Oral Selective JAK1 Inhibitor Research Articles

The Effect of Upadacitinib on Lipid Profile and Cardiovascular Events: A Meta-Analysis of Randomized Controlled Trials

Our aim was to systematically investigate the effect of upadacitinib, an oral JAK-1 selective inhibitor, on lipid profile and cardiovascular disease risk. PubMed, PubMed Central and ClinicalTrials.gov databases were searched for relevant randomized controlled trials (RCTs) up to 31 July 2022. We performed a qualitative synthesis of published RCTs to investigate the associations of upadacitinib with lipoprotein changes, along with a quantitative synthesis of MACE and mean lipoprotein changes where there were available data. Nineteen RCTs were eligible for the present systematic review, which included 10,656 patients with a mean age of 51 years and a follow-up period of 12-52 weeks. Increases in low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were noted upon upadacitinib administration (3-48 mg/day) in 15 studies, while the LDL-C:HDL-C ratio remained unchanged. The pooled analyses of three placebo-controlled RCTs (n = 2577) demonstrated that upadacitinib at 15 mg increased the LDL-C by 15.18 mg/dL (95% CI: 7.77-22.59) and HDL-C by 7.89 mg/dL (95% CI: 7.08-8.69). According to the pooled analysis of 15 placebo-controlled RCTs (n = 7695), upadacitinib had no effect on MACE (risk ratio, RR: 0.62; 95% CI: 0.24-1.60). A sub-analysis focusing on upadacitinib at 15 mg (12 studies, n = 5395) demonstrated similar results (RR: 0.67; 95% CI: 0.19-2.36). Treatment with upadacitinib increases both LDL-C and HDL-C levels. Nevertheless, upadacitinib had no significant effect on the cardiovascular disease risk during a ≤52-week follow-up.

A systematic review on the effect of upadacitinib on lipid profile

Background and Aims : To systematically address the association between upadacitinib, an oral JAK-1 selective inhibitor, and its effect on lipid profile, as well as the role of this association in cardiovascular risk.

Abrocitinib in atopic dermatitis: review of the current literature and clinical trials.

Atopic dermatitis (AD) is an inflammatory chronic-relapsing skin disease affecting approximately 15% to 20% of children and 10% of adults in industrialized countries. Both loss of epidermal barrier permeability and immune dysregulation seem to be the most important actors in AD pathogenesis. Several studies have demonstrated the role of Janus kinase (JAK) enzymes in AD pathogenesis suggesting oral and topical JAK inhibitors as new emerging therapies for AD. Among the JAK inhibitors, abrocitinib is an oral JAK1-selective inhibitor. The aim of this study is reviewing current literature about the efficacy and safety of abrocitinib in AD. The literature search was carried out considering the main search engines relating to medical literature and clinical trials. The efficacy and safety of abrocitinib have been confirmed in several studies suggesting this drug as a valuable treatment for moderate to severe AD.

THU0215 WHOLE BLOOD TRANSCRIPTIONAL CHANGES FOLLOWING SELECTIVE INHIBITION OF JANUS KINASE 1 (JAK1) BY FILGOTINIB IN ADULTS WITH MODERATELY-TO-SEVERELY ACTIVE RHEUMATOID ARTHRITIS WITH PRIOR INADEQUATE RESPONSE TO METHOTREXATE (FINCH1)

Background:Filgotinib (FIL), an oral selective JAK1 inhibitor, has shown efficacy and safety in multiple phase 3 studies in adults with moderately-to-severely active rheumatoid arthritis (RA). We have previously described the molecular response to FIL in large-scale RNA sequencing studies of gene expression in other RA populations1-3and herein conducted a similar study in RA patients (pts) with prior inadequate response to methotrexate (MTX; FINCH1).Objectives:Identify RA-associated gene transcripts and biological pathways that are altered in response to FIL treatment.Methods:RA pts who had an inadequate response to MTX were enrolled in FINCH1 (ClinicalTrials.govNCT02889796) and randomized to receive either a stable dose of MTX with placebo (PBO+MTX), adalimumab (ADA+MTX), or one of two doses of FIL (FIL 100mg+MTX, FIL 200mg+MTX) once daily (QD). Whole blood samples were collected from pts using PAXgene tubes at baseline, week 4, and week 12. RNA from these samples was extracted and sequenced on the Illumina HiSeq 2500 platform following globin RNA depletion. Correlations between baseline gene expression and disease measurements were performed using Spearman’s rank partial correlation with covariates. Differentially expressed genes (DEGs) were identified using voom-limma. Pathway analysis was performed on v6.1 of the Molecular Signature Database using single sample gene set enrichment analysis (GSEA) with the focus on immune signaling pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG). A false-discovery rate of 5% was applied for all analyses.Results:Differential gene expression analyses comparing baseline samples with after-treatment samples revealed more rapid transcriptional kinetics for FIL-treated pts compared to ADA+MTX-treated pts. No significant DEGs were observed in PBO-treated pts. More significant DEGs were observed in the FIL 200mg+MTX arm compared to the FIL 100mg+MTX arm, consistent with the superior clinical efficacy of the FIL 200mg dosage. As with other FIL clinical trial RNA-seq studies and consistent with the selective MoA of FIL, JAK-STAT pathway-induced genes SOCS2 and CISH were significantly downregulated across both FIL treatment arms and timepoints, but not in the ADA+MTX arm. RA disease activity associated genes2-3FAM20A and METTL7B were significantly reduced at both 4 and 12 weeks only in the FIL 200mg+MTX arm. While no significant changes in KEGG immune signaling pathways were observed in the PBO+MTX arm, a dose-dependent effect on pathway modulation was observed in the FIL arms. The most prominently down-regulated KEGG pathways included JAK-STAT signaling and leukocyte transendothelial migration.Conclusion:More rapid and sustained changes of transcriptional activity were observed in the whole blood transcriptional profile of RA pts following FIL 200mg+MTX compared to ADA+MTX treatment. Dose-dependent changes were observed in FIL-treated pts, most notably in the KEGG JAK-STAT signaling pathway. These observations confirm an inhibition of JAK-STAT signaling by FIL and are consistent with the observed clinical efficacy of FIL in these pts.

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

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

DOP17 Identification of biomarkers and mechanistic insight for upadacitinib in ulcerative colitis: Analysis of serum inflammatory mediators in the phase 2b U-ACHIEVE study

Abstract Background The U-ACHIEVE trial evaluated upadacitinib (UPA), an oral JAK1 selective inhibitor, in patients with moderately to severely active ulcerative colitis (UC). Patient-reported and endoscopic outcomes improved after UPA treatment. This analysis used pharmacodynamic profiling to link changes in serum biomarkers to changes in UC disease activity, and to assess the UPA mechanism of action in UC. Methods U-ACHIEVE (NCT02819635) was a randomised, double-blind, placebo (PBO)-controlled phase 2b clinical trial. Adults with an inadequate response, loss of response, or intolerance to corticosteroids, immunosuppressants, or biologic therapies were randomised to receive 7.5, 15, 30, or 45 mg UPA once daily or PBO for 8 weeks (weeks). Serum samples (baseline [BL], weeks 2, 4, and 8) were analysed by OLINK® inflammation panel (92 proteins) and by Singulex immunoassay for interleukin-1b (IL-1b), IL-17A, IL-17F, and IL-22. Protein-level changes were analysed by a mixed-effect model; BL protein level was adjusted as a covariate; treatment group, time point, and their interaction were included as fixed effects. Spearman rank-correlation coefficients were used to determine the relationship between changes of serum biomarker levels and improvements in adapted Mayo scores and endoscopic subscores. Multiplicity adjusted P values were calculated using 1000 runs of random permutations. Results Paired BL and week 8 serum samples were available from 114 patients (PBO, n = 17; UPA 7.5 mg, n = 21; UPA 15 mg, n = 21; UPA 30 mg, n = 29; UPA 45 mg, n = 26). UPA treatment reduced expression of pro-inflammatory mediators associated with immune cell migration, type I/II IFN responses, T-cell responses, macrophage and dendritic cell activity and increased expression of biomarkers associated with haematopoiesis, neuroprotection and mucosal repair in a dose-dependent manner. Improvements in adapted Mayo score, endoscopic subscore, and stool frequency correlated with increases in CX3CL1, DNER and FLt3L (p < 0.05 for all). Endoscopic improvements correlated with reductions in OSM, and improvements in fatigue correlated with increases in CCL25 and NT-3. There was a substantial overlap in biomarkers modulated by UPA in patients with UC and Crohn’s disease (Figure). Conclusion UPA modulated expression of serum pro-inflammatory mediators found in pathways associated with the pathogenesis of UC, including immune cell migration, type I/II IFN responses, T-cell responses, macrophage and dendritic cell activity, haematopoiesis, neuroprotection, and mucosal repair. Consistent correlations were observed between changes in biomarker expression and improvements in disease activity and symptoms of UC.

P722 Upadacitinib was not associated with anaemia in patients with moderately to severely active ulcerative colitis: Results from the U-ACHIEVE study

Abstract Background Anaemia is a frequent complication in patients with Crohn’s disease and ulcerative colitis (UC), and patients who respond to treatment generally show improvement in anaemia. Decrease in haemoglobin (Hgb) levels and anaemia may be associated with Janus kinase (JAK) inhibitors. Upadacitinib (UPA), an oral JAK1 selective inhibitor, has demonstrated favourable dose-dependent efficacy in patients with moderately to severely active UC.1 This analysis of data from the U-ACHIEVE study addressed effects of UPA treatment on Hgb levels in patients with UC. Methods U-ACHIEVE (NCT02819635) was a randomised, double-blind, placebo (PBO)-controlled phase 2b clinical trial. Adults with moderately to severely active UC were randomised to receive 7.5, 15, 30, or 45 mg UPA or PBO once daily (QD) for 8 weeks. Hgb levels were measured for all groups at baseline (BL) and weeks 2, 4, 6, and 8. Mean change from BL was calculated for each group. p-values for comparison between UPA and PBO groups were calculated using one-way ANOVA; no multiplicity adjustment was applied. Percentage of patients with Hgb values grade 2 (15–20 g/l Hgb decrease from BL), grade 3 (<80 g/l Hgb level or 21–29 g/l Hgb decrease from BL), and grade 4 (<70 g/l Hgb level or >29 g/l Hgb decrease BL) anaemia were determined for all treatment groups using the Common Terminology Criteria for Adverse Events version 5. Adverse events (AE) were reported by investigators. Results Included in the analysis were 250 patients (mean age ± SD, 42.3 ± 14.2 years; disease duration, 8.2 ± 2.5 years). At BL, most treatment groups had similar mean Hgb levels, except for the 15 mg UPA group, which had significantly lower Hgb levels vs. PBO group (Table). Increased or stable mean levels of Hgb at week 8 vs. BL were observed in most UPA treatment groups. The PBO group had the greatest decrease in Hgb vs. BL at week 8 compared with UPA treatment groups (Figure). Grade ≥2 anaemia was reported in 17.4% of patients receiving PBO and 14.4% of all patients receiving UPA (14.9%, 12.2%, 12.0%, and 17.9% of patients receiving 7.5, 15, 30, and 45 mg UPA, respectively). Grade ≥3 anaemia was reported in 8.7% of patients receiving PBO and 5% of all patients receiving UPA (6.4%, 6.1%, 6.0%, and 1.8% of patients receiving 7.5, 15, 30, and 45 mg UPA, respectively). One subject receiving 7.5 mg QD UPA had grade 4 anaemia. AE of anaemia was reported in 6.5% of patients receiving PBO and in 2.1%, 8.2%, and 3.8% of patients receiving 7.5, 15, and 30 mg UPA, respectively, but not in the 45 mg UPA group. Conclusion Decreased Hgb levels over time were observed more frequently in the PBO group. The maintenance of Hgb levels in patients receiving UPA was likely because of improvement of underlying UC. Reference

P515 Comparability of upadacitinib pharmacokinetics in Japanese and non-Japanese subjects with ulcerative colitis with the extended-release formulation

Abstract Background Upadacitinib (UPA), an oral selective JAK1 inhibitor, is being developed for treatment of patients with moderately-to-severely active ulcerative colitis (UC) in addition to several other inflammatory diseases. UPA has shown favourable efficacy and acceptable safety in UC in an 8-week double-blind placebo-controlled dose-ranging Phase 2b induction study in subjects with moderately-to-severely active UC (U-ACHIEVE trial). Methods Sparse blood samples were collected from subjects with UC who were enrolled in the U-ACHIEVE trial, which included Japanese and non-Japanese subjects. UPA plasma concentration vs. time after dose were summarised from the U-ACHIEVE trial. Additionally, data from U-ACHIEVE were pooled with data from UPA Phase 1 and other Phase 2 studies across different inflammatory diseases to characterise UPA population pharmacokinetics. The population pharmacokinetic model was used to estimate UPA plasma exposures from extended-release formulation (dose range 7.5 – 45mg QD) in 168 non-Japanese and 28 Japanese subjects with UC in U-ACHIEVE. Results UPA plasma exposures were approximately dose proportional over the evaluated dose range in Japanese subjects with UC. Observed dose-normalised plasma concentrations vs. time since the last dose (Figure 1) and dose-normalised model-estimated UPA exposures were comparable (within 25%) between Japanese and non-Japanese subjects with UC (Table 1). Conclusion UPA plasma exposures are similar between Japanese and non-Japanese subjects with UC. This is in agreement with prior assessments in healthy subjects and in subjects with RA which demonstrated comparable UPA exposures between Asian and Western subjects.

DOP79 Dose escalation of upadacitinib in Crohn’s disease patients with an inadequate response: Data from the randomised CELEST study

Abstract Background Patients with Crohn’s disease (CD) may lose response to treatment, requiring dose adjustments. This analysis from the CELEST study evaluated efficacy and safety in patients with CD who required an escalated dose of upadacitinib (UPA), an oral selective JAK1 inhibitor. Methods CELEST (NCT02365649) was a placebo-controlled phase 2 study of adults with moderate-to-severe CD refractory to immunosuppressants/biologics. Patients were randomised to placebo or UPA 3, 6, 12, or 24 mg twice daily (BID) or 24mg once daily (QD) for 16 weeks (weeks), followed by a 36-week double-blind maintenance period to receive 3, 6 or 12mg BID or 24mg QD (Figure 1). Patients who met criteria for inadequate response (average daily liquid/soft stool frequency [SF] >2.2 or average daily abdominal pain score >1.8, and increase in hs-CRP >1 mg/l from baseline [BL] or hs-CRP ≥5 mg/l at previous or current visit) at or after week 20 were eligible to receive open-label (OL) therapy with UPA 12mg BID. Patients with inadequate response at or after 4 weeks of OL 12 mg BID could further escalate to OL 24 mg BID. Data were analysed using descriptive statistics of clinical/endoscopic improvement, change from BL in hs-CRP and faecal calprotectin (FC), and AEs at week 52. Results Among 220 randomised patients, 180 were re-randomised into the maintenance period; 60 had inadequate response and received OL 12 mg BID. Of the 60 patients, 25 (42%) were in clinical response at week 16. After receiving OL 12 mg, 27 patients (45%) required escalation to OL 24 mg BID. A higher proportion of patients who received OL 24 mg received 2 or more prior TNF antagonists, and had higher BL FC, SF, and Simplified Endoscopic Score for CD (SES-CD) compared with patients who remained on OL 12 mg BID (Table 1). At week 52, 15% of patients who received OL 12 mg achieved clinical remission and 10% achieved endoscopic response. Of the patients who escalated to OL 24 mg, 39% achieved clinical remission and 41% were in endoscopic response at week 52 (Table 2). At week 52, change from BL in FC and hs-CRP was −2123 ± 2475 µg/g and −5.1 mg/l, respectively, for patients who received OL 24 mg vs. −423 ± 2953 and −6.4 mg/l for OL 12 mg. Serious infection was reported in 3 patients (2 receiving OL 12 mg and 1 receiving OL 24 mg). Two nonserious herpes zoster events were reported (1 on each dose), but neither event led to discontinuation of UPA. No malignancies, cardiovascular events, thromboembolic events, intestinal perforations, tuberculosis, or deaths were reported for patients who dose-escalated. Conclusion Patients with non-response or loss of response during CELEST gained clinical remission and endoscopic response with UPA 12 mg BID or further escalation to 24 mg BID. No new safety risks were observed for either dose of UPA, consistent with double-blind CELEST results.

Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1)

ObjectivesTo evaluate the efficacy and safety of different doses and regimens of filgotinib, an oral Janus kinase 1 inhibitor, as add-on treatment to methotrexate (MTX) in patients with active rheumatoid...

Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2)

ObjectivesTo evaluate the efficacy and safety of different doses of filgotinib, an oral Janus kinase 1 inhibitor, as monotherapy in patients with active rheumatoid arthritis (RA) and previous inadequate response...

Meeting summaries: GI disorders, diabetes, cancer, and more

■ Interim data from the Phase II FITZROY study of lgotinib, a novel oral JAK1 selective inhibitor developed by Galapagos, showed that this agent induced clinical remission in patients with moderate to severe Crohn disease. Speci cally, the percentage of patients achieving a Crohn’s Disease Activity Index score lower than 150 was statistically signi cantly higher in patients treated with lgotinib compared with those receiving placebo.

812c Filgotinib (GLPG0634), an Oral JAK1 Selective Inhibitor, Induces Clinical Remission in Patients With Moderate-to-Severe Crohn's Disease: Results From the Phase 2 FITZROY Study Interim Analysis

812c Filgotinib (GLPG0634), an Oral JAK1 Selective Inhibitor, Induces Clinical Remission in Patients With Moderate-to-Severe Crohn's Disease: Results From the Phase 2 FITZROY Study Interim Analysis

A randomized, double-blind, placebo-controlled, dose-escalation study of the safety and efficacy of INCB039110, an oral janus kinase 1 inhibitor, in patients with stable, chronic plaque psoriasis

Background: Chronic plaque psoriasis is partially mediated by elevation of proinflammatory cytokines, including several within the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Objective: To evaluate the safety and efficacy of the oral selective JAK1 inhibitor INCB039110 in stable, chronic plaque psoriasis. Methods: This was a phase 2, randomized, double-blind, placebo-controlled, dose-escalation study of INCB039110 (100 mg once daily, 200 mg once daily, 200 mg twice daily and 600 mg once daily) for 28 days. The primary endpoint was mean percent change from baseline in the static Physician Global Assessment (sPGA) at day 28. The protocol was institutional review board approved. Results: Of 50 patients, 48 completed the study. At day 28, mean percent reduction from baseline in sPGA was 22.2% for INCB039110 100 mg once daily (p = 0.270 vs. placebo), 29.4% for 200 mg once daily (p = 0.118), 35.2% for 200 mg twice daily (p = 0.053), 42.4% for 600 mg once daily (p = 0.003) and 12.5% for placebo. Across groups, 11.1% to 45.5% achieved an sPGA score of 1 versus 0% for placebo. INCB039110 was generally well tolerated; the most common treatment-emergent adverse event was nasopharyngitis (18.4%). Conclusion: INCB039110 produced significant improvements in sPGA, demonstrating proof of concept in chronic plaque psoriasis.