FILGOTINIB IN ADULTS WITH MODERATELY-TO-SEVERELY ACTIVE RHEUMATOID ARTHRITIS WITH PRIOR INADEQUATE RESPONSE TO METHOTREXATE (FINCH1)

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 650.2-651
Author(s):  
P. C. Taylor ◽  
E. Elboudwarej ◽  
B. Downie ◽  
J. Liu ◽  
R. E. Hawtin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Migration ◽  
Active Rheumatoid Arthritis ◽  
Immune Cell ◽  
Janus Kinase ◽  
Inadequate Response ◽  
Bone Biology ◽  
Janus Kinase 1 ◽  
Immune Cell Migration ◽  
Dose Dependent

Background:Filgotinib (FIL), an oral selective Janus kinase 1 (JAK1) inhibitor has shown efficacy and safety in multiple phase 3 studies in adults with moderately-to-severely active rheumatoid arthritis (RA), including those with prior inadequate response to methotrexate (MTX) therapy (FINCH1;NCT02889796).Objectives:A longitudinal study of protein biomarkers related to JAK signaling1, bone biology2, immune cell migration2, and inflammation2was conducted to identify RA-associated markers altered by FIL vs MTX or adalimumab (ADA).Methods:FINCH1 RA patients (pts) were randomized to receive either a stable dose of MTX with placebo (PBO+MTX), ADA+MTX, and either FIL100mg+MTX or FIL200mg+MTX, once daily. Plasma, serum, and urine samples were taken from a subset of pts (~548) at baseline (BL) and weeks (wks) 4 and 12. Twenty-six pre-defined cytokines (biomarkers) were evaluated using ELISA. BL correlation between biomarkers and clinical response measures (DAS28CRP, SJC28, TJC28, CDAI, Patient Assessment and FACIT), were analyzed by Spearman Rank. Multiscale bootstrap resampling evaluated significant intra-cluster biomarker membership. Mean changes in biomarker levels from BL to wks 4 and 12 were compared between arms using PBO-adjusted estimates from a linear mixed effects model. A 5% false-discovery rate was applied for all analyses.Results:At BL, distinct biomarker-based pt clusters (CL) were identified. The strongest intra-group correlations were in bone-cartilage resorption/inflammation (CL1; Rho range 0.37–0.88) and JAK activity (CL2; Rho range 0.41–0.71). Individual BL cytokine levels were significantly associated with DAS28CRP, with unique biomarkers specific to various subcomponents of the score. Eleven biomarkers were associated with DAS28CRP, while 5, 3, and 2 were associated with CDAI, SJC28, and TJC28, respectively. The magnitude of FIL-associated treatment effects was time- and dose-dependent. Significant biomarker changes from BL were observed in FIL pts, relative to PBO+MTX pts. FIL100mg+MTX led to a significant change in 8 biomarkers by either 4 or 12 wks of treatment; FIL200mg+MTX significantly changed these and an additional 4 biomarkers by either time point. The greatest effect of FIL200mg+MTX was at 12 wks for CXCL13 (-38.4%) and IL6 (-53.7%). All treatment arms led to significant reductions in TNFα relative to PBO+MTX. FIL200mg+MTX treatment led to larger reductions of TNFα than ADA+MTX treatment at both wk4 (-24.7% vs -17.9%) and wk12 (-20.5% vs -12.2%), although the differences were not statistically significant.FIL and ADA caused differential patterns of cytokine response at either wks 4 or 12. Of 12 biomarkers with a significant FIL200mg+MTX treatment effect, there was a significantly larger reduction in TNFSF13B and CTX1 relative to ADA+MTX at 12 wks. Of 8 biomarkers with FIL100mg+MTX effects, only 2 (CXCL10 at wk 4; CXCL13 at wks 4 and 12) had significant differences from ADA+MTX. Relative either to FIL200mg+MTX or FIL100mg+MTX, and despite the same direction of effect, ADA+MTX led to a significantly larger reduction in CCL2, CXCL10, CCL4, and CXCL13.Conclusion:Compared with PBO, 12 wks of FIL treatment significantly reduced cytokines associated with JAK activity1, bone biology2, inflammation2, and immune cell migration2in MTX-IR pts. The effects were largely FIL dose-dependent; most cytokines exhibited similar effects regardless of treatment arms, but differential changes between FIL+MTX and ADA+MTX were observed, supportive of the different mechanisms of action of these therapies.References:[1]Majoros A, et al. Front Immunol. 2017;8:29[2]Brennan F, and McInnes I. J Clin Invest. 2008;118:3537-45Acknowledgments:This study was funded by Gilead Sciences, Inc. Editorial support was provided by Fishawack Communications Inc and funded by Gilead Sciences, Inc.Disclosure of Interests:Peter C. Taylor Grant/research support from: Celgene, Eli Lilly and Company, Galapagos, and Gilead, Consultant of: AbbVie, Biogen, Eli Lilly and Company, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Nordic Pharma, Pfizer Roche, and UCB, Emon Elboudwarej Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Bryan Downie Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Jinfeng Liu Shareholder of: Gilead Sciences Inc., Roche, Employee of: Gilead Sciences Inc., Rachael E. Hawtin Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc., Amer M. Mirza Shareholder of: Gilead Sciences Inc., Employee of: Gilead Sciences Inc.

scholarly journals P215 Filgotinib, a janus kinase 1 selective inhibitor, modulates disease-associated cytokines in patients with active RA

Rheumatology ◽  
2020 ◽  
Vol 59 (Supplement_2) ◽  
Author(s):  
Peter C Taylor ◽  
Emon Elboudwarej ◽  
Wanying Li ◽  
Rachael E Hawtin ◽  
Jinfeng Liu ◽  
...  
Keyword(s):  
Cell Migration ◽  
Disease Activity ◽  
Clinical Response ◽  
Immune Cell ◽  
Selective Inhibitor ◽  
Janus Kinase ◽  
Stock Ownership ◽  
Inadequate Response ◽  
Bone Biology ◽  
Immune Cell Migration

Abstract Background Filgotinib (FIL), an oral JAK1-selective inhibitor, was safe and effective in FINCH2, a randomised, double-blind, placebo (PBO)-controlled, phase 3 study in patients with active rheumatoid arthritis (RA) who had an inadequate response to methotrexate (MTX) and ≥1 biologic disease-modifying antirheumatic drug. A longitudinal study of cytokines from patients in FINCH2 was conducted to identify RA-associated biomarkers related to bone biology, immune cell migration, and inflammation that are altered by FIL therapy; and FIL-associated biomarkers that correlate with clinical response (DAS28CRP, swollen and tender joint counts, pain, and fatigue). Methods Plasma, serum and urine samples from RA patients (n = 449) receiving FIL (100mg, 200mg) or PBO once daily plus MTX were analysed at baseline (BL) and week 12 (W12) for 42 disease-relevant cytokines using validated, commercially available single- or multiplex assays. PBO corrected on-treatment changes in cytokine levels from BL to W12 were compared between treatment arms (Wilcoxon rank sum). Spearman rank correlation was used to compare changes in cytokine level from BL to W12 and clinical response. P-values <0.05 were considered significant. Results At W12, 18 of 42 cytokines significantly decreased with FIL 100mg treatment relative to PBO; FIL 200mg decreased these cytokines to a similar or greater degree. An additional 6 cytokines were significantly decreased by FIL 200mg. Conversely, 2 cytokines increased relative to PBO with FIL 100mg, and 6 cytokines increased with FIL 200mg (sIL-6R, IL10, GMCSF, IL2, leptin, and IL17A). Biomarkers most significantly modulated by FIL 200mg (p < 0.0001) included markers related to bone biology (MMP1 [-22.8%], MMP3 [-24.7%], CTX1 [-27.4% ], and NTX [-16.4%]), immune cell migration (VCAM1 [-20.0%], ICAM1 [-14.2%], CXCL13 [-45.0%], and CXCL10 [-32.3%]), and inflammation (TNFRI[-20.7%], CRP [-77.4%], SAA [-61.8%], and resistin [-20.2%]). Hierarchical clustering of BL biomarker levels revealed distinct groups of cytokines that were strongly correlated with each other. Among them, SAA, IL6 and CXCL10, were significantly positively correlated with each other (rho>0.6) and with RA disease activity (DAS28CRP) at BL (rho>0.3). Biomarkers, including CRP (IL6, SAA), PainVAS (CRP, SAA), and SJC28 (CRP, IL6, CXCL10), were also significantly correlated with individual components of DAS28CRP. Several biomarkers associated with RA disease activity at BL were decreased with FIL at W12 relative to PBO (FIL 100mg: CRP [-48.7%], SAA [-36.9%], and IL6 [-2.6%] and FIL 200mg: CRP [-77.4%], SAA [-61.8%], IL6 [-13.6%], CXCL10 [-32.3%]), suggesting FIL impacts these disease activities at a molecular level. Conclusion Twelve weeks of FIL treatment significantly reduced 24 disease-relevant cytokines in patients with active RA. Effects were dose-dependent and suggest a shift toward restored immune homeostasis. Findings are consistent with the clinical efficacy of FIL in FINCH2. Disclosures P.C. Taylor: Consultancies; Consultant for AbbVie, BMS, Jansses, Pfizer, Roche, Lilly, Sanofi, MSD, Novartis, Celgene and Gilead. E. Elboudwarej: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. W. Li: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. R.E. Hawtin: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. J. Liu: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc. A.M. Mirza: Corporate appointments; Employee of Gilead Sciences, Inc. Shareholder/stock ownership; Shareholder of Gilead Sciences, Inc.

scholarly journals 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)

2016 ◽  
Vol 76 (6) ◽  
pp. 1009-1019 ◽  
Author(s):  
A Kavanaugh ◽  
J Kremer ◽  
L Ponce ◽  
R Cseuz ◽  
O V Reshetko ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Active Rheumatoid Arthritis ◽  
Activity Index ◽  
Disease Activity Index ◽  
Rapid Onset ◽  
Janus Kinase ◽  
Inadequate Response ◽  
Onset Of Action ◽  
End Points

ObjectivesTo 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).MethodsIn 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.ResultsOverall, 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.ConclusionsOver 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 numberNCT01894516.

scholarly journals 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)

2016 ◽  
Vol 76 (6) ◽  
pp. 998-1008 ◽  
Author(s):  
R Westhovens ◽  
P C Taylor ◽  
R Alten ◽  
D Pavlova ◽  
F Enríquez-Sosa ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Active Rheumatoid Arthritis ◽  
Activity Index ◽  
Disease Activity Index ◽  
Rapid Onset ◽  
Janus Kinase ◽  
Onset Of Action ◽  
End Points ◽  
Once Daily

ObjectivesTo 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.MethodsIn 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.ResultsOverall, 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.ConclusionsFilgotinib 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.

scholarly journals Changes in Adhesion Molecule Expression During Distinct Patterns of Immune Cell Migration in the Inflamed Lung.

1996 ◽  
Vol 59 (5) ◽  
pp. 443-452 ◽  
Author(s):  
Sanae ICHIKAWA ◽  
Yasuhide GOTO ◽  
Shigeo UCHINO ◽  
H. Benfer KALTREIDER ◽  
Edward J. GOETZL ◽  
...  
Keyword(s):  
Cell Migration ◽  
Adhesion Molecule ◽  
Immune Cell ◽  
Adhesion Molecule Expression ◽  
Immune Cell Migration

scholarly journals Subcellular optogenetic activation of Cdc42 controls local and distal signaling to drive immune cell migration

2016 ◽  
Vol 27 (9) ◽  
pp. 1442-1450 ◽  
Author(s):  
Patrick R. O’Neill ◽  
Vani Kalyanaraman ◽  
N. Gautam
Keyword(s):  
Cell Migration ◽  
Intracellular Signaling ◽  
Immune Cell ◽  
Leading Edge ◽  
Signaling Networks ◽  
Membrane Protrusions ◽  
A Cell ◽  
Immune Cell Migration ◽  
Directional Cell Migration ◽  
Rhoa Signaling

Migratory immune cells use intracellular signaling networks to generate and orient spatially polarized responses to extracellular cues. The monomeric G protein Cdc42 is believed to play an important role in controlling the polarized responses, but it has been difficult to determine directly the consequences of localized Cdc42 activation within an immune cell. Here we used subcellular optogenetics to determine how Cdc42 activation at one side of a cell affects both cell behavior and dynamic molecular responses throughout the cell. We found that localized Cdc42 activation is sufficient to generate polarized signaling and directional cell migration. The optically activated region becomes the leading edge of the cell, with Cdc42 activating Rac and generating membrane protrusions driven by the actin cytoskeleton. Cdc42 also exerts long-range effects that cause myosin accumulation at the opposite side of the cell and actomyosin-mediated retraction of the cell rear. This process requires the RhoA-activated kinase ROCK, suggesting that Cdc42 activation at one side of a cell triggers increased RhoA signaling at the opposite side. Our results demonstrate how dynamic, subcellular perturbation of an individual signaling protein can help to determine its role in controlling polarized cellular responses.

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