A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone

2012 ◽  
Vol 64 (4) ◽  
pp. 970-981 ◽  
Author(s):  
Joel M. Kremer ◽  
Stanley Cohen ◽  
Bethanie E. Wilkinson ◽  
Carol A. Connell ◽  
Jonathan L. French ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Active Rheumatoid Arthritis ◽  
Inadequate Response ◽  
Jak Inhibitor ◽  
Dose Ranging

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.

SAT0136 RELATIVE EFFICACY AND SAFETY OF TOFACITINIB, BARICITINIB, UPADACITINIB, AND FILGOTINIB, IN COMPARISON WITH ADALIMUMAB IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS: A BAYESIAN NETWORK META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1005.1-1005
Author(s):  
Y. H. Lee ◽  
G. G. Song
Keyword(s):  
Rheumatoid Arthritis ◽  
Active Rheumatoid Arthritis ◽  
Response Rate ◽  
Meta Analysis ◽  
Inadequate Response ◽  
Efficacy And Safety ◽  
Double Blind ◽  
Acr20 Response ◽  
Randomized Controlled ◽  
Acr20 Response Rate

Background:Methotrexate (MTX), an effective disease-modifying antirheumatic drug (DMARD) [2], is the most widely used DMARD for the treatment of rheumatoid arthritis (RA). However, not all patients are responsive to the drug; 30% of the patients discontinue therapy within 1 year of commencing the treatment, usually because of the lack of efficacy or undesirable adverse effects Small-molecule Janus kinase inhibitors are clinically developed for the treatment of RA.Objectives:The aim of this study is to investigate the relative efficacy and safety of tofacitinib, baricitinib, upadacitinib, and filgotinib in comparison with adalimumab in patients with active RA and having inadequate responses to MTX.Methods:We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib, and adalimumab in RA patients having inadequate responses to MTX.Results:Four RCTs, comprising 5,451 patients, met the inclusion criteria. The baricitinib 4mg+MTX and upadacitinib 15mg+MTX group showed a significantly higher American College of Rheumatology 20% (ACR20) response rate than the adalimumab 40mg+MTX group. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that baricitinib 4mg+MTX had the highest probability of being the best treatment for achieving the ACR20 response rate, followed by upadacitinib 15mg+MTX, tofacitinib 5mg+MTX, filgotinib 200mg+MTX, filgotinib 100mg+MTX, adalimumab 40mg+MTX, and placebo+MTX. The upadacitinib 15mg+MTX and baricitinib 4mg+MTX groups showed significantly higher ACR50 and ACR70 response rates than adalimumab 40mg+MTX. In terms of Herpes zoster infection, the ranking probability based on the SUCRA indicated that placebo+MTX were likely to be the safest treatments, followed by filgotinib 200mg+MTX, filgotinib 100mg+MTX, adalimumab 40mg+MTX, tofacitinib 5mg+MTX, upadacitinib 15mg+MTX, and baricitinib 4mg+MTX. Regarding safety analysis, no statistically significant differences were found between the respective intervention groups.Conclusion:In RA patients with an inadequate response to MTX, baricitinib 4mg+MTX and upadacitinib 15mg+MTX showed the highest ACR response rates, suggesting a difference in efficacy among the different JAK inhibitors.References:[1]Fleischmann R, Mysler E, Hall S, Kivitz AJ, Moots RJ, Luo Z, DeMasi R, Soma K, Zhang R, Takiya LJTL (2017) Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial. 390:457-468[2]Taylor PC, Keystone EC, van der Heijde D et al (2017) Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis. N Engl J Med 376:652-662[3]Fleischmann R, Pangan AL, Mysler E, Bessette L, Peterfy C, Durez P, Ostor A, Li Y, Zhou Y, Othman AA (2018) A phase 3, randomized, double-blind study comparing upadacitinib to placebo and to adalimumab, in patients with active rheumatoid arthritis with inadequate response to methotrexate. ARTHRITIS & RHEUMATOLOGY. WILEY 111 RIVER ST, HOBOKEN 07030-5774, NJ USA, pp[4]Combe B, Kivitz A, Tanaka Y, van der Heijde D, Matzkies F, Bartok B, Ye L, Guo Y, Tasset C, Sundy J (2019) LB0001 EFFICACY AND SAFETY OF FILGOTINIB FOR PATIENTS WITH RHEUMATOID ARTHRITIS WITH INADEQUATE RESPONSE TO METHOTREXATE: FINCH1 PRIMARY OUTCOME RESULTS. BMJ Publishing Group Ltd, ppDisclosure of Interests:None declared

scholarly journals Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial

2016 ◽  
Vol 76 (5) ◽  
pp. 840-847 ◽  
Author(s):  
Gerd R Burmester ◽  
Yong Lin ◽  
Rahul Patel ◽  
Janet van Adelsberg ◽  
Erin K Mangan ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Active Rheumatoid Arthritis ◽  
Activity Index ◽  
Joint Disease ◽  
Phase Iii ◽  
Inadequate Response ◽  
Efficacy And Safety ◽  
Double Blind ◽  
End Point

ObjectivesTo compare efficacy and safety of sarilumab monotherapy with adalimumab monotherapy in patients with active rheumatoid arthritis (RA) who should not continue treatment with methotrexate (MTX) due to intolerance or inadequate response.MethodsMONARCH was a randomised, active-controlled, double-blind, double-dummy, phase III superiority trial. Patients received sarilumab (200 mg every 2 weeks (q2w)) or adalimumab (40 mg q2w) monotherapy for 24 weeks. The primary end point was change from baseline in 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) at week 24.ResultsSarilumab was superior to adalimumab in the primary end point of change from baseline in DAS28-ESR (−3.28 vs −2.20; p<0.0001). Sarilumab-treated patients achieved significantly higher American College of Rheumatology 20/50/70 response rates (sarilumab: 71.7%/45.7%/23.4%; adalimumab: 58.4%/29.7%/11.9%; all p≤0.0074) and had significantly greater improvement in Health Assessment Questionnaire-Disability Index (p=0.0037). Importantly, at week 24, more patients receiving sarilumab compared with adalimumab achieved Clinical Disease Activity Index remission (7.1% vs 2.7%; nominal p=0.0468) and low disease activity (41.8% vs 24.9%; nominal p=0.0005, supplemental analysis). Adverse events occurred in 63.6% (adalimumab) and 64.1% (sarilumab) of patients, the most common being neutropenia and injection site reactions (sarilumab) and headache and worsening RA (adalimumab). Incidences of infections (sarilumab: 28.8%; adalimumab: 27.7%) and serious infections (1.1%, both groups) were similar, despite neutropenia differences.ConclusionsSarilumab monotherapy demonstrated superiority to adalimumab monotherapy by improving the signs and symptoms and physical functions in patients with RA who were unable to continue MTX treatment. The safety profiles of both therapies were consistent with anticipated class effects.Trial registration numberNCT02332590.

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