glpg0634 and Arthritis--Rheumatoid

Rheumatoid Arthritis (RA) remains a challenge for rheumatologists and patients despite implementation of intensive treat-to-target strategies in shared decision with patients and an increasing availability of drugs. Janus kinase inhibitors (JAKi) are a new generation of oral targeted drugs. Filgotinib preferentially inhibits JAK1 and is the latest JAKi to be approved for use in RA.. This narrative review focuses on drug characteristics, efficacy, and safety of filgotinib in patients with RA, summarizing available literature. Trial data are detailed, put into perspective for practice and discussed in regulatory perspective.. Preclinical studies demonstrate preferential inhibition of JAK1 and a promising pharmacokinetic profile with few drug-drug interactions. Increase in hemoglobin in line with preferential inhibition of JAK1 over JAK2 is seen in early-phase clinical trials. A phase III program demonstrates efficacy in several disease stages, numerically higher with 200 mg versus 100 mg daily. In the overall RA population such dose-related effect is not observed for safety except for herpes zoster and increases in lipids and creatine phosphokinase. This reassuring safety profile is to be confirmed in future practice. It also needs to be unraveled if JAK1 preferential inhibition plays a key role in this safety profile.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Janus Kinase Inhibitors; Pyridines; Triazoles

The relative efficacy of Janus kinase (JAK) inhibitors in producing remission and low disease activity (LDA) states remains unknown since there are currently no trials that provide direct comparisons among JAK inhibitors in disease-modifying antirheumatic drug (DMARD)-naive patients with rheumatoid arthritis (RA).. This study aimed to assess the relative remission and LDA rates of tofacitinib, baricitinib, upadacitinib, and filgotinib compared to those of methotrexate (MTX) in DMARD-naive patients with RA.. We conducted Bayesian network meta-analysis and included information from direct and indirect comparisons from randomized controlled trials that examined remission (Disease Activity Score in 28 Joints using C-reactive protein level [DAS28-CRP] <2.6) and LDA (DAS28-CRP ≤ 3.2) produced by tofacitinib, baricitinib, upadacitinib, filgotinib monotherapy, and MTX in patients with DMARD-naive RA.. Four randomized controlled trials, comprising 2,185 patients, met the inclusion criteria. This network meta-analysis showed that treatment with tofacitinib, baricitinib, upadacitinib, and filgotinib achieved a significantly higher remission rate than that with MTX (odds ratio [OR] = 4.13, 95% CI = 2.88-6.02; OR = 2.12, 95% CI = 1.17-4.13; OR = 1.95, 95% CI = 1.10-3.50; OR = 1.79, 95% CI = 1.27-3.53). The ranking probability based on the surface under the cumulative ranking curve indicated that upadacitinib 15 mg had the highest probability of achieving remission (SUCRA = 0.985), followed by tofacitinib 5 mg (SUCRA = 0.574), baricitinib 4 mg (SUCRA = 0.506), filgotinib 200 mg (SUCRA = 0.431), and MTX (SUCRA = 0.004). Moreover, treatment with tofacitinib, baricitinib, upadacitinib, and filgotinib achieved significantly higher LDA rate than that with MTX. The ranking probability for LDA was similar to that for remission; upadacitinib 15 mg had the highest probability of achieving LDA, followed by tofacitinib 5 mg, baricitinib 4 mg, filgotinib 200 mg, and MTX.. Upadacitinib seems to be one of most effective interventions for achieving remission and LDA in DMARD-naive patients with RA based on the comparative analysis, and there are differences in remission and LDA rates induced by different JAK inhibitors.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Bayes Theorem; Drug Therapy, Combination; Humans; Janus Kinase Inhibitors; Methotrexate; Treatment Outcome

Filgotinib (GS-6034, formerly GLPG0634; Jyseleca

Topics: Arthritis, Rheumatoid; Humans; Janus Kinase Inhibitors; Pharmacology, Clinical; Pyridines; Triazoles

Filgotinib has been approved for the treatment of rheumatoid arthritis (RA) in adults who respond inadequately to disease-modifying antirheumatic drugs (DMARDs) in Europe and Japan. Several randomized controlled trials (RCTs) have investigated its efficacy and safety in adult patients with RA. This meta-analysis aimed to study the efficacy and safety of filgotinib in patients with RA withan inadequate response to methotrexateor other DMARDs.. A systematic literature search was conducted to identify articles in PubMed, MEDLINE, EMBASE, and Cochrane Library from inceptionto December 1, 2021. Outcomes of interest included ACR20/50/70 responses, DAS28-CRP ≤ 3.2, SF-36 PCS Score, FACIT-fatigue, SDAI,CDAI, and HAQ-DI, which were assessed after treatment. The safety outcomes included treatment-emergent adverse events (TEAEs) and serious TEAEs. Odds ratios (ORs) with 95% confidence intervals (CI) were pooled for categorical variables, and the mean difference with 95%CI were pooled for continuous variables. We used Review Manager 5.3 for the standard meta-analysis. This study followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).. Four RCTs comparing filgotinib (200 and 100 mg once daily) with placebo were identified. Compared with placebo, 200 and 100 mg filgotinib was more effective in achieving ACR20/50/70 responses and other outcomes at weeks 12 and 24 (P < 0.05), with no significant difference in safety outcomes (P > 0.05). Filgotinib 200 mg performed better than filgotinib 100 mg in terms of ACR20/50 responses, DAS28-CRP ≤ 3.2, SDAI, and CDAI at weeks 12 and 24, and caused fewer serious TEAEs than the 100 mg dose.. Filgotinib is effective in the treatment of RA, and the 200 mg dose has a more beneficialprofile thanthe 100 mg dose.

Topics: Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Randomized Controlled Trials as Topic

In the treatment of rheumatoid arthritis (RA), Janus kinase inhibitors (jakinibs) represent an emerging class of targeted therapies in addition to biologics. The number of jakinibs has been growing and as of 2020, filgotinib was the latest jakinib to enter the international market for treating RA. Filgotinib has demonstrated preferential inhibition of JAK1-dependent cytokine signaling in in vitro assays. It has been evaluated in the DARWIN (phase 2) and FINCH (phase 3) series of clinical studies for treating patients with moderately-to-severely active RA. Filgotinib received regulatory approval in Japan and Europe in September 2020, while in August 2020 the United States Food and Drug Administration requested additional data from two ongoing clinical studies assessing the potential impact of filgotinib on sperm parameters. This article will review the pharmacological properties, efficacy, and safety of filgotinib as demonstrated in clinical studies. Expert opinion will be provided on jakinibs for RA treatment from the viewpoints of basic research and clinical practice.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Janus Kinase 1; Janus Kinase Inhibitors; Pyridines; Triazoles

The relative efficacy and tolerability of tofacitinib, baricitinib, upadacitinib, and filgotinib were assessed in patients with rheumatoid arthritis (RA) with inadequate responses to biologic disease-modifying antirheumatic drugs (bDMARDs).. 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, and filgotinib in RA patients with inadequate responses to bDMARDs.. Four RCTs comprising 1399 patients met the inclusion criteria. Tofacitinib, baricitinib, upadacitinib, and filgotinib achieved significant American College of Rheumatology 20% (ACR20) responses versus placebo. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that upadacitinib 15 mg had the highest probability of being the best treatment for achieving the ACR20 response rate, followed by filgotinib 200 mg, baricitinib 4 mg, filgotinib 100 mg, tofacitinib 5 mg, and placebo. The ranking in SUCRA based on the ACR50 response rate indicated that baricitinib 4 mg had the highest probability of achieving the ACR50 response rate, followed by filgotinib 200 mg, tofacitinib 5 mg, upadacitinib 15 mg, filgotinib 100 mg, and placebo. Tofacitinib 5 mg showed a significantly higher ACR70 response rate than filgotinib 100 mg and upadacitinib 15 mg. Tofacitinib 5 mg, filgotinib 200 mg, and placebo showed a significantly lower serious adverse event rate than upadacitinib 15 mg.. Tofacitinib, baricitinib, upadacitinib, and filgotinib were effective treatment options for RA patients with an inadequate response to bDMARDs but with different efficacy and safety profiles.. ZIEL: Bei Patienten mit rheumatoider Arthritis (RA) und inadäquater Reaktion auf biologische krankheitsmodizifierende Antirheumatika (bDMARD) wurde die relative Wirksamkeit und Verträglichkeit von Tofacitinib, Baricitinib, Upadacitinib und Filgotinib ermittelt.. Eine Bayes-Netzwerk-Metaanalyse wurde durchgeführt, um direkte und indirekte Evidenz aus randomisierten kontrollierten Studien (RCT) zu kombinieren und so die Wirksamkeit und Sicherheit von Tofacitinib, Baricitinib, Upadacitinib und Filgotinib bei RA-Patienten mit inadäquatem Ansprechen auf bDMARD zu untersuchen.. Die Einschlusskriterien wurden von 4 RCT mit 1399 Patienten erfüllt. Unter Tofacitinib, Baricitinib, Upadacitinib und Filgotinib zeigte sich eine signifikant höhere ACR20-Ansprechrate (gemäß American College of Rheumatology) als unter Placebo. Wie die Rangfolgewahrscheinlichkeit, basierend auf der Oberfläche unter der kumulativen Rangfolgenkurve (SUCRA, „surface under the cumulative ranking curve“), ergab, stellte Upadacitinib 15 mg mit größter Wahrscheinlichkeit die beste Behandlung zur Erzielung der ACR20-Ansprechrate dar, es folgten Filgotinib 200 mg, Baricitinib 4 mg, Filgotinib 100 mg, Tofacitinib 5 mg und Placebo. Die auf der ACR50-Ansprechrate basierende SUCRA-Rangfolge zeigte, dass für Baricitinib 4 mg die höchste Wahrscheinlichkeit bestand, die ACR50-Ansprechrate zu erzielen, es folgten Filgotinib 200 mg, Tofacitinib 5 mg, Upadacitinib 15 mg, Filgotinib 100 mg und Placebo. Tofacitinib 5 mg wies eine signifikant höhere ACR70-Ansprechrate auf als Filgotinib 100 mg und Upadacitinib 15 mg. Für Tofacitinib 5 mg, Filgotinib 200 mg und Placebo zeigte sich eine signifikant niedrigere Rate schwerer unerwünschter Ereignisse als für Upadacitinib 15 mg.. Für RA-Patienten mit inadäquater Reaktion auf bDMARD erwiesen sich Tofacitinib, Baricitinib, Upadacitinib und Filgotinib als wirksame Therapieoptionen, jedoch mit unterschiedlichen Wirksamkeits- und Sicherheitsprofilen.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Biological Products; Heterocyclic Compounds, 3-Ring; Humans; Methotrexate; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Sulfonamides; Treatment Outcome; Triazoles

An assessment of the relative efficacy and tolerability of tofacitinib, baricitinib, upadacitinib, and filgotinib compared to those of methotrexate (MTX) was performed in disease-modifying antirheumatic drug (DMARD)-naive patients with rheumatoid arthritis (RA). We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) so as to examine the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib, and MTX in DMARD-naïve RA patients. Four RCTs comprising 2185 patients met the inclusion criteria. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that upadacitinib 15 mg had the highest probability of achieving the American College of Rheumatology 20% (ACR20) response rate, followed by baricitinib 4 mg, tofacitinib 5 mg, filgotinib 200 mg, and MTX. Tofacitinib, baricitinib, upadacitinib, and filgotinib treatments achieved significantly higher ACR50 and ACR70 responses compared to MTX. Tofacitinib 5 mg had the highest probability of achieving the ACR50 and ACR70 response rates, followed by upadacitinib 15 mg, baricitinib 4 mg, filgotinib 200 mg, and MTX. The safety analysis based on serious adverse events, adverse events (AEs), and withdrawals due to AEs revealed no statistically significant differences between the respective intervention groups. In conclusion, tofacitinib, baricitinib, upadacitinib, and filgotinib were effective treatment options for DMARD-naïve RA patients, suggesting a difference in efficacy and safety among the different JAK inhibitors.. Die relative Wirksamkeit und Verträglichkeit von Tofacitinib, Baricitinib, Upadacitinib und Filgotinib wurde im Vergleich zu Methotrexat (MTX) bei DMARD-naiven („disease-modifying antirheumatic drug“) Patienten mit rheumatoider Arthritis (RA) untersucht. Die Autoren führten eine Netzwerk-Metaanalyse nach Bayes durch, um direkte und indirekte Evidenz aus randomisierten kontrollierten Studien (RCT) zu kombinieren und so die Wirksamkeit und Sicherheit von Tofacitinib, Baricitinib, Upadacitinib, Filgotinib und MTX bei DMARD-naiven RA-Patienten zu ermitteln. Die Einschlusskriterien wurden von 4 RCT mit 2185 Patienten erfüllt. Die Ranking-Wahrscheinlichkeit auf Grundlage der Fläche unter der kumulativen Ranking-Kurve („surface under the cumulative ranking curve“, SUCRA) zeigte, dass unter Upadacitinib 15 mg die höchste Wahrscheinlichkeit zur Erzielung der Responserate gemäß American College of Rheumatology 20 % (ACR20) bestand, dann folgten Baricitinib 4 mg, Tofacitinib 5 mg, Filgotinib 200 mg und MTX. Die Behandlung mit Tofacitinib, Baricitinib, Upadacitinib und Filgotinib führten zu signifikant höheren ACR50- und ACR70-Therapieantworten als MTX. Tofacitinib 5 mg wies die höchste Wahrscheinlichkeit für die Erzielung der ACR50- und ACR70-Responseraten auf, es folgten Upadacitinib 15 mg, Baricitinib 4 mg, Filgotinib 200 mg und MTX. Die Sicherheitsanalyse basierte auf den Parametern schwere unerwünschte Ereignisse, unerwünschte Ereignisse („adverse events“, AE) und Therapieabbruch aufgrund von AE, aber es waren keine statistisch signifikanten Unterschiede zwischen den jeweiligen Interventionsgruppen festzustellen. Als Fazit ist festzuhalten, dass Tofacitinib, Baricitinib, Upadacitinib und Filgotinib wirksame Therapieoptionen bei DMARD-naiven RA-Patienten waren, dabei ergaben sich Hinweise auf Unterschiede zwischen der Wirksamkeit und Sicherheit zwischen den verschiedenen JAK-Inhibitoren.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Bayes Theorem; Drug Therapy, Combination; Heterocyclic Compounds, 3-Ring; Humans; Methotrexate; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Sulfonamides; Treatment Outcome; Triazoles

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

Rheumatoid arthritis (RA) is a chronic autoimmune disease, whose natural course has been deeply modified thanks to the development of new therapeutic approaches. The Janus kinase inhibitors (Jakinibs) represent the newest class of drugs introduced for treating RA. Among these, Filgotinib (FIL) has been developed as Janus kinase1 (JAK1) selective inhibitor, specifically targeting key pro-inflammatory mediators in RA pathogenesis.. This narrative review provides an overview on FIL as new therapeutic approach for RA, with focus on its pharmacological properties, clinical efficacy, and safety profile. The following electronic databases were adopted for the study search: PubMed, Google Scholar, ClinicalTrials.gov and Abstract archive from the American College of Rheumatology and the European Alliance of Associations for Rheumatology.. The phase II and phase III randomized controlled trials (RCTs) performed so far and their long-term extensions showed a comparable clinical efficacy of FIL to biologic treatments, with an acceptable safety profile. Thanks to these data, FIL was approved in Europe and Japan for the treatment of active RA, increasing the spectrum of therapeutic approaches and improving the possibility of a more tailored therapeutic strategy. Real-life data and head-to-head clinical trials will be needed to confirm its efficacy and safety.

Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Janus Kinase 1; Janus Kinase Inhibitors; Pyridines; Randomized Controlled Trials as Topic; Triazoles

Upadacitinib and filgotinib, two JAK1 selective drugs have undergone extensive phase III clinical trials in RA and have demonstrated rapid improvements in disease activity, function and patient reported outcomes. Six global phase III randomized controlled clinical trials (SELECT phase III program) evaluated the efficacy and safety of upadacitinib and four clinical phase III trials (the FINCH program) evaluated the efficacy and safety of filgotinib. This article is a critical review of all these studies with focus on the therapeutic efficacy in RA. The aim is to display the data that could allow the approval of these new drugs for the treatment of RA (upadacitinib has been already approved in most of the markets around the world).

Topics: Arthritis, Rheumatoid; Clinical Trials, Phase III as Topic; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinase 1; Janus Kinase Inhibitors; Pyridines; Treatment Outcome; Triazoles

The first approved Janus kinase (JAK) inhibitors for treatment of RA targeted more than one JAK molecule. Although this brings an advantage of simultaneous blocking of more cytokines involved in RA, it may also carry an increased risk of toxicity. Subsequently, more selective JAK inhibitors were developed with the aim of improving the safety-efficacy profile and to further increase drug maintenance. With this proposal, early phase trials of selective JAK1 inhibitors, namely upadacitinib, filgotinib and itacitinib, were initiated in recent years to identify the efficacy and adverse effects of these agents and to define their potential role in treatment of inflammatory and autoimmune diseases. Early phase (Phase I-II) studies of upadacitinib and filgotinib provided evidence for efficacy and safety of the selective JAK1 inhibitors in refractory populations of RA patients and allowed informed selection of the appropriate dose by balancing the optimal benefit-risk profile for further evaluation in the later successfully performed Phase III trials. Although itacitinib also demonstrated a good efficacy and safety in a Phase II trial in RA patients, it is mainly in development for haematologic and oncologic conditions.

Topics: Acetonitriles; Arthritis, Rheumatoid; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinase 1; Janus Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Triazoles

The uptake of Jak inhibitors in the RA space has been among the most rapid in rheumatology, based on the results of comprehensive clinical trial programmes of five agents. Newer generations of Jak inhibitors, like upadacitinib and filgotinib, target Jak 1 selectively with the aim of maximizing efficacy and to improve safety. This article will review the clinical significance of evidence on: (i) Jak 1 selectivity; (ii) efficacy from the SELECT and FINCH clinical trial programmes including patient intolerant or inadequately responding to MTX (MTX-IR) and other csDMARDs patients who are bDMARD-IR) and those using monotherapy when MTX is not tolerated or contraindicated and those treated when methotrexate naive; and (iii) safety from the clinical trial programmes of these two agents will be discussed.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinase 1; Janus Kinase Inhibitors; Methotrexate; Practice Patterns, Physicians'; Pyridines; Triazoles

As efficacy and safety data emerge, differences between JAK inhibitor subclasses are appearing. JAK1 selective drugs, upadacitinib and filgotinib, have broadly come with the same overarching safety recommendations as other immunosuppressive drugs for RA: caution is needed regarding infection risk; monitoring for laboratory abnormalities, including lipids and muscle enzymes, is indicated. A distinguishing feature of JAK inhibitors is a risk for zoster reactivation. Numerically, overall rates of serious infection are similar among JAK inhibitor classes. There are currently no signals for diverticular perforation. VTE incidence rates were similar across comparator groups for the JAK1 selective agents. These observations are not yet conclusive evidence for different safety profiles between JAK1 selective agents and other JAK inhibitors. Differences in study population, design, and concomitant steroid use are examples of potential confounders. It is too early to draw conclusions on long-term outcomes such as malignancy and cardiovascular risk. Post-marketing pharmacovigilance studies will be essential.

Topics: Arthritis, Rheumatoid; Chemical and Drug Induced Liver Injury; Diverticular Diseases; Herpes Simplex; Herpes Zoster; Heterocyclic Compounds, 3-Ring; Humans; Immunocompromised Host; Infections; Intestinal Perforation; Janus Kinase 1; Janus Kinase Inhibitors; Latent Infection; Opportunistic Infections; Pyridines; Triazoles

Filgotinib (Jyseleca. Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease mainly affecting the small joints of the hands and feet. While there is no cure for RA, biologic disease-modifying antirheumatic drugs (DMARDs), which target the inflammatory cytokines (and their receptors) involved in RA, can achieve low disease activity or disease remission. However, these drugs are not always effective or well tolerated and their administration routes (intravenous or subcutaneous) can be a barrier to use. More recently, oral drugs that act on pathways downstream of cytokine receptors have been developed. These drugs, the Janus kinase (JAK) inhibitors, are targeted synthetic DMARDs. Filgotinib (Jyseleca

Topics: Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Humans; Pyridines; Triazoles

Despite the availability of an extensive armamentarium, rheumatoid arthritis (RA) remains a therapeutic challenge for rheumatologists. Janus kinase inhibitors (JAKi) are an emerging class of targeted therapies. The number of JAKi has been growing and to date, filgotinib is the latest JAKi to be approved for use in RA.. This review focuses on the pharmacodynamics, pharmacokinetics, efficacy and safety of filgotinib in patients with RA.. Filgotinib is an oral targeted synthetic disease-modifying antirheumatic drug (DMARD) that specifically inhibits JAKi. Filgotinib monotherapy, or a combination regimen with conventional synthetic (cs) DMARDs, has demonstrated efficacy in decreasing disease activity, with a well-managed safety profile in patients with early RA naive to DMARDs, and in RA that does not adequately respond to csDMARDs and/or biologic DMARDs. The selective inhibition of JAK1 may confer an improved safety profile, but further study is required as a potential testicular toxicity has been suggested. Filgotinib offers several advantages: oral administration, rapidity of action, efficacy as monotherapy, and demonstrated activity in difficult to treat RA. However, the placement of filgotinib in the therapeutic arsenal for RA may be influenced by the ongoing collection of long-term safety data from JAKi as a class.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Pyridines; Triazoles

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Gilead) of filgotinib (Jyseleca

Topics: Arthritis, Rheumatoid; Cost-Benefit Analysis; Humans; Pyridines; Quality-Adjusted Life Years; Technology; Technology Assessment, Biomedical; Triazoles

We compared the efficacy and safety of tofacitinib and filgotinib in patients with rheumatoid arthritis (RA) showing inadequate response to conventional synthetic (cs) or biologic (b) disease-modifying anti-rheumatic drugs (DMARDs).. 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 and filgotinib in combination with methotrexate (MTX) in patients with RA exhibiting inadequate cs- or bDMARD response.. Nine RCTs consisting of 5466 patients met the inclusion criteria. We obtained 15 pairwise comparisons, including 11 direct comparisons from 6 interventions. Tofacitinib 10 mg + MTX and filgotinib 200 mg + MTX were among the most effective treatments for active RA showing an inadequate cs- or bDMARD response, followed by tofacitinib 5 mg + MTX, filgotinib 100 mg + MTX, and adalimumab + MTX. Ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that tofacitinib 10 mg + MTX and filgotinib 200 mg + MTX showed the highest probability of being the best treatment options in terms of ACR20 response rate (SUCRA = 0.898, 0.782), followed by tofacitinib 5 mg + MTX (SUCRA = 0.602), filgotinib 100 mg + MTX (SUCRA = 0.359), adalimumab + MTX (SUCRA = 0.358), and placebo + MTX (SUCRA = 0.001). No significant differences were observed in the incidence of serious adverse events after treatment with tofacitinib + MTX, filgotinib + MTX, adalimumab + MTX, or placebo + MTX.. In patients with RA exhibiting an inadequate response to cs- or bDMARDs, tofacitinib 10 mg + MTX and filgotinib 200 mg + MTX were the most efficacious interventions and risks of serious adverse events did not differ between tofacitinib and filgotinib groups.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Bayes Theorem; Drug Therapy, Combination; Humans; Methotrexate; Network Meta-Analysis; Piperidines; Pyridines; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Treatment Outcome; 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

We assessed the relative efficacy and safety of once-daily administration of 100 and 200 mg filgotinib (a JAK1-selective inhibitor) in patients with active rheumatoid arthritis (RA).. We conducted a Bayesian network meta-analysis combining the direct and indirect evidence from randomized controlled trials (RCTs) that examined the efficacy and safety of filgotinib in patients with active RA.. Five RCTs involving 3,920 patients met the inclusion criteria. There were 15 pairwise comparisons, including 8 direct comparisons and 7 interventions. The ACR20 response rate was significantly higher in the filgotinib 200 mg + methotrexate (MTX) group than in the placebo or placebo + MTX group (odds ratio (OR): 12.39, 95% credible interval (CrI): 3.36 - 45.98.10; OR: 2.68, 95% CrI: 1.80 - 4.39). Compared to the placebo group, the filgotinib 100 mg, adalimumab 40 mg + MTX, filgotinib 200 mg, and placebo + MTX groups showed a significantly higher ACR20 response rate. The ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated filgotinib 200 mg + MTX was likely to achieve the best ACR20 response rate (SUCRA = 0.902), followed by filgotinib 100 mg + MTX (SUCRA = 0.694), filgotinib 100 mg (SUCRA = 0.675), adalimumab 40 mg + MTX (SUCRA = 0.661), filgotinib 200 mg (SUCRA = 0.305), placebo + MTX (SUCRA = 0.259), and placebo (SUCRA = 0.005). The safety based on the number of serious adverse events (SAEs) did not differ significantly among 6 six interventions.. Filgotinib 100 and 200 mg administration once daily in combination with MTX was the most efficacious intervention for active RA, with no significant risk of SAEs.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Bayes Theorem; Drug Therapy, Combination; Humans; Janus Kinase 1; Methotrexate; Network Meta-Analysis; Pyridines; Randomized Controlled Trials as Topic; Treatment Outcome; Triazoles

Several clinical trials have attempted to evaluate the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy in patients with active rheumatoid arthritis (RA), but their relative efficacy and safety as monotherapy remain unclear due to the lack of data from head-to-head comparison trials. The relative efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy for rheumatoid arthritis (RA) were assessed.. We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) and examine the efficacy and safety of tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy relative to placebo in patients with RA.. Five RCTs comprising 1547 patients met the inclusion criteria. Compared with placebo, tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib as monotherapy showed a significantly higher American College of Rheumatology 20% (ACR20) response rate. Peficitinib 150 mg monotherapy showed the highest ACR20 response rate (odds ratio, 17.24.39; 95% credible interval, 6.57-51.80). The ranking probability based on the surface under the cumulative ranking curve indicated that peficitinib 150 mg had the highest probability of being the best treatment for achieving the ACR20 response rate, followed by peficitinib 100 mg, filgotinib 200 mg, filgotinib 100 mg, tofacitinib 5 mg, upadacitinib 15 mg, baricitinib 4 mg and placebo. However, the number of patients who experienced serious adverse events did not differ significantly between the JAK inhibitors, except for tofacitinib 5 mg, and placebo.. All five JAK inhibitors-tofacitinib, baricitinib, upadacitinib, filgotinib and peficitinib-were efficacious monotherapy interventions for active RA, and differences were noted in their efficacy and safety in monotherapy.

Topics: Adamantane; Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Bayes Theorem; Heterocyclic Compounds, 3-Ring; Humans; Niacinamide; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides; Triazoles

Rheumatoid arthritis is a world leading cause of musculoskeletal disease. With the introduction of biological agents as treatment alternatives the clinical possibilities have grown exponentially. Currently most common Disease-modifying anti-rheumatic drugs (DMARDs) treatment option involves intravenous or subcutaneous injection, and some patients struggle to respond to DMARDs or lose their primary reaction. An oral drug formulation with lowered costs of manufacturing and flexibility for healthcare workers to preferably perform treatment will result in decreased healthcare expenditures and increased medication compliance. The JAK-STAT inhibitors, a new class of small molecules drugs, fulfills these criteria and has recently shown efficacy in rheumatoid arthritis. Here we give a summary of how JAK-STAT inhibitors function and a detailed review of current clinical trials. Convincing clinical results suggest that therapeutic inhibition of the JAK proteins can effectively modulate a complex cytokine-driven inflammation.

Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Clinical Trials as Topic; Cytokines; Humans; Inflammation; Janus Kinase Inhibitors; Janus Kinases; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyridines; Signal Transduction; STAT Transcription Factors; Sulfonamides; Triazoles

Janus kinase inhibition is promising in the treatment of RA, with already two oral drugs marketed. New compounds are under investigation that are more selective for Janus kinase 1 or Janus kinase 3. Phase II results for filgotinib, upadacitinib, peficitinib and decernotinib are reviewed showing almost consistently a fast dose-dependent clinical improvement similar to already approved drugs tofacitinib and baricitinib. I will reflect on the most frequently reported dose-dependent adverse events and laboratory changes. Some are similar for all drugs of this class, some are more specific for a certain drug, but all may influence future treatment effectiveness in daily practice. This implies the need for a critical evaluation of phase III trials, and eventually trials specifically powered for conclusions on the safety profile and registries once these drugs become marketed. These innovative drugs also need head-to-head trials versus biologics or in-class as well as specific strategy studies to determine their optimal future use.

Topics: Adamantane; Arthritis, Rheumatoid; Azetidines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinase 1; Janus Kinase 3; Janus Kinase Inhibitors; Niacinamide; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Sulfonamides; Treatment Outcome; Triazoles; Valine

Biologics were the first targeted therapies for rheumatoid arthritis (RA), having in common high clinical efficacy. Being proteins, they are administered parenterally. The first oral targeted small molecules approved for RA are competitive inhibitors of the Janus kinase (JAK) enzyme family which mediate signalling for a cytokine subset important in RA pathogenesis. Areas covered: Several JAK inhibitors have been developed with differing selectivity for the four JAK enzymes with a view to generating oral, multi-cytokine inhibitors. Here we review the pharmacology and clinical trial data for efficacy and safety of filgotinib, an investigational selective JAK1 inhibitor. We contextualise the contemporary approach to RA management and substantial unmet needs that remain. Expert opinion: The selectivity of filgotinib for JAK1 may have theoretical advantages in terms of limiting toxicity. However, establishing whether this is so before larger numbers of patients are exposed in phase III and beyond in the real word setting, will be difficult. Filgotinib clinical trial data to date has been encouraging with rapid, sustained efficacy with promising safety and tolerability. We are likely to see an expanding choice of approved JAK inhibitors in the clinic but it may not be straightforward to distinguish safety and efficacy differences.

Topics: Administration, Oral; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Design; Humans; Janus Kinase 1; Molecular Targeted Therapy; Protein Kinase Inhibitors; Pyridines; Triazoles

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by synovial inflammation and joint destruction. Considerable advance in the treatment of RA has been made following the advent of biological disease-modifying anti-rheumatic drugs (DMARDs). However, these biologics require intravenous or subcutaneous injection and some patients fail to respond to biological DMARDs or lose their primary response. Various cytokines and cell surface molecules bind to receptors on the cell surface, resulting in the activation of various cell signaling pathways, including phosphorylation of kinase proteins. Among these kinases, the non-receptor tyrosine kinase family Janus kinase (JAK) plays a pivotal role in the pathological processes of RA. Several JAK inhibitors have been developed as new therapies for patients with RA. These are oral synthetic DMARDs that inhibit JAK1, 2, and 3. One JAK inhibitor, tofacitinib, has already been approved in many countries. Results of phase III clinical trials using a JAK1/2 inhibitor, baricitinib, have shown feasible efficacy and tolerable safety. Both drugs are effective in patients who showed inadequate response to biological DMARDs as well as synthetic DMARDs. In addition, clinical phase III trials using filgotinib and ABT-494, specific JAK1 inhibitors, are currently underway. JAK inhibitors are novel therapies for RA, but further studies are needed to determine their risk-benefit ratio and selection of the most appropriate patients for such therapy.

Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinases; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Sulfonamides; Triazoles

The constitutional isomers and tautomers of oxadiazolones, as well as their mono- and disulfur analogues, were calculated at the B3LYP/aug-cc-pVDZ level. Four groups of 30 molecules each were considered: oxadiazolone, oxadiazolthione, thiadiazolone, and thiadiazolthione isomers. The compounds were categorized into six groups according to permutations of three heteroatoms in the five-membered ring. Additionally, each of the constitutional isomer was considered to have five tautomers conserving stable five-membered ring: two NH tautomers, two rotameric OH (or SH) forms and one CH. La trombocitosis es un hallazgo casual frecuente en pediatría. En niños, predominan las formas secundarias, siendo las infecciones su causa más prevalente. Se distinguen 4 grados de trombocitosis en función del número de plaquetas; en la forma extrema, se supera el 1.000.000/mm. Endoscopic thrombin injection was similar to glue injection in achieving successful hemostasis of AGVH. However, a higher incidence of complications may be associated with glue injection.

Topics: Acetaminophen; Administration, Oral; Adolescent; Adsorption; Adult; Allyl Compounds; Amylopectin; Amylose; Anaerobiosis; Animals; Anti-Bacterial Agents; Anura; Arginase; Arthritis, Rheumatoid; Asthma; Atmosphere; B-Lymphocytes; Basic Helix-Loop-Helix Transcription Factors; Bioelectric Energy Sources; Biofilms; Biofuels; Biomarkers; Biopolymers; Bioreactors; Brain; Brain Injuries, Traumatic; Breast Neoplasms; Calibration; Carbon Tetrachloride; Caspase 3; Catalysis; Catechin; Cations; Cattle; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Body; Cell Line, Tumor; Cell Plasticity; Chemical and Drug Induced Liver Injury; Chemistry Techniques, Synthetic; China; Chitosan; Chloride Channels; Chromatography, High Pressure Liquid; Chromosome Mapping; Cognition; Cognitive Dysfunction; Cohort Studies; Colitis, Ulcerative; Colloids; Coloring Agents; Congresses as Topic; Correlation of Data; Crystallization; Cyanoacrylates; Cyclohexane Monoterpenes; Cyprinidae; Cytochrome P-450 CYP1A1; Death, Sudden; Dent Disease; Dietary Supplements; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Disease Progression; Disease Resistance; Disulfides; Drug Monitoring; Drug Stability; Ecotoxicology; Electricity; Electrodes; Endocytosis; Environmental Exposure; Environmental Monitoring; Enzyme Inhibitors; Epithelial-Mesenchymal Transition; Esophageal and Gastric Varices; Esters; Fagopyrum; Female; Ferrosoferric Oxide; Flame Retardants; Flavobacteriaceae; Flow Cytometry; Follow-Up Studies; Formoterol Fumarate; Fusarium; Garlic; Gastrointestinal Hemorrhage; Gene Expression; Genes, Plant; Genetic Markers; Glial Fibrillary Acidic Protein; Gliosis; Global Health; Glutathione Transferase; Glycine max; Gum Arabic; Hemostasis, Endoscopic; Hepatocytes; Hippocampus; Humans; Hydrogen-Ion Concentration; Illinois; Immunoglobulin G; Indoleamine-Pyrrole 2,3,-Dioxygenase; Infant, Newborn; Infant, Small for Gestational Age; Injections, Intraperitoneal; Interleukin-4; Iowa; Iron; Ki-67 Antigen; Kidney; Kinetics; Kynurenine; Lakes; Levofloxacin; Lipid Peroxidation; Lipids; Liver; Liver Cirrhosis, Experimental; Magnetic Fields; Magnetic Iron Oxide Nanoparticles; Male; Manure; Maze Learning; Memory, Short-Term; Metal Nanoparticles; Metals, Heavy; Methane; Mice; Mice, Inbred C57BL; Mice, Knockout; Michigan; Microalgae; Microbial Consortia; Mitochondria; Models, Animal; Models, Chemical; Models, Neurological; Molecular Structure; Molecular Weight; Mutation; Myeloid-Derived Suppressor Cells; NADPH Oxidase 2; Neoplasm Recurrence, Local; Neurites; Neurons; Neuroprotective Agents; NF-kappa B; NIH 3T3 Cells; Nitric Oxide Synthase Type II; Nitrogen; Ohio; Ointments; Ontario; Organelle Biogenesis; Organophosphates; Organophosphorus Compounds; Oxidative Stress; Palladium; Particle Size; Pectins; Phenotype; Phytotherapy; Piperidines; Placenta; Plant Diseases; Plant Extracts; Polymers; Polymorphism, Genetic; Polyphenols; Powders; Pregnancy; Pregnancy Trimester, First; Prospective Studies; Protein Kinase Inhibitors; Protein Structure, Secondary; Proteins; Pyridines; Pyrimidines; Rats, Wistar; Real-Time Polymerase Chain Reaction; Receptors, Aryl Hydrocarbon; Receptors, Chemokine; Receptors, Formyl Peptide; Receptors, Lipoxin; Recovery of Function; Recurrence; Reference Standards; Reference Values; Reproducibility of Results; Respiratory Function Tests; Retrospective Studies; Risk; Sensitivity and Specificity; Sewage; Signal Transduction; Sodium Glutamate; Soil; Solanum tuberosum; Solubility; Solutions; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spermatozoa; STAT3 Transcription Factor; Sulfamethoxazole; Tea; Temperature; Thermodynamics; Thrombin; Treatment Outcome; Triazoles; United States; Viscosity; Waste Disposal, Fluid; Wastewater; Water; Water Pollutants, Chemical; Water Purification; White Matter; Wisconsin; X-Ray Diffraction; Zea mays

To present safety and efficacy of the JAK1 preferential inhibitor filgotinib in Japanese patients with prior inadequate response (IR) to methotrexate (MTX) from a 52-week randomised controlled parent study (PS) and long-term extension (LTE) through June 2020.. The PS (NCT02889796) randomised MTX-IR patients to filgotinib 200 (FIL200) or 100 mg (FIL100), adalimumab (ADA) 40 mg, or placebo; all took stable background MTX. At week (W) 24, placebo patients were rerandomised to FIL200 or FIL100. The primary endpoint was W12 American College of Rheumatology 20% improvement; safety was assessed by adverse event (AE) reporting. For the LTE (NCT03025308), eligible filgotinib patients continued FIL200/FIL100; ADA patients were rerandomised (blinded) to FIL200 or FIL100; all continued MTX.. In all, 114/147 Japanese patients completed the PS, 115 enrolled in LTE, and 103 remained on study in June 2020. In the PS, AEs were consistent with the overall population, and W24 efficacy was maintained or improved through W52, comparable with the overall population. LTE AE incidences were similar between doses; filgotinib efficacy was consistent from baseline to W48 and similar between PS ADA and filgotinib patients.. Among MTX-IR Japanese patients, filgotinib maintained efficacy over 1 year; LTE safety was consistent with the PS.

Topics: Adalimumab; Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Double-Blind Method; Drug Therapy, Combination; East Asian People; Humans; Janus Kinase 1; Janus Kinase Inhibitors; Methotrexate; Treatment Outcome

To evaluate the long-term safety and efficacy of filgotinib (FIL) for Japanese patients with rheumatoid arthritis (RA) and limited/no prior methotrexate (MTX) exposure. We present a Japanese population subanalysis of a global randomised-controlled trial at Week 52 and interim long-term extension (LTE) to Week 48 through June 2020.. Patients were randomised to FIL 200 mg plus MTX, FIL 100 mg plus MTX, FIL 200 mg, or MTX for 52 weeks. At completion, eligible patients could enrol in the LTE. Those receiving FIL continued; those receiving MTX were rerandomised (blinded) to FIL 200 or 100 mg upon discontinuation of MTX. After a 4-week washout period, MTX could be re-added.. Adverse event rates at Week 52 and in the LTE to Week 48 were comparable across treatment groups. Week 52 American College of Rheumatology 20% improvement (ACR20) rates were 83% (19/23), 82% (9/11), 75% (9/12), and 76% (19/25) for FIL 200 mg plus MTX, FIL 100 mg plus MTX, FIL 200 mg, and MTX, respectively. Through LTE Week 48, ACR20 rates were maintained.. In the 56 Japanese patients treated with FIL, efficacy was maintained through Week 52 and beyond, with no increases in the incidence of adverse events.

Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Double-Blind Method; Drug Therapy, Combination; East Asian People; Humans; Methotrexate; Treatment Outcome

Administration of Janus kinase (JAK) inhibitors and biological disease-modifying antirheumatic drugs has dramatically improved even the clinical outcomes in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX). Dysregulation of JAK-STAT pathways via overproduction of cytokines, such as interleukin-6, is involved in the pathogenesis of RA. Filgotinib is a selective JAK1 inhibitor pending approval for use in RA. By inhibition of the JAK-STAT pathway, filgotinib is effective in suppressing disease activity and preventing the progression of joint destruction. Similarly, interleukin-6 inhibitors such as tocilizumab also inhibit the JAK-STAT pathways by inhibition of interleukin-6 signaling. We present the protocol for a study that will evaluate whether the effectiveness of filgotinib monotherapy is non-inferior to that of tocilizumab monotherapy in RA patients with an inadequate response to MTX.. This study is an interventional, multicenter, randomized, open-label, parallel-group, and non-inferiority clinical trial with a 52-week follow-up. Study participants will be 400 RA patients with at least moderate disease activity during treatment with MTX. Participants will be randomized in a 1:1 ratio to administer filgotinib monotherapy or subcutaneous tocilizumab monotherapy switched from MTX. We will evaluate disease activity by measuring clinical disease activity indices and by using musculoskeletal ultrasound (MSUS). The primary endpoint is the proportion of patients who achieve an American College of Rheumatology 50 response at week 12. Secondary endpoints are changes from baseline in the MSUS scores. We will also comprehensively analyze serum levels of multiple biomarkers, such as cytokines and chemokines.. The study results are expected to show the non-inferiority of the effectiveness of filgotinib monotherapy to that of tocilizumab monotherapy in RA patients with inadequate response to MTX. The strength of this study is its prospective evaluation of therapeutic efficacy using not only clinical disease activity indices, but also MSUS, which accurately and objectively evaluates disease activity at the joint level among patients drawn from multiple centers with a standardized evaluation by MSUS. We will evaluate the effectiveness of both drugs by integrating multilateral assessments-clinical disease activity indices, MSUS findings, and serum biomarkers.. Japan Registry of Clinical Trials ( https://jrct.niph.go.jp ) jRCTs071200107. Registered on March 3, 2021.. gov NCT05090410. Registered on October 22, 2021.

Topics: Arthritis, Rheumatoid; Cytokines; Equivalence Trials as Topic; Humans; Interleukin-6; Janus Kinases; Methotrexate; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Signal Transduction; STAT Transcription Factors

The phase 2 MANTA and MANTA-RAy studies aimed to determine if the oral Janus kinase 1 preferential inhibitor filgotinib affects semen parameters and sex hormones in men with inflammatory diseases.. MANTA (NCT03201445) and MANTA-RAy (NCT03926195) included men (21-65 years) with active inflammatory bowel disease (IBD) and rheumatic diseases (rheumatoid arthritis, spondyloarthritis or psoriatic arthritis), respectively. Eligible participants had semen parameters in the normal range per the WHO definition. In each study, participants were randomised 1:1 to receive once-daily, double-blind filgotinib 200 mg or placebo for 13 weeks for pooled analysis of the primary endpoint (proportion of participants with a ≥50% decrease from baseline in sperm concentration at week 13). Participants who met the primary endpoint were monitored over an additional 52 weeks for 'reversibility'. Secondary endpoints included change from baseline to week 13 in: sperm concentration, total motility, normal morphology, total count and ejaculate volume. Sex hormones (luteinising hormone, follicle stimulating hormone, inhibin B and total testosterone) and reversibility were exploratory endpoints.. Across both studies, 631 patients were screened, and 248 were randomised to filgotinib 200 mg or placebo. Baseline demographics and characteristics were similar within indications between treatment groups. Numerically similar proportions of filgotinib-treated versus placebo-treated patients met the primary endpoint (8/120 (6.7%) vs 10/120 (8.3%)), Δ-1.7% (95% CI -9.3% to 5.8%)). There were no clinically relevant changes from baseline to week 13 in semen parameters or sex hormones, or patterns of reversibility between treatment groups. Filgotinib was well tolerated, with no new safety events.. Results suggest that once daily filgotinib 200 mg for 13 weeks has no measurable impact on semen parameters or sex hormones in men with active IBD or inflammatory rheumatic diseases.

Topics: Arthritis, Rheumatoid; Double-Blind Method; Gonadal Steroid Hormones; Humans; Inflammatory Bowel Diseases; Janus Kinase Inhibitors; Male; Semen; Treatment Outcome

Evaluate the efficacy and safety of the Janus kinase-1 inhibitor filgotinib in Japanese patients with rheumatoid arthritis (RA) and inadequate response to methotrexate (MTX).. Data from 147 Japanese patients in FINCH 1, a 52-week global Phase 3 study, were analysed up to 24 weeks. Patients received once-daily filgotinib 200 or 100 mg, biweekly adalimumab, or placebo, all with stable background MTX.. In the Japanese population, American College of Rheumatology 20% response rates at Week 12 (primary endpoint) were 77.5%, 65.9%, 53.6%, and 36.8% for filgotinib 200 mg, filgotinib 100 mg, adalimumab, and placebo. Proportions of patients achieving Disease Activity Score with 28 joints <2.6 at Week 24: filgotinib 200 mg, 65.0%; filgotinib 100 mg, 51.2%; adalimumab, 42.9%; and placebo, 5.3%. Incidence rates of serious infections: filgotinib 200 mg, 2.5%; filgotinib 100 mg, 0%; adalimumab, 10.7%; and placebo, 5.3%. Treatment-emergent laboratory abnormalities Grade ≥3 occurred in five (12.5%) filgotinib 200 mg, three (7.3%) filgotinib 100 mg, one (3.6%) adalimumab, and no placebo patients. No deaths were reported among Japanese patients.. Filgotinib once daily combined with MTX was effective and generally safe and well tolerated up to Week 24 in Japanese patients with RA and inadequate response to MTX.

Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Double-Blind Method; Drug Therapy, Combination; Finches; Humans; Japan; Methotrexate; Pyridines; Treatment Outcome; Triazoles

To evaluate the efficacy and safety of filgotinib for Japanese patients with rheumatoid arthritis (RA) and limited or no prior methotrexate (MTX) exposure.. Data up to 24 weeks were analysed for 71 Japanese patients from a 52-week global Phase 3 study. Patients with RA and limited or no prior MTX exposure were randomised in a 2:1:1:2 ratio to filgotinib 200 mg plus MTX, filgotinib 100 mg plus MTX, filgotinib 200 mg, or MTX. Maximum MTX dose was 15 mg/week. Primary endpoint was proportion achieving 20% improvement in American College of Rheumatology criteria (ACR20) at Week 24.. Week 24 ACR20 rates in Japanese patients were 82.6%, 90.9%, 83.3%, and 80.0% for filgotinib 200 mg plus MTX, filgotinib 100 mg plus MTX, filgotinib 200 mg, and MTX, respectively. Greater ACR20 rates with filgotinib vs MTX occurred at Week 2. Greater proportions receiving filgotinib vs MTX achieved DAS28-CRP <2.6 at Weeks 12 and 24. Adverse event rates were comparable across treatments and between the Japanese and overall populations.. While Week 24 ACR20 rates were similar, filgotinib provided faster responses and higher remission rates vs MTX. In Japanese patients with RA and limited or no prior MTX exposure, filgotinib was generally well tolerated.

Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Double-Blind Method; Drug Therapy, Combination; Finches; Humans; Japan; Methotrexate; Pyridines; Treatment Outcome; Triazoles

The effects of filgotinib on patient-reported outcomes (PROs) from 3 trials in patients with active rheumatoid arthritis were investigated.. Methotrexate (MTX)-naïve patients received filgotinib 200 or 100 mg plus MTX (FIL200+MTX, FIL100+MTX), filgotinib 200 mg monotherapy (FIL200), or MTX monotherapy through 52 weeks (NCT02886728). Patients with inadequate response (IR) to MTX (MTX-IR) received FIL200+MTX, FIL100+MTX, adalimumab 40 mg +MTX (ADA+MTX), or placebo (PBO)+MTX (rerandomized to FIL200+MTX or FIL100+MTX at week 24) through 52 weeks (NCT02889796). Patients with IR to biologic disease-modifying antirheumatic drugs (bDMARD-IR) received FIL200 or FIL100 or PBO with background stable conventional synthetic (cs) DMARDs for up to 24 weeks (NCT02873936). PROs included Health Assessment Questionnaire-Disability Index (HAQ-DI), Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) physical/mental component summary (PCS/MCS), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis (WPAI-RA), and Patient Global Assessment of Disease Activity (PtGA). Data are reported as least-squares mean changes from baseline with standard error to the timepoint representing each study's primary endpoint. All statistical comparisons are of filgotinib groups vs their respective control groups.. At week 24, among MTX-naïve patients, change from baseline (standard deviation) in HAQ-DI was - 1.00 (0.03; P < 0.001) with FIL200+MTX, - 0.94 (0.04; P < 0.01) with FIL100+MTX, and - 0.91 (0.04; P < 0.05) with FIL200 alone compared with - 0.81 (0.03) with MTX alone. At week 12, among MTX-IR patients, change from baseline in HAQ-DI was - 0.69 (0.04; P < 0.001 vs PBO+MTX, P < 0.05 vs ADA) with FIL200+MTX, - 0.57 (0.04; P < 0.001 vs placebo) with FIL100+MTX, and - 0.60 (0.04) with ADA vs - 0.40 (0.04) with PBO+MTX. At week 12, among bDMARD-IR patients, change from baseline in HAQ-DI was - 0.50 (0.06; P < 0.001) with FIL200+csDMARD and - 0.46 (0.05; P < 0.001) with FIL100+csDMARD vs - 0.19 (0.06) with placebo+csDMARD. Changes in SF-36 PCS and MCS, FACIT-Fatigue, WPAI, and PtGA tended to favor filgotinib over PBO, MTX, and ADA. Greater proportions of patients experienced clinically meaningful differences with either dosage of FIL in combination with csDMARDs (including MTX) and with FIL200 monotherapy vs comparators.. Filgotinib provided improvements in PROs across patient populations. These findings suggest filgotinib can be an effective treatment option for patients with insufficient response to MTX or bDMARDs and patients who are MTX-naïve.. ClinicalTrials.gov , FINCH 1, NCT02889796 , first posted September 7, 2016; FINCH 2, NCT02873936 , first posted August 22, 2016, retrospectively registered; FINCH 3, NCT02886728 , first posted September 1, 2016, retrospectively registered.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Double-Blind Method; Drug Therapy, Combination; Humans; Methotrexate; Patient Reported Outcome Measures; Pyridines; Quality of Life; Treatment Outcome; Triazoles

Filgotinib is a potent, oral, JAK1-preferential inhibitor for the treatment of rheumatoid arthritis (RA). This report describes exposure-response (ER) analyses of filgotinib for dose confirmation based on three phase 3 and two phase 2 studies in moderate to severe RA patients.. The pharmacokinetic exposures used in ER analyses were derived from population pharmacokinetic analysis. The exposure-efficacy relationships were assessed for efficacy endpoints (ACR20/50/70 and DAS28) over effective area under curve (AUC. ER analyses confirmed that filgotinib produced more robust therapeutic effects across the exposure range observed at 200 mg once daily compared to lower doses, and collectively with the lack of exposure-safety relationship, the 200 mg once daily dose was supported for commercialization.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Janus Kinase Inhibitors; Pyridines; Treatment Outcome; Triazoles

To evaluate efficacy and safety of filgotinib in Japanese RA patients who have failed or were intolerant to one or more biologic disease-modifying antirheumatic drugs (bDMARD) from the global FINCH 2 study (NCT02873936).. This subgroup analysis was performed using the predefined statistical analyses. The FINCH 2 study is a randomized, double-blind, placebo-controlled, Phase 3 study in adult RA patients with inadequate response to bDMARDs. The randomized patients were treated with once-daily filgotinib 200 mg, filgotinib 100 mg or placebo on a background of csDMARDs for 24 weeks.. Of 449 patients enrolled in the overall population, 40 patients were enrolled from Japan. In the Japanese population, the American College of Rheumatology 20% response rates at week 12 (primary endpoint) were 83.3% and 53.3% for filgotinib, 200 mg and 100 mg, respectively, vs 30.8% for placebo. Filgotinib was well tolerated, similar to the overall population.. Both doses of once-daily filgotinib 200 mg and filgotinib 100 mg were effective, and generally well-tolerated in Japanese patients with active refractory RA.

Topics: Adult; Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Double-Blind Method; Drug Therapy, Combination; Finches; Humans; Japan; Methotrexate; Pyridines; Treatment Outcome; Triazoles

To investigate efficacy and safety of the Janus kinase-1 inhibitor filgotinib in patients with active rheumatoid arthritis (RA) with limited or no prior methotrexate (MTX) exposure.. This 52-week, phase 3, multicentre, double-blind clinical trial (NCT02886728) evaluated once-daily oral filgotinib in 1252 patients with RA randomised 2:1:1:2 to filgotinib 200 mg with MTX (FIL200 +MTX), filgotinib 100 mg with MTX (FIL100 +MTX), filgotinib 200 mg monotherapy (FIL200), or MTX. The primary endpoint was proportion achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 24.. The primary endpoint was achieved by 81% of patients receiving FIL200+ MTX versus 71% receiving MTX (p<0.001). A significantly greater proportion treated with FIL100+ MTX compared with MTX achieved an ACR20 response (80%, p=0.017) at week 24. Significant improvement in Health Assessment Questionnaire-Disability Index was seen at week 24; least-squares mean change from baseline was -1.0 and -0.94 with FIL200+MTX and FIL100+MTX, respectively, versus -0.81 with MTX (p<0.001, p=0.008, respectively). Significantly higher proportions receiving FIL200+MTX (54%) and FIL100+MTX (43%) achieved DAS28(CRP) <2.6 versus MTX (29%) (p<0.001 for both) at week 24. Hierarchical testing stopped for comparison of ACR20 for FIL200 monotherapy (78%) versus MTX (71%) at week 24 (p=0.058). Adverse event rates through week 52 were comparable between all treatments.. FIL200+MTX and FIL100+MTX both significantly improved signs and symptoms and physical function in patients with active RA and limited or no prior MTX exposure; FIL200 monotherapy did not have a superior ACR20 response rate versus MTX. Filgotinib was well tolerated, with acceptable safety compared with MTX.

Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Double-Blind Method; Drug Therapy, Combination; Finches; Humans; Methotrexate; Pyridines; Treatment Outcome; Triazoles

To evaluate the efficacy and safety of the Janus kinase-1-preferential inhibitor filgotinib versus placebo or tumour necrosis factor-α inhibitor therapy in patients with active rheumatoid arthritis (RA) despite ongoing treatment with methotrexate (MTX).. This 52-week, multicentre, double-blind, placebo-controlled and active-controlled phase III trial evaluated once-daily oral filgotinib in patients with RA randomised 3:3:2:3 to filgotinib 200 mg (FIL200) or filgotinib 100 mg (FIL100), subcutaneous adalimumab 40 mg biweekly, or placebo (through week 24), all with stable weekly background MTX. The primary endpoint was the proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Additional efficacy outcomes were assessed sequentially. Safety was assessed from adverse events and laboratory abnormalities.. The proportion of patients (n=1755 randomised and treated) achieving ACR20 at week 12 was significantly higher for FIL200 (76.6%) and FIL100 (69.8%) versus placebo (49.9%; treatment difference (95% CI), 26.7% (20.6% to 32.8%) and 19.9% (13.6% to 26.2%), respectively; both p<0.001). Filgotinib was superior to placebo in key secondary endpoints assessing RA signs and symptoms, physical function and structural damage. FIL200 was non-inferior to adalimumab in terms of Disease Activity Score in 28 joints with C reactive protein ≤3.2 at week 12 (p<0.001); FIL100 did not achieve non-inferiority. Adverse events and laboratory abnormalities were comparable among active treatment arms.. Filgotinib improved RA signs and symptoms, improved physical function, inhibited radiographic progression and was well tolerated in patients with RA with inadequate response to MTX. FIL200 was non-inferior to adalimumab.. NCT02889796.

Topics: Adalimumab; Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Male; Methotrexate; Middle Aged; Pyridines; Triazoles

The long-term safety and efficacy of filgotinib (from phase II studies), with or without methotrexate (MTX), for the treatment of patients with rheumatoid arthritis was assessed in DARWIN 3, a long-term, open-label extension study (ClinicalTrials.gov: NCT02065700).. Eligible patients completing the 24-week DARWIN 1 (filgotinib + MTX) and DARWIN 2 (filgotinib monotherapy) studies entered DARWIN 3, where they received filgotinib 200 mg/day, except for 15 men who received filgotinib 100 mg/day. Safety analyses were performed using the safety analysis set and the exposure-adjusted incidence rate (EAIR) of treatment-emergent adverse events (TEAEs) was calculated. Efficacy was assessed from baseline in the parent studies.. Of 790 patients completing the phase II parent studies, 739 enrolled in the study. Through April 2019, 59.5% of patients had received ≥ 4 years of the study drug. Mean (SD) exposure to filgotinib was 3.55 (1.57) years in the filgotinib + MTX group and 3.38 (1.59) years in the filgotinib monotherapy group. EAIR per 100 patient-years of exposure for TEAEs was 24.6 in the filgotinib + MTX group and 25.8 in the filgotinib monotherapy group, and for serious TEAEs, the EAIR was 3.1 and 4.3, respectively. American College of Rheumatology 20/50/70 responses among patients remaining in the study could be maintained through 4 years, with 89.3%/69.6%/49.1% of the filgotinib + MTX group and 91.8%/69.4%/44.4% of the monotherapy group maintaining ACR20/50/70 responses, respectively, based on observed data.. Filgotinib was well tolerated with a 4-year safety profile comparable to that of the parent trials, both in patients receiving combination therapy with MTX or as monotherapy.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Double-Blind Method; Drug Therapy, Combination; Humans; Male; Methotrexate; Pyridines; Treatment Outcome; Triazoles

This analysis evaluated efficacy and safety of filgotinib, a Janus-associated kinase 1-preferential inhibitor, in methotrexate (MTX)-naive patients with rheumatoid arthritis (RA) with multiple poor prognostic factors (PPFs).. This was a post hoc analysis of the phase III, randomised, double-blind, active-controlled, FINCH 3 study (clinicaltrials.gov NCT02886728). Patients received once-daily oral filgotinib 200 or 100 mg plus once-weekly oral MTX ≤20 mg (FIL200 + MTX and FIL100 + MTX), filgotinib 200 mg monotherapy (FIL200), or oral MTX monotherapy (MTX-mono) for up to 52 weeks. PPFs investigated were seropositivity for rheumatoid factor or anticyclic citrullinated peptide antibodies, high-sensitivity C reactive protein (CRP) ≥4 mg/L, Disease Activity Score in 28 joints with CRP (DAS28(CRP)) >5.1, and presence of erosions. Filgotinib efficacy and safety in patients with all four PPFs at baseline were explored versus MTX-mono within this subgroup and compared informally with the overall population.. Of 1249 patients in FINCH 3, 510 (40.8%) had all PPFs. Efficacy of FIL200 + MTX among these patients was comparable to the overall population, with higher rates of 20%/50%/70% improvement from baseline by American College of Rheumatology criteria, DAS28(CRP) <2.6, and remission; greater improvement in physical function and pain; and better inhibition of structural damage relative to MTX-mono. FIL100 + MTX and FIL200 were not consistently more efficacious versus MTX-mono. Safety of filgotinib in patients with PPFs was comparable to the overall population; no new safety signals were observed.. FIL200 + MTX efficacy and safety in patients with multiple PPFs were similar to the overall population.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Drug Therapy, Combination; Humans; Methotrexate; Prognosis; Pyridines; Treatment Outcome; Triazoles

Patients with active rheumatoid arthritis (RA) despite treatment with biologic disease-modifying antirheumatic drug (bDMARD) therapy need treatment options.. To evaluate the effects of filgotinib vs placebo on the signs and symptoms of RA in a treatment-refractory population.. A 24-week, randomized, placebo-controlled, multinational phase 3 trial conducted from July 2016 to June 2018 at 114 sites internationally, randomizing 449 adult patients (and treating 448) with moderately to severely active RA and inadequate response/intolerance to 1 or more prior bDMARDs.. Filgotinib, 200 mg (n = 148); filgotinib, 100 mg (n = 153); or placebo (n = 148) once daily; patients continued concomitant stable conventional synthetic DMARDs (csDMARDs).. The primary end point was the proportion of patients who achieved 20% improvement in the American College of Rheumatology criteria (ACR20) at week 12. Secondary outcomes included week 12 assessments of low disease activity (disease activity score in 28 joints-C-reactive protein [DAS28-CRP] ≤3.2) and change in Health Assessment Questionnaire-Disability Index, 36-Item Short-Form Health Survey Physical Component, and Functional Assessment of Chronic Illness Therapy-Fatigue scores, as well as week 24 assessment of remission (DAS28-CRP <2.6) and adverse events.. Among 448 patients who were treated (mean [SD] age, 56 [12] years; 360 women [80.4%]; mean [SD] DAS28-CRP score, 5.9 [0.96]; 105 [23.4%] with ≥3 prior bDMARDs), 381 (85%) completed the study. At week 12, more patients receiving filgotinib, 200 mg (66.0%) or 100 mg (57.5%), achieved ACR20 response (placebo, 31.1%; difference vs placebo: 34.9% [95% CI, 23.5%-46.3%] and 26.4% [95% CI, 15.0%-37.9%], respectively; both P < .001), including among patients with prior exposure to 3 or more bDMARDs (70.3%, 58.8%, and 17.6%, respectively; difference vs placebo: 52.6% [95% CI, 30.3%-75.0%] for filgotinib, 200 mg, and 41.2% [95% CI, 17.3%-65.0%] for filgotinib, 100 mg; both P < .001). The most common adverse events were nasopharyngitis (10.2%) for filgotinib, 200 mg; headache, nasopharyngitis, and upper respiratory infection (5.9% each) for filgotinib, 100 mg; and RA (6.1%) for placebo. Four uncomplicated herpes zoster cases and 1 retinal vein occlusion were reported with filgotinib; there were no opportunistic infections, active tuberculosis, malignancies, gastrointestinal perforations, or deaths.. Among patients with active RA who had an inadequate response or intolerance to 1 or more bDMARDs, filgotinib, 100 mg daily or 200 mg daily, compared with placebo resulted in a significantly greater proportion achieving a clinical response at week 12. However, further research is needed to assess longer-term efficacy and safety.. ClinicalTrials.gov Identifier: NCT02873936.

Topics: Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Biomarkers; C-Reactive Protein; Dose-Response Relationship, Drug; Double-Blind Method; Drug Tolerance; Female; Hematologic Tests; Humans; Infections; Janus Kinase 1; Male; Middle Aged; Pyridines; Remission Induction; Severity of Illness Index; Triazoles

The aim was to assess patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) treated with filgotinib during two phase 2b, 24-week, randomized, placebo-controlled studies.. Patients with moderate-to-severe active RA and an inadequate response to methotrexate (MTX) were randomized to daily placebo or filgotinib 50 mg, 100 mg, or 200 mg as add-on therapy to MTX (NCT01888874) or as monotherapy (NCT01894516). At week 12, nonresponders receiving filgotinib 50 mg in both studies or placebo in the add-on study, and all patients receiving placebo as monotherapy, were re-assigned to filgotinib 100 mg. PROs were measured using the Health Assessment Questionnaire - Disability Index (HAQ-DI) including Patient Pain assessed by visual analog scale, and the Patient Global Assessment of Disease Activity (Patient Global), the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale (Version 4), and the 36-Item Short Form Health Survey (SF-36).. At week 12, improvements in all PROs, apart from the SF-36 mental component in the add-on study, were statistically better with filgotinib than placebo; some improvements were noted as early as the first assessment time point (week 1 or week 4). Filgotinib improved HAQ-DI by 0.58-0.84 points, FACIT-Fatigue by 6.9-11.4 points, Patient Global by 25.2-35.6 mm, and Pain by 24.2-37.9 mm; scores were maintained or improved to week 24. Across all PROs, more patients achieved minimal clinically important differences and normative values with filgotinib 200 mg than placebo. Patients re-assigned to filgotinib 100 mg at week 12 experienced improvements in PROs between weeks 12 to 24.. Filgotinib as MTX add-on therapy or as monotherapy demonstrated rapid and sustained (to 24 weeks) improvements in health-related quality of life and functional status in patients with active RA.. MTX add-on study: ClinicalTrials.gov , NCT01888874 . Registered on 28 June 2013. Monotherapy study: ClinicalTrials.gov , NCT01894516 . Registered on 10 July 2013.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Janus Kinase 1; Male; Methotrexate; Middle Aged; Patient Reported Outcome Measures; Protein Kinase Inhibitors; Pyridines; Treatment Outcome; Triazoles

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.. In two 4-week exploratory, double-blind, placebo-controlled phase IIa trials, 127 RA patients with an insufficient response to methotrexate (MTX) received filgotinib (GLPG0634, GS-6034) oral capsules (100 mg twice daily or 30, 75, 150, 200, or 300 mg once daily) or placebo, added onto a stable regimen of MTX, to evaluate safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of filgotinib. The primary efficacy end point was the number and percentage of patients in each treatment group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 4.. Treatment with filgotinib at 75-300 mg met the primary end point and showed early onset of efficacy. ACR20 response rates progressively increased to week 4, and the Disease Activity Score in 28 joints using the C-reactive protein (CRP) level decreased. Marked and sustained improvements were observed in serum CRP level and other PD markers. The PK of filgotinib and its major metabolite was dose proportional over the 30-300 mg range. Early side effects seen with other less selective JAK inhibitors were not observed (e.g., there was no worsening of anemia [JAK-2 inhibition related], no effects on liver transaminases, and no increase in low-density lipoprotein or total cholesterol). A limited decrease in neutrophils without neutropenia was consistent with immunomodulatory effects through JAK-1 inhibition. There were no infections. Overall, filgotinib was well tolerated. Events related to study drug were mild or moderate and transient during therapy, and the most common such event was nausea.. Selective inhibition of JAK-1 with filgotinib shows initial efficacy in RA with an encouraging safety profile in these exploratory studies.

Topics: Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; C-Reactive Protein; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Janus Kinase 1; Male; Methotrexate; Middle Aged; Pyridines; Treatment Outcome; Triazoles; Young Adult

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.. 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.. 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.. 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.. NCT01888874.

Topics: Administration, Oral; Antirheumatic Agents; Arthritis, Rheumatoid; C-Reactive Protein; Disability Evaluation; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Hemoglobins; Humans; Infections; Janus Kinase 1; Male; Methotrexate; Middle Aged; Protein Kinase Inhibitors; Pyridines; Severity of Illness Index; Surveys and Questionnaires; Triazoles

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).. 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.. 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.. 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.. NCT01894516.

Topics: Administration, Oral; Antirheumatic Agents; Arthritis, Rheumatoid; C-Reactive Protein; Disability Evaluation; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hemoglobins; Humans; Infections; Janus Kinase 1; Male; Methotrexate; Middle Aged; Protein Kinase Inhibitors; Pyridines; Retreatment; Severity of Illness Index; Surveys and Questionnaires; Treatment Outcome; Triazoles

Filgotinib (GLPG0634) is a selective inhibitor of Janus kinase 1 (JAK1) currently in development for the treatment of rheumatoid arthritis and Crohn's disease. While less selective JAK inhibitors have shown long-term efficacy in treating inflammatory conditions, this was accompanied by dose-limiting side effects. Here, we describe the pharmacokinetics of filgotinib and its active metabolite in healthy volunteers and the use of pharmacokinetic-pharmacodynamic modeling and simulation to support dose selection for phase IIB in patients with rheumatoid arthritis.. Two trials were conducted in healthy male volunteers. In the first trial, filgotinib was administered as single doses from 10 mg up to multiple daily doses of 200 mg. In the second trial, daily doses of 300 and 450 mg for 10 days were evaluated. Non-compartmental analysis was used to determine individual pharmacokinetic parameters for filgotinib and its metabolite. The overall pharmacodynamic activity for the two moieties was assessed in whole blood using interleukin-6-induced phosphorylation of signal-transducer and activator of transcription 1 as a biomarker for JAK1 activity. These data were used to conduct non-linear mixed-effects modeling to investigate a pharmacokinetic/pharmacodynamic relationship.. Modeling and simulation on the basis of early clinical data suggest that the pharmacokinetics of filgotinib are dose proportional up to 200 mg, in agreement with observed data, and support that both filgotinib and its metabolite contribute to its pharmacodynamic effects. Simulation of biomarker response supports that the maximum pharmacodynamic effect is reached at a daily dose of 200 mg filgotinib.. Based on these results, a daily dose range up to 200 mg has been selected for phase IIB dose-finding studies in patients with rheumatoid arthritis.

Topics: Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Dose-Response Relationship, Drug; Double-Blind Method; Healthy Volunteers; Humans; Janus Kinase 1; Male; Middle Aged; Phosphorylation; Pyridines; Triazoles

The constitutional isomers and tautomers of oxadiazolones, as well as their mono- and disulfur analogues, were calculated at the B3LYP/aug-cc-pVDZ level. Four groups of 30 molecules each were considered: oxadiazolone, oxadiazolthione, thiadiazolone, and thiadiazolthione isomers. The compounds were categorized into six groups according to permutations of three heteroatoms in the five-membered ring. Additionally, each of the constitutional isomer was considered to have five tautomers conserving stable five-membered ring: two NH tautomers, two rotameric OH (or SH) forms and one CH. La trombocitosis es un hallazgo casual frecuente en pediatría. En niños, predominan las formas secundarias, siendo las infecciones su causa más prevalente. Se distinguen 4 grados de trombocitosis en función del número de plaquetas; en la forma extrema, se supera el 1.000.000/mm. Endoscopic thrombin injection was similar to glue injection in achieving successful hemostasis of AGVH. However, a higher incidence of complications may be associated with glue injection.

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Characterize safety of the Janus kinase-1 preferential inhibitor filgotinib (FIL) in Japanese patients with moderately to severely active rheumatoid arthritis (RA).. Data from three Phase 3 trials (NCT02889796, NCT02873936, and NCT02886728) and a long-term extension (NCT03025308) through September 2019 were integrated; patients received ≥1 dose of FIL 200 (FIL200) or 100 mg (FIL100) daily, or placebo (PBO). We calculated exposure-adjusted incidence rates (EAIRs) per 100 patient-years FIL exposure (100PYE) for treatment-emergent adverse events (TEAEs) and adverse events of special interest.. Among 3691 total patients and 6080.7 PYE, 229 Japanese patients received FIL for 311.4 PYE (median 1.5, maximum 2.5 years). During the 12-week PBO-controlled period, serious TEAEs and TEAEs leading to study drug disruption were comparable between FIL and PBO. Serious infection rates were 1.9%, 0%, and 2% for FIL200, FIL100, and PBO during the PBO-controlled period; long-term FIL200 and FIL100 EAIRs were 3.8 and 2.1/100PYE. No herpes zoster (HZ) or major adverse cardiovascular events (MACEs) occurred during the PBO-controlled period; long-term FIL200 and FIL100 EAIRs were 3.0 and 2.1/100PYE (HZ) and 0.6 and 0/100PYE (MACE).. Long-term FIL treatment (median 1.5, maximum 2.5 years exposure) was well tolerated at 100- and 200-mg doses in Japanese patients with RA.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Double-Blind Method; Humans; Janus Kinase Inhibitors; Japan; Pyridines; Treatment Outcome

Comparisons of Janus kinase inhibitors (JAKi) for treatment of rheumatoid arthritis in patients with inadequate response to biologic disease-modifying anti-rheumatic drugs are lacking. We assessed the relative efficacy and safety of four JAKi (tofacitinib, baricitinib, upadacitinib, and filgotinib) in this context.. We performed an adjusted indirect comparison (IC) of randomized clinical trials using Bucher's method with an IC and mixed calculator. Endpoints were Disease Activity Score C-reactive protein (DAS28-CRP) and American College of Rheumatology-20 (ACR20). Equivalence was assessed using the equivalent therapeutic alternatives (ETA) guidelines.. We included four of 133 potentially relevant studies. IC showed no statistically significant differences between the four JAKi regarding DAS28-CRP < 3.2. Results were similar in terms of ACR20 except for tofacitinib showing lower efficacy than upadacitinib (RAR -18.4% [IC95% -33.4 to -3.5], p=0.0157). Statistically significant differences were related to the relevant difference for tofacitinib in both endpoints. Despite no statistical differences for baricitinib, we observed a probably clinically relevant difference regarding DAS28-CRP. Probably clinically relevant differences were found for tofacitinib vs. upadacitinib in both endpoints, and for baricitinib vs. upadacitinib in DAS28-CRP. Safety, drug-drug interactions, and convenience considerations did not modify the result of therapeutic equivalence assessment based on efficacy data.. In conclusion, our results show that filgotinib and upadacitinib are ETA. Baricitinib and upadacitinib are also ETA due to a lack of clear differences and for showing superiority over placebo. The results for tofacitinib and upadacitinib show some inconsistency and more data are needed. Key Points • To date, neither a head-to-head comparison nor an indirect comparison between the Janus kinase inhibitors has been performed in patients with rheumatoid arthritis and an inadequate response to biologic disease-modifying anti-rheumatic drugs. • We performed an adjusted indirect comparison that included randomized clinical trials of tofacitinib, baricitinib, upadacitinib, and filgotinib to assess their equivalence in this scenario. • Our results show that baricitinib and filgotinib are equivalent therapeutic alternatives compared to upadacitinib. However, there is some inconsistency in the results of tofacitinib in front of upadacitinib.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; C-Reactive Protein; Humans; Janus Kinase Inhibitors; Methotrexate

Janus kinase 1 (JAK1) is a potential target for the treatment of rheumatoid arthritis (RA). In this study, the introduction of a spiro ring with a difluoro-substituted cyclopropionamide resulted in the identification of TUL01101 (compound

Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Biological Assay; Dogs; Janus Kinase 1; Janus Kinase Inhibitors; Mice; Rats

To characterise safety of the Janus kinase-1 preferential inhibitor filgotinib in patients with moderately to severely active rheumatoid arthritis.. Data were integrated from seven trials (NCT01668641, NCT01894516, NCT02889796, NCT02873936, NCT02886728, NCT02065700, NCT03025308). Results are from placebo (PBO)-controlled (through week (W)12) and long-term, as-treated (all available data for patients receiving ≥1 dose filgotinib 200 (FIL200) or 100 mg (FIL100) daily) datasets. We calculated exposure-adjusted incidence rates (EAIRs)/100 patient-years filgotinib exposure (100PYE) for treatment-emergent adverse events (TEAEs).. 3691 patients received filgotinib for 6080.7 PYE (median 1.6, maximum 5.6 years). During the PBO-controlled period, TEAEs, including those of grade ≥3, occurred at comparable rates with filgotinib or PBO; long-term EAIRs of TEAEs grade ≥3 were 6.4 and 7.6/100PYE for FIL200 and FIL100. EAIRs for deaths were 0.6/100PYE for FIL200, FIL100 and PBO; long-term EAIRs were 0.5 and 0.3/100PYE for FIL200 and FIL100. EAIRs for serious infection were 3.9, 3.3 and 2.4/100PYE for FIL200, FIL100 and PBO; long-term EAIRs were 1.6 and 3.1/100PYE for FIL200 and FIL100. EAIRs for herpes zoster were 0.6, 1.1, and 1.1/100PYE for FIL200, FIL100 and PBO; long-term EAIRs were 1.8 and 1.1/100PYE for FIL200 and FIL100. EAIRs for major adverse cardiovascular events were 0, 1.7 and 1.1/100PYE for FIL200, FIL100 and PBO; long-term EAIRs were 0.4 and 0.6/100PYE for FIL200 and FIL100. No venous thromboembolism occurred during the PBO-controlled period; long-term EAIRs were 0.2 and 0/100PYE for FIL200 and FIL100.. Over a median of 1.6 and maximum of 5.6 years of exposure, safety/tolerability of FIL200 and FIL100 were similar, with a lower incidence of infections with FIL200 among the long-term, as-treated dataset.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Janus Kinase Inhibitors; Pyridines; Triazoles

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and progressive disability when inflammation cannot be sufficiently controlled. Despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biological DMARDs (bDMARDs), up to 30% of RA patients do not reach or fail to maintain a good response over time. The recent introduction of Janus kinase inhibitors (JAKis) has widened the rheumatologist's armamentarium. Filgotinib, a selective JAK1 inhibitor, has been approved by the European Medicines Agency (EMA) for treatment of RA. Phase II and III studies highlighted filgotinib safety and efficacy in RA patients naive to DMARDs or with inadequate response to csDMARDs and bDMARDs. Filgotinib is administered orally at 200 mg every day. For patients older than 75 years or with moderate to severe renal impairment, a dose of filgotinib 100 mg every day is recommended.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Pyridines; Triazoles

Janus kinase inhibitors (JAKinibs) are efficacious in rheumatoid arthritis (RA) with variable reported rates of adverse events, potentially related to differential JAK family member selectivity. Filgotinib was compared with baricitinib, tofacitinib and upadacitinib to elucidate the pharmacological basis underlying its clinical efficacy and safety.. In vitro JAKinib inhibition of signal transducer and activator of transcription phosphorylation (pSTAT) was measured by flow cytometry in peripheral blood mononuclear cells and whole blood from healthy donors and patients with RA following cytokine stimulation of distinct JAK/STAT pathways. The average daily pSTAT and time above 50% inhibition were calculated at clinical plasma drug exposures in immune cells. The translation of these measures was evaluated in ex vivo-stimulated assays in phase 1 healthy volunteers.. JAKinib potencies depended on cytokine stimulus, pSTAT readout and cell type. JAK1-dependent pathways (interferon (IFN)α/pSTAT5, interleukin (IL)-6/pSTAT1) were among the most potently inhibited by all JAKinibs in healthy and RA blood, with filgotinib exhibiting the greatest selectivity for JAK1 pathways. Filgotinib (200 mg once daily) had calculated average daily target inhibition for IFNα/pSTAT5 and IL-6/pSTAT1 that was equivalent to tofacitinib (5 mg two times per day), upadacitinib (15 mg once daily) and baricitinib (4 mg once daily), with the least average daily inhibition for the JAK2-dependent and JAK3-dependent pathways including IL-2, IL-15, IL-4 (JAK1/JAK3), IFNγ (JAK1/JAK2), granulocyte colony stimulating factor, IL-12, IL-23 (JAK2/tyrosine kinase 2) and granulocyte-macrophage colony-stimulating factor (JAK2/JAK2). Ex vivo pharmacodynamic data from phase 1 healthy volunteers clinically confirmed JAK1 selectivity of filgotinib.. Filgotinib inhibited JAK1-mediated signalling similarly to other JAKinibs, but with less inhibition of JAK2-dependent and JAK3-dependent pathways, providing a mechanistic rationale for its apparently differentiated efficacy:safety profile.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Cells, Cultured; Cytokines; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinase Inhibitors; Janus Kinases; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Sulfonamides; Triazoles

The relative efficacy and tolerability of tofacitinib, baricitinib, upadacitinib, and filgotinib compared to adalimumab were assessed in rheumatoid arthritis (RA) patients with inadequate responses to methotrexate (MTX).. 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 with inadequate responses to MTX.. Four RCTs comprising 5451 patients met the inclusion criteria. Baricitinib 4 mg + MTX and upadacitinib 15 mg + MTX showed a significantly higher American College of Rheumatology 20% (ACR20) response rate than adalimumab 40 mg + MTX. Ranking probability based on the surface under the cumulative ranking curve (SUCRA) indicated that baricitinib 4 mg + MTX had the highest probability of being the best treatment for achieving the ACR20 response rate, followed by upadacitinib 15 mg + MTX, tofacitinib 5 mg + MTX, filgotinib 200 mg + MTX, filgotinib 100 mg + MTX, adalimumab 40 mg + MTX, and placebo + MTX. Upadacitinib 15 mg + MTX and baricitinib 4 mg + MTX showed significantly higher ACR50 and ACR70 response rates than adalimumab 40 mg + MTX. For herpes zoster infection, the ranking probability based on SUCRA indicated that placebo + MTX was likely to be the safest treatment, followed by filgotinib 200 mg + MTX, filgotinib 100 mg + MTX, adalimumab 40 mg + MTX, tofacitinib 5 mg + MTX, upadacitinib 15 mg + MTX, and baricitinib 4 mg + MTX. No statistically significant differences were found between the intervention groups in terms of safety.. In RA patients with an inadequate response to MTX, baricitinib 4 mg + MTX and upadacitinib 15 mg + MTX showed the highest ACR response rates, suggesting a difference in efficacy among the different JAK inhibitors.. ZIEL DER ARBEIT: Bei Patienten mit rheumatoider Arthritis (RA) und inadäquatem Ansprechen auf Methotrexat (Mtx) wurde die relative Wirksamkeit und Verträglichkeit von Tofacitinib, Baricitinib, Upadacitinib und Filgotinib im Vergleich zu Adalimumab untersucht.. Die Autoren führten eine Bayes-Netzwerk-Metaanalyse durch, um direkte und indirekte Evidenz aus randomisierten kontrollierten Studien (RCT) zu kombinieren und so die Wirksamkeit und Sicherheit von Tofacitinib, Baricitinib, Upadacitinib, Filgotinib und Adalimumab bei RA-Patienten mit inadäquatem Ansprechen auf MTX zu untersuchen.. Die Einschlusskriterien wurden von 4 RCT mit 5451 Patienten erfüllt. Unter Baricitinib 4 mg + MTX und Upadacitinib 15 mg + MTX zeigte sich eine signifikant höhere ACR20-Ansprechrate (gemäß American College of Rheumatology) als unter Adalimumab 40 mg + MTX. Wie die Rangfolgewahrscheinlichkeit, basierend auf der Oberfläche unter der kumulativen Rangfolgenkurve (SUCRA, „surface under the cumulative ranking curve“), ergab, stellte Baricitinib 4 mg + MTX mit größter Wahrscheinlichkeit die beste Behandlung zur Erzielung der ACR20-Ansprechrate dar, es folgten Upadacitinib 15 mg + MTX, Tofacitinib 5 mg + MTX, Filgotinib 200 mg + MTX, Filgotinib 100 mg + MTX, Adalimumab 40 mg + MTX und Placebo + MTX. Upadacitinib 15 mg + MTX und Baricitinib 4 mg + MTX wiesen signifikant höhere ACR50- und ACR70-Ansprechraten auf als Adalimumab 40 mg + MTX. In Bezug auf eine Herpes-zoster-Infektion ergab die auf SUCRA basierende Rangfolgewahrscheinlichkeit, dass Placebo + MTX am ehesten die sicherste Therapie darstellte, dem folgten Filgotinib 200 mg + MTX, Filgotinib 100 mg + MTX, Adalimumab 40 mg + MTX, Tofacitinib 5 mg + MTX, Upadacitinib 15 mg + MTX und Baricitinib 4 mg + MTX. Es wurden keine statistisch signifikanten Unterschiede zwischen den Interventionsgruppen hinsichtlich der Sicherheit festgestellt.. Bei RA-Patienten mit inadäquatem Ansprechen auf MTX ergaben Baricitinib 4 mg + MTX und Upadacitinib 15 mg + MTX die höchsten ACR-Ansprechraten, was ein Hinweis auf einen Unterschied in der Wirksamkeit der verschiedenen JAK-Inhibitoren sein könnte.

Topics: Adalimumab; Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Bayes Theorem; Drug Therapy, Combination; Heterocyclic Compounds, 3-Ring; Humans; Methotrexate; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Sulfonamides; Treatment Outcome; Triazoles

Janus kinase (JAK) inhibitors have emerged as an effective class of therapies for various inflammatory diseases such as rheumatoid arthritis (RA). JAK inhibitors function intracellularly by modulating the catalytic activity of JAKs and disrupting the receptor-mediated signaling of multiple cytokines and growth factors, including those with pro-inflammatory activity. Understanding the inhibition profiles of different JAK inhibitors, based on the associated cytokine receptors and downstream inflammatory pathways affected, is important to identify the potential mechanisms for observed differences in efficacy and safety. This study applied an integrated modeling approach, using in vitro whole blood cytokine inhibition potencies and plasma pharmacokinetics, to determine JAK-dependent cytokine receptor inhibition profiles, in the context of doses estimated to provide a similar clinical response in RA clinical trials. The calculated profiles of cytokine receptor inhibition for the JAK inhibitors tofacitinib, baricitinib, upadacitinib, and filgotinib and its metabolite, were generally similar when clinically efficacious doses for RA were considered. Only minor numerical differences in percentage cytokine receptor inhibition were observed, suggesting limited differentiation of these inhibitors based on JAK pharmacology, with each showing a differential selectivity for JAK1 heterodimer inhibition. Nevertheless, only robust clinical testing involving head-to-head studies will ultimately determine whether there are clinically meaningful differences between these JAK inhibitors. Furthermore, ongoing and future research into inhibitors with alternative JAK selectivity remains of clinical importance. Thus, all JAK inhibitors should be characterized via thorough preclinical, metabolic and pharmacological evaluation, adequate long-term clinical data, and when available, real-world experience.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Azetidines; Cell Line; Cytokines; Enzyme Assays; Female; Healthy Volunteers; Heterocyclic Compounds, 3-Ring; Humans; Inhibitory Concentration 50; Janus Kinase 1; Janus Kinase Inhibitors; Male; Piperidines; Purines; Pyrazoles; Pyridines; Pyrimidines; Pyrroles; Receptors, Cytokine; Sulfonamides; Triazoles

Topics: Arthritis, Psoriatic; Arthritis, Rheumatoid; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinase Inhibitors; Pyridines; Triazoles

Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Finches; Humans; Janus Kinase 1; Pyridines; Triazoles

A series of 3(R)-aminopyrrolidine derivatives were designed and synthesized for JAK1-selective inhibitors through the modification of tofacitinib's core structure, (3R,4R)-3-amino-4-methylpiperidine. From the new core structures, we selected (R)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a scaffold for further SAR studies. From biochemical enzyme assays and liver microsomal stability tests, (R)-3-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile (6) was chosen for further in vivo test through oral administration. Compound 6 showed improved selectivity for JAK1 compared to that of tofacitinib (IC

Topics: Animals; Arthritis, Rheumatoid; Dogs; Dose-Response Relationship, Drug; Humans; Janus Kinase 1; Male; Mice; Mice, Inbred DBA; Mice, Inbred ICR; Microsomes, Liver; Molecular Structure; Protein Kinase Inhibitors; Pyrimidines; Pyrrolidines; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship