glpg0634 and Spondylitis--Ankylosing

Janus kinase inhibitors (JAKi) have been approved for use in various immune-mediated inflammatory diseases. With five agents licensed, it was timely to summarise the current understanding of JAKi use based on a systematic literature review (SLR) on efficacy and safety.. Existing data were evaluated by a steering committee and subsequently reviewed by a 29 person expert committee leading to the formulation of a consensus statement that may assist the clinicians, patients and other stakeholders once the decision is made to commence a JAKi. The committee included patients, rheumatologists, a gastroenterologist, a haematologist, a dermatologist, an infectious disease specialist and a health professional. The SLR informed the Task Force on controlled and open clinical trials, registry data, phase 4 trials and meta-analyses. In addition, approval of new compounds by, and warnings from regulators that were issued after the end of the SLR search date were taken into consideration.. The Task Force agreed on and developed four general principles and a total of 26 points for consideration which were grouped into six areas addressing indications, treatment dose and comedication, contraindications, pretreatment screening and risks, laboratory and clinical follow-up examinations, and adverse events. Levels of evidence and strengths of recommendations were determined based on the SLR and levels of agreement were voted on for every point, reaching a range between 8.8 and 9.9 on a 10-point scale.. The consensus provides an assessment of evidence for efficacy and safety of an important therapeutic class with guidance on issues of practical management.

Topics: Adamantane; Advisory Committees; Antirheumatic Agents; Arthritis, Psoriatic; Arthritis, Rheumatoid; Azetidines; Cytokines; Drug Therapy, Combination; Europe; Heterocyclic Compounds, 3-Ring; Humans; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Niacinamide; Piperidines; Psoriasis; Purines; Pyrazoles; Pyridines; Pyrimidines; Rheumatology; Spondylarthropathies; Spondylitis, Ankylosing; Sulfonamides; Triazoles

JAK inhibitor therapies are effective treatment options for immune-mediated inflammatory diseases (IMIDs), but their use has been limited by venous thromboembolism (VTE) risk warnings from licensing authorities. We undertook this study to evaluate the VTE risk of JAK inhibitors in patients with IMIDs.. Systematic searches of Medline and Embase databases from inception to September 30, 2020 were conducted. Phase II and phase III double-blind, randomized controlled trials (RCTs) of JAK inhibitors at licensed doses were included in our analyses. RCTs with no placebo arm, long-term extension studies, post hoc analyses, and pooled analyses were excluded. Three researchers independently extracted data on exposure to JAK inhibitors or placebo and VTE events (e.g., pulmonary embolism [PE] and deep vein thrombosis [DVT]) and assessed study quality.. A total of 42 studies were included, from an initial search that yielded 619. There were 6,542 JAK inhibitor patient exposure years (PEYs) compared to 1,578 placebo PEYs. There were 15 VTE events in the JAK inhibitor group and 4 in the placebo group. The pooled incidence rate ratios (IRRs) of VTE, PE, and DVT in patients receiving JAK inhibitors were 0.68 (95% confidence interval [95% CI] 0.36-1.29), 0.44 (95% CI 0.28-0.70), and 0.59 (95% CI 0.31-1.15), respectively.. This meta-analysis of RCT data defines the VTE risk with JAK inhibitors as a class in IMID patients. The pooled IRRs do not provide evidence that support the current warnings of VTE risk for JAK inhibitors. These findings will aid continued development of clinical guidelines for the use of JAK inhibitors in IMIDs.

Topics: Arthritis, Psoriatic; Arthritis, Rheumatoid; Azetidines; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Heterocyclic Compounds, 3-Ring; Humans; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Piperidines; Psoriasis; Pulmonary Embolism; Purines; Pyrazoles; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Risk; Spondylarthropathies; Spondylitis, Ankylosing; Sulfonamides; Triazoles; Venous Thromboembolism; Venous Thrombosis

As our understanding of the pathogenesis of SpA improves, focus has turned to the role janus kinase (JAK)-mediated signal transduction and inhibiting its actions as a therapeutic mechanism. Small molecule inhibitors of JAK exist, with variable selectivity for the different JAK isoforms. Less selective JAK inhibitors have variable efficacy and safety profiles, prompting the investigation of selective JAK1 inhibition. In this review, we summarize the current phase 2 and 3 clinical trial data, evaluating the use of JAK1 selective inhibitors in the treatment of SpA, particularly AS and PsA. Selective JAK1 inhibition offers a promising therapeutic approach, however further longer-term trials are needed to fully establish their efficacy and safety at higher doses, and their use in the greater continuum of SpA.

Topics: Arthritis, Psoriatic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinase 1; Janus Kinase Inhibitors; Pyridines; Spondylarthropathies; Spondylitis, Ankylosing; Triazoles

Inhibitors of Janus kinases (JAKs) are being developed for treatment of inflammatory bowel diseases and other immune-mediated diseases. Tofacitinib is effective in treatment of ulcerative colitis, but there are safety concerns. We performed a systematic review and meta-analysis to investigate the safety profile of tofacitinib, upadacitinib, filgotinib, and baricitinib in patients with rheumatoid arthritis, inflammatory bowel diseases, psoriasis, or ankylosing spondylitis.. We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from January 1, 1990, through July 1, 2019. We performed a manual review of conference databases from 2012 through 2018. The primary outcome was incidence rates of adverse events (AEs) and serious AEs. We also estimated incidence rates of serious infections, herpes zoster infection, non-melanoma skin cancer, other malignancies, major cardiovascular events, venous thromboembolism, and mortality. We performed a meta-analysis, which included controlled studies, to assess the relative risk of these events.. We identified 973 studies; of these, 82 were included in the final analysis, comprising 66,159 patients with immune-mediated diseases who were exposed to a JAK inhibitor. Two-thirds of the included studies were randomized controlled trials. The incidence rate of AEs was 42.65 per 100 person-years and of serious AEs was 9.88 per 100 person-years. Incidence rates of serious infections, herpes zoster infection, malignancy, and major cardiovascular events were 2.81 per 100 person-years, 2.67 per 100 person-years, 0.89 per 100 person-years, and 0.48 per 100 person-years, respectively. Mortality was not increased in patients treated with JAK inhibitors compared with patients given placebo or active comparator (relative risk 0.72; 95% confidence interval 0.40-1.28). The meta-analysis showed a significant increase in risk of herpes zoster infection among patients who received JAK inhibitors (relative risk 1.57; 95% confidence interval 1.04-2.37).. In a systematic review and meta-analysis, we found an increased risk of herpes zoster infection among patients with immune-mediated diseases treated with JAK inhibitors. All other AEs were not increased among patients treated with JAK inhibitors.

Topics: Arthritis, Rheumatoid; Azetidines; Herpes Zoster; Heterocyclic Compounds, 3-Ring; Humans; Incidence; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Janus Kinases; Piperidines; Placebos; Psoriasis; Purines; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Spondylitis, Ankylosing; Sulfonamides; Survival Analysis; Treatment Outcome; Triazoles

To assess the effect of filgotinib, which preferentially inhibits Janus kinase 1 (JAK1), on MRI measures of structural change in the SI joint in patients with active AS in the TORTUGA trial.. Adults with active AS and inadequate response/intolerance to two or more NSAIDs were randomized 1:1 to filgotinib 200 mg (n = 58) or placebo (n = 58) once daily for 12 weeks. In this post hoc analysis, T1-weighted MRI scans of the SI joint were evaluated by two independent readers using Spondyloarthritis Research Consortium of Canada (SPARCC) Sacroiliac Joint Structural Score (SSS) definitions for erosion, backfill, fat metaplasia and ankylosis. Correlations between SPARCC SSS and improvement in clinical outcomes were also assessed.. MRI scans from 87 patients (48 filgotinib, 39 placebo) were evaluated. At baseline there were no notable differences between filgotinib and placebo for any MRI structural lesion types. From baseline to week 12, filgotinib was associated with a significant reduction in SI joint erosion score (P = 0.02) and an increase in backfill score (P = 0.005) vs placebo, with no significant between-group differences for ankylosis (P = 0.46) or fat metaplasia (P = 0.17). At week 12, the change in SPARCC MRI SI joint inflammation scores correlated positively with erosion scores but negatively with backfill scores.. The significant changes in MRI structural lesions induced by filgotinib in the SI joint by week 12 demonstrate that tissue repair can be observed very soon after starting treatment with a JAK1 preferential inhibitor. This could have prognostic implications for development of ankylosis.. ClinicalTrials.gov, http://clinicaltrials.gov, NCT03117270.

Topics: Adult; Humans; Janus Kinase Inhibitors; Magnetic Resonance Imaging; Metaplasia; Pyridines; Sacroiliac Joint; Spondylarthritis; Spondylitis, Ankylosing; Triazoles

At present, biological disease-modifying anti-rheumatic drugs (DMARDs) are the only treatment recommended for patients with ankylosing spondylitis who have not responded to first-line treatment with non-steroidal anti-inflammatory drugs (NSAIDs). The TORTUGA trial investigated the efficacy and safety of filgotinib, an oral selective Janus kinase 1 (JAK1) inhibitor, for the treatment of patients with active ankylosing spondylitis.. In this completed, randomised, double-blind, placebo-controlled, phase 2 trial, we enrolled adult patients from 30 sites in seven countries (Belgium, Bulgaria, Czech Republic, Estonia, Poland, Spain, and Ukraine). Eligible patients had active ankylosing spondylitis and an inadequate response or intolerance to two or more NSAIDs. Patients were randomly assigned (1:1) with an interactive web-based response system to receive filgotinib 200 mg or placebo orally once daily for 12 weeks. Randomisation was stratified by current use of conventional synthetic DMARDs and previous receipt of anti-tumour necrosis factor therapy. The patients, study team, and study sponsor were masked to treatment assignment. The primary endpoint was the change from baseline in ankylosing spondylitis disease activity score (ASDAS) at week 12, which was assessed in the full analysis set (ie, all randomised patients who received at least one dose of study drug). Safety was assessed according to actual treatment received. This trial is registered with ClinicalTrials.gov, number NCT03117270.. Between March 7, 2017, and July 2, 2018, 263 patients were screened and 116 randomly assigned to filgotinib (n=58) or placebo (n=58). 55 (95%) patients in the filgotinib group and 52 (90%) in the placebo group completed the study; three (5%) patients in the filgotinib group and six (10%) in the placebo group discontinued treatment. The mean ASDAS change from baseline to week 12 was -1·47 (SD 1·04) in the filgotinib group and -0·57 (0·82) in the placebo group, with a least squares mean difference between groups of -0·85 (95% CI -1·17 to -0·53; p<0·0001). Treatment-emergent adverse events were reported in 18 patients in each group, the most common being nasopharyngitis (in two patients in the filgotinib group and in four patients in the placebo group). Treatment-emergent adverse events led to permanent treatment discontinuation in two patients (a case of grade 3 pneumonia in the filgotinib group and of high creatine kinase in the placebo group). No deaths were reported during the study.. Filgotinib is efficacious and safe for the treatment of patients with active ankylosing spondylitis who have not responded to first-line pharmacological therapy with NSAIDs. Further investigation of filgotinib for ankylosing spondylitis is warranted.. Galapagos and Gilead Sciences.

Topics: Adult; Antirheumatic Agents; Double-Blind Method; Female; Humans; Janus Kinase 1; Janus Kinase Inhibitors; Male; Middle Aged; Nasopharyngitis; Opportunistic Infections; Pneumonia; Pyridines; Severity of Illness Index; Spondylitis, Ankylosing; Treatment Outcome; Triazoles

To assess the effects of filgotinib on inflammatory and structural changes at various spinal locations, based on MRI measures in patients with active AS in the TORTUGA trial.. In the TORTUGA trial, patients with AS received filgotinib 200 mg (n = 58) or placebo (n = 58) once daily for 12 weeks. In this post hoc analysis, spine MRIs were evaluated using the Canada-Denmark (CANDEN) MRI scoring system to assess changes from baseline to week 12 in total spine and subscores for inflammation, fat, erosion and new bone formation (NBF) at various anatomical locations. Correlations were assessed between CANDEN inflammation and clinical outcomes and Spondyloarthritis Research Consortium of Canada (SPARCC) MRI scores and between baseline CANDEN NBF and baseline BASFI and BASMI scores.. MRIs from 47 filgotinib- and 41 placebo-treated patients were evaluated. There were significantly larger reductions with filgotinib vs placebo in total spine inflammation score and most inflammation subscores, including posterolateral elements (costovertebral joints, transverse/spinous processes, soft tissues), facet joints and vertebral bodies. No significant differences were observed for corner or non-corner vertebral body inflammation subscores, spine fat lesion, bone erosion or NBF scores. In the filgotinib group, the change from baseline in the total inflammation score correlated positively with the SPARCC spine score. Baseline NBF scores correlated with baseline BASMI but not BASFI scores.. Compared with placebo, filgotinib treatment was associated with significant reductions in MRI measures of spinal inflammation, including in vertebral bodies, facet joints and posterolateral elements.. ClinicalTrials.gov (https://clinicaltrials.gov), NCT03117270.

Topics: Humans; Inflammation; Magnetic Resonance Imaging; Pyridines; Severity of Illness Index; Spine; Spondylarthritis; Spondylitis, Ankylosing; Triazoles; Vertebral Body; Zygapophyseal Joint

Topics: Humans; Immune System Diseases; Janus Kinase 1; Protein Kinase Inhibitors; Pyridines; Spondylitis, Ankylosing; Triazoles

Topics: Humans; Janus Kinase 1; Protein Kinase Inhibitors; Pyridines; Spondylitis, Ankylosing; Triazoles