glpg0634 and Crohn-Disease

For a significant proportion of patients with inflammatory bowel disease (IBD), primary non-response and secondary loss of response to treatment remain significant issues. Anti-tumor necrosis factor therapies have been licensed for use in IBD. Other disease-related pathways have been targeted as well, including the interleukin 12/23 axis and lymphocyte tracking. However, the need for parenteral administration and the associated costs of dispensing and monitoring all biologics remain a burden on healthcare systems and patients. Janus kinase inhibitors are small-molecule drugs that can be administered orally and are relatively inexpensive, thus offering an additional option for treating IBD. They have been shown to be effective in patients with ulcerative colitis (UC), but they are less effective in those with Crohn's disease (CD). Nonetheless, given the immune-system-based mechanism of these drugs, their safety profile remains a cause for concern. This article provides an overview of Janus kinase (JAK) inhibitors and new trends in the treatment of IBD.

Topics: Adamantane; Colitis; Colitis, Ulcerative; Crohn Disease; Heterocyclic Compounds, 3-Ring; Humans; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Janus Kinases; Niacinamide; Piperidines; Pyridines; Pyrimidines; Pyrroles; Triazoles

Inhibition of Janus kinases [JAKs] in Crohn's disease [CD] patients has shown conflicting results in clinical trials. Tofacitinib, a pan-JAK inhibitor, showed efficacy in ulcerative colitis [UC] and has been approved for the treatment of patients with moderate to severe UC. In contrast, studies in CD patients were disappointing and the primary end point of clinical remission could not be met in the respective phase II induction and maintenance trials. Subsequently, the clinical development of tofacitinib was discontinued in CD. In contrast, efficacy of filgotinib, a selective JAK1 inhibitor, in CD patients was demonstrated in the randomized, double-blinded, placebo-controlled phase II FITZROY study. Upadacitinib also showed promising results in a phase II trial in moderate to severe CD. Subsequently, phase III programmes in CD have been initiated for both substances, which are still ongoing. Several newer molecules of this class of orally administrated immunosuppressants are being tested in clinical programmes. The concern of side effects of systemic JAK inhibition is addressed by either exclusively intestinal action or higher selectivity [Tyk2 inhibitors]. In general, JAK inhibitors constitute a new promising class of drugs for the treatment of CD.

Topics: Crohn Disease; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinase Inhibitors; Piperidines; Pyridines; Pyrimidines; Treatment Failure; Treatment Outcome; Triazoles

Janus kinases inhibitors (JAKi) are new small molecules recently introduced in the armamentarium of treatments for Inflammatory Bowel Disease (IBD). Janus Kinases (JAK) are tyrosine kinases that act by linkage with different intracellular receptors, regulating cytokines gene transcription implicated in the inflammatory burden seen in IBD patients.. A comprehensive literature search was performed to retrieve studies on JAKi and IBD to discuss the latest developments and how the selectivity of these drugs is changing the natural course of IBD.. Available data on efficacy and safety of JAKi in IBD are highly encouraging and because of their selectivity, these drugs might become among the foremost options in the treatment algorithm.

Topics: Colitis, Ulcerative; Crohn Disease; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinase 1; Janus Kinase 2; Janus Kinase 3; Janus Kinase Inhibitors; Naphthyridines; Nitriles; Piperidines; Pyridines; Pyrimidines; Signal Transduction; Triazoles; TYK2 Kinase

Inflammatory bowel diseases (IBDs) are immune-mediated chronic inflammatory disorders of the gastrointestinal tract whose pathogenesis is not yet fully understood. Despite the advent of biological agents, there are still unmet needs for IBD patients, due to suboptimal rate of sustained remission achieved. Small molecule drugs (SMDs), the next generation of selective drugs in IBD, show promising results in ongoing trials.. We describe the pharmacodynamics and pharmacokinetic features of novel SMDs and their main differences with biologic agents.. Small molecule drugs are a promising class of drugs for the treatment of ulcerative colitis and Crohn's disease with good results in inducing and maintaining remission. Hence, over the next few years physicians will have numerous options of small molecule drugs for the treatment of patients with IBD. This group of drugs are potentially easier to use over biological agents due to pharmacokinetic features such as oral administration, short half-life, high volume of distribution, and lack of immunogenicity. On the other hand, drug-drug interactions can happen with small-molecule drugs, principally due to competitive metabolic and clearance mechanisms.

Topics: Acetates; Animals; Clinical Trials as Topic; Colitis, Ulcerative; Crohn Disease; Heterocyclic Compounds, 3-Ring; Humans; Indans; Indoles; Janus Kinase Inhibitors; Oxadiazoles; Piperidines; Pyridines; Pyrimidines; Quinolones; Sphingosine-1-Phosphate Receptors; Triazoles

Inflammatory bowel diseases, such as Crohn's disease (CD) and ulcerative colitis (UC), are widespread diseases (with an estimated 2.2 million Europeans affected), and even populations previously considered 'low risk' (such as Japan and India) are witnessing an increasing incidence. CD is a chronic, progressive immunologically driven disease, with an evolution characterized by succession of periods of progression and remission. New physiopathological pathways are continuously being discovered, the more we understand about how the disease appears and progresses, the more targets become available for the development of novel therapies. Areas covered: Filgotinib is one of these promising new therapies; this article discusses the currently available data. We used an exhaustive search of the PubMed database to corroborate information regarding its chemical characteristics, and the studies evaluating clinical efficacy and safety. Expert opinion: Up to now, the phase-II study evaluating Filgotinib yielded very promising results in moderate to severe CD patients, with good clinical response, mucosal healing, while having few and moderate adverse effects, both in anti-TNF naïve and resistant patients. Phase-III studies are still ongoing and will help decide whether Filgotinib will be a worthwhile drug in the treatment of CD and the best way to use it.

Topics: Crohn Disease; Disease Progression; Gastrointestinal Agents; Humans; Janus Kinase Inhibitors; Pyridines; Severity of Illness Index; Triazoles; Tumor Necrosis Factor-alpha

There is an ongoing, unmet need for effective therapies for Crohn's disease. Treatments for Crohn's disease continue to evolve from the traditional biologics to novel small molecules, with targeted mechanisms directed toward pathways that are dysregulated in Crohn's disease. There are multiple emerging mechanisms of action, including Janus kinase inhibition, Smad7 inhibition, and sphingosine-1-phosphate receptor modulators, that are administered as oral medications, and small molecules represent the next generation of therapies for Crohn's disease.

Topics: B-Lymphocytes; Colitis, Ulcerative; Crohn Disease; Humans; Indans; Janus Kinase 1; Janus Kinase Inhibitors; Oligonucleotides; Oxadiazoles; Piperidines; Pyridines; Pyrimidines; Pyrroles; Receptors, Lysosphingolipid; Smad7 Protein; T-Lymphocytes; Triazoles

The validity and relevance of histologic disease activity in Crohn's disease (CD) is unclear, owing to disconnects with endoscopic pathology. Here, we explore relationships between endoscopic, histologic, and molecular activity. This post hoc analysis of the Phase 2 FITZROY trial (NCT02048618) assessed baseline and week 10 (W10) inflammation across matched ileal and colonic segments in CD patients receiving filgotinib 200 mg (n = 42) vs placebo (n = 18). Macroscopic and microscopic disease were assessed by Simple Endoscopic Score for CD ulceration subscore (uSES-CD) and Global Histologic Activity Score activity subscore (aGHAS), respectively. Molecular activity was quantified by phosphorylated signal transducer and activator of transcription (pSTAT)1 and pSTAT3 in epithelium and nonepithelium. Segments were classified as "low" or "high" activity; correlations and concordance were calculated. Logistic regression identified W10 outcome predictors. Overall, 300 segments in 60 patients were assessed. Baseline uSES-CD and aGHAS correlations were 0.72 and 0.53 in colon and ileum, respectively. pSTAT levels had poor-to-moderate concordance with uSES-CD (κ range, 0.11-0.49) but moderate-to-good concordance with aGHAS (0.43-0.77). With filgotinib vs placebo, uSES-CD and aGHAS decreased in significantly more segments with high baseline uSES-CD and aGHAS, and significantly more segments with high baseline pSTAT improved at W10. pSTAT1 was more sensitive to change than uSES-CD and aGHAS. Low baseline pSTAT3 in colon nonepithelium predicted W10 low uSES-CD (

Topics: Crohn Disease; Endoscopy, Gastrointestinal; Humans; Intestinal Mucosa; Pyridines; STAT1 Transcription Factor

Filgotinib (GLPG0634, GS-6034) is a once-daily, orally administered, Janus kinase 1 (JAK1)-selective inhibitor. The FITZROY study examined the efficacy and safety of filgotinib for the treatment of moderate-to-severe Crohn's disease.. We did a randomised, double-blind, placebo-controlled phase 2 study, which recruited patients from 52 centres in nine European countries. We enrolled eligible patients aged 18-75 years with a documented history of ileal, colonic, or ileocolonic Crohn's disease for 3 months or more before screening, as assessed by colonoscopy and supported by histology, and a Crohn's Disease Activity Index (CDAI) score during screening between 220 and 450 inclusive. Patients were randomly assigned (3:1) to receive filgotinib 200 mg once a day or placebo for 10 weeks. Patients were stratified according to previous anti-tumour necrosis factor alpha exposure, C-reactive protein concentration at screening (≤10 mg/L or >10 mg/L), and oral corticosteroid use at baseline, using an interactive web-based response system. The primary endpoint was clinical remission, defined as CDAI less than 150 at week 10. After week 10, patients were assigned based on responder status to filgotinib 100 mg once a day, filgotinib 200 mg once a day, or placebo for an observational period lasting a further 10 weeks. The filgotinib and placebo treatment groups were compared using ANCOVA models and logistic regression models containing baseline values and randomisation stratification factors as fixed effects. Analyses were done on the intention-to-treat non-responder imputation set. The trial was registered at ClinicalTrials.gov, number NCT02048618.. Between Feb 3, 2014, and July 10, 2015, we enrolled 174 patients with active Crohn's disease confirmed by centrally read endoscopy (130 in the filgotinib 200 mg group and 44 in the placebo group). In the intention-to-treat population, 60 (47%) of 128 patients treated with filgotinib 200 mg achieved clinical remission at week 10 versus ten (23%) of 44 patients treated with placebo (difference 24 percentage points [95% CI 9-39], p=0·0077). In a pooled analysis of all periods of filgotinib and placebo exposure over 20 weeks, serious treatment-emergent adverse effects were reported in 14 (9%) of 152 patients treated with filgotinib and three (4%) of 67 patients treated with placebo.. Filgotinib induced clinical remission in significantly more patients with active Crohn's disease compared with placebo, and had an acceptable safety profile.. Galapagos.

Topics: Administration, Oral; Adolescent; Adult; Aged; Analysis of Variance; Crohn Disease; Double-Blind Method; Drug Administration Schedule; Female; Humans; Janus Kinase Inhibitors; Male; Middle Aged; Pyridines; Treatment Outcome; Triazoles; Young Adult

Topics: Crohn Disease; Humans; Intestinal Diseases; Pyridines; Triazoles

Pro-inflammatory cytokines are dysregulated in Crohn's disease (CD) and could serve as surrogate markers to improve diagnostic and therapeutic approaches, potentially addressing an unmet need. We profiled circulating biomarkers and whole blood transcriptional pathway activity to identify those associated with CD using data from the phase 2 FITZROY study with filgotinib, an oral preferential janus kinase-1 inhibitor.. Patients with serum and whole blood samples taken from the induction period were included. Serum cytokines were measured (ELISA), whole blood RNA sequenced, and stool samples taken to measure fecal calprotectin (FC). Spearman's Rank correlations were assessed between biomarkers and baseline disease activity; post-treatment endoscopic improvement was measured by the Simplified Endoscopy Score for CD (SES-CD), FC and the Crohn's Disease Activity Index. Effect of filgotinib on circulating biomarkers was also evaluated.. Serum biomarkers (n = 168) and whole blood RNA sequencing (n = 104) were assessed. Moderate correlation between serum analytes with SES-CD and FC was noted; most highly correlated were acute phase proteins CRP (rho = 0.35 [SES-CD] and 0.47 [FC]), serum amyloid A (rho = 0.40 and 0.39, respectively) and pro-inflammatory cytokines interleukin (IL)-6 (rho = 0.31 and 0.30, respectively), IL-22 (rho = 0.36 and 0.35, respectively), and oncostatin M (rho = 0.35 and 0.33, respectively). Filgotinib treatment was associated with reduction of many candidate biomarkers, particularly in patients with treatment response. Early changes in IL-6 and IL-10 may be prognostic for endoscopic response.. Several circulating factors with potential as CD activity biomarkers were identified. Larger studies are necessary to investigate the best utility of these markers for CD.

Topics: Biomarkers; C-Reactive Protein; Crohn Disease; Cytokines; Feces; Humans; Interleukin-6; Janus Kinase 1; Janus Kinase Inhibitors; Leukocyte L1 Antigen Complex; Pyridines; Severity of Illness Index; Triazoles

Topics: Administration, Oral; Adult; Antibodies, Monoclonal, Humanized; Biosimilar Pharmaceuticals; Combined Modality Therapy; Crohn Disease; Digestive System Surgical Procedures; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Male; Pregnancy; Pregnancy, High-Risk; Pyridines; Randomized Controlled Trials as Topic; Recurrence; Severity of Illness Index; Triazoles; Ustekinumab; Young Adult

Topics: Crohn Disease; Humans; Pyridines; Triazoles

Janus kinases (JAK1, JAK2, JAK3, and TYK2) are involved in the signaling of multiple cytokines important in cellular function. Blockade of the JAK-STAT pathway with a small molecule has been shown to provide therapeutic immunomodulation. Having identified JAK1 as a possible new target for arthritis at Galapagos, the compound library was screened against JAK1, resulting in the identification of a triazolopyridine-based series of inhibitors represented by 3. Optimization within this chemical series led to identification of GLPG0634 (65, filgotinib), a selective JAK1 inhibitor currently in phase 2B development for RA and phase 2A development for Crohn's disease (CD).

Topics: Adenosine Triphosphate; Animals; Arthritis; Chemistry, Pharmaceutical; Collagen; Crohn Disease; Crystallography, X-Ray; Cytokines; Dimerization; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Humans; Inhibitory Concentration 50; Janus Kinase 1; Kinetics; Phosphorylation; Protein Kinase Inhibitors; Pyridines; Rats; Recombinant Proteins; Structure-Activity Relationship; Triazoles