glpg0634 and Sjogren-s-Syndrome

The aim of this study was to characterize the safety and efficacy of filgotinib, lanraplenib and tirabrutinib in patients with active SS.. This multicentre, double-blind study randomized patients with active primary or secondary SS [EULAR SS disease activity index (ESSDAI) ≥5) to receive filgotinib 200 mg (Janus kinase-1 inhibitor), lanraplenib 30 mg (spleen tyrosine kinase inhibitor), tirabrutinib 40 mg (Bruton's tyrosine kinase inhibitor), or placebo. The composite primary end point was the week-12 proportion of patients fulfilling protocol-specified improvement criteria (based on CRP and SS-related symptoms). The EULAR SS patient-reported index (ESSPRI) and the ESSDAI change from baseline (CFB) were secondary end points. Exploratory end points included disease-related biomarkers. Treatment-emergent adverse events (AEs) represented safety outcomes.. The mean of the baseline ESSDAI was 10.1, and of ESSPRI was 6.2 in the 150 patients who were treated; 125 completed the 24-week placebo-controlled treatment period. At week 12, 43.3% of the filgotinib group achieved the primary end point (P = 0.17 vs placebo) vs 42.3% (P = 0.16), 34.7% (P = 0.33), and 26.7% of lanraplenib, tirabrutinib, and placebo groups, respectively. Neither secondary end point was met. Biomarker reductions included immunoglobulins classically associated with SS disease activity. Filgotinib ESSDAI CFB appeared more pronounced in subgroups with baseline ESSDAI ≥14 or without DMARDs/CSs. Most AEs were Grade 1 or 2.. Three drugs with disparate mechanisms were tested, but no significant differences vs placebo in primary or secondary end points were observed. These results may be considered hypothesis-generating, given the drug tolerability, subgroup analysis, and biomarker findings.. ClinicalTrials.gov, https://clinicaltrials.gov, NCT03100942.

Topics: Biomarkers; Double-Blind Method; Humans; Protein Kinase Inhibitors; Severity of Illness Index; Sjogren's Syndrome; Treatment Outcome

To examine whether a JAK inhibitor regulates functional responses of human salivary gland epithelial cells (SGECs) and disease parameters in an animal model of Sjögren's syndrome (SS).. Common differentially expressed genes (DEGs) were analyzed among peripheral blood mononuclear cells from patients with primary SS and other data sets, using blood and SG tissue. Validation of expression in SGs was analyzed by focus score. Inhibition of messenger RNA expression of DEGs and BAFF by filgotinib was analyzed using reverse transcription-polymerase chain reaction in primary SGECs. SG organoid cultures were used to determine the association between DEGs and BAFF via knockdown using small interfering RNAs or to determine regulation of BAFF by JAK inhibitor. Filgotinib (1.5 mg/kg) was intraperitoneally injected into 8-week-old NOD/ShiLtJ mice 3 times per week to analyze manifestations of disease. Finally, STAT signaling was assessed in human and mouse SGECs.. Expression of the DEGs IFNG and BAFF increased in SGs from patients with primary SS, as assessed by focus score. There was a significant correlation between IFIT2 and BAFF expression. JAK inhibitor suppressed interferon (IFN)-induced transcription of DEGs and BAFF in human primary SGECs. Knockdown of DEGs or inhibition of JAK caused reduced secretion of BAFF in human SG organoid cultures. In addition, filgotinib-treated mice exhibited increased salivary flow rates and marked reductions in lymphocytic infiltration of SGs. JAK inhibitor regulated IFNα- and IFNγ-induced pSTAT-1. JAK inhibition controls aberrant activation of SGECs and may be a novel therapeutic approach for primary SS.

Topics: Animals; B-Cell Activating Factor; Disease Models, Animal; Epithelial Cells; Humans; Interferons; Janus Kinase 1; Leukocytes, Mononuclear; Mice; Mice, Inbred NOD; Pyridines; RNA, Messenger; Salivary Glands; Signal Transduction; Sjogren's Syndrome; Triazoles