JAK selectivity and the implications for clinical inhibition of pharmacodynamic cytokine signalling by filgotinib, upadacitinib, tofacitinib and baricitinib.

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.

Traves PG ，Murray B ，Campigotto F ，Galien R ，Meng A ，Di Paolo JA ... -  《-》

Comparison of baricitinib, upadacitinib, and tofacitinib mediated regulation of cytokine signaling in human leukocyte subpopulations.

McInnes IB ，Byers NL ，Higgs RE ，Lee J ，Macias WL ，Na S ，Ortmann RA ，Rocha G ，Rooney TP ，Wehrman T ，Zhang X ，Zuckerman SH ，Taylor PC ... -  《-》

In vitro and in vivo analysis of a JAK inhibitor in rheumatoid arthritis.

Tanaka Y ，Maeshima K ，Yamaoka K 《-》

Comparative Efficacy and Safety of Three Janus Kinase Inhibitors in Ulcerative Colitis: A Real-World Multicentre Study in Japan.

Three Janus kinase (JAK) inhibitors are approved for ulcerative colitis (UC) in Japan. To compare the real-world efficacy and safety of these three JAK inhibitors in UC. This was a multicentre, retrospective study of patients with UC started on JAK inhibitors. The primary outcome was clinical remission at 10, 26 and 58 weeks, and at the most recent follow-up. To compare the efficacy and safety among the JAK inhibitors, we created three matched cohorts (upadacitinib vs. filgotinib, tofacitinib vs. filgotinib and upadacitinib vs. tofacitinib) using propensity score matching. We identified 228 upadacitinib-treated patients (median follow-up 49 weeks; IQR 25-72), 215 filgotinib-treated patients (follow-up 56 weeks; IQR 17-82) and 159 tofacitinib-treated patients (follow-up 112 weeks; IQR 10-258). Clinical remission rates for upadacitinib, filgotinib and tofacitinib at the most recent follow-up were 72.8%, 50.6% and 45.8%, respectively. Over 70% of the patients previously treated with other biologics or JAK inhibitors achieved clinical remission with upadacitinib. On multivariate analysis, the number of previous advanced therapies was inversely associated with the efficacy of filgotinib and tofacitinib. Comparative analysis showed that upadacitinib-treated patients had higher efficacy and lower risk of discontinuation than patients treated with other JAK inhibitors. However, upadacitinib had a significant risk of acne. Considering the particularly high efficacy of upadacitinib, even in patients with refractory UC, filgotinib or tofacitinib may be considered as an upfront JAK inhibitor before using upadacitinib.

Akiyama S ，Shimizu H ，Tamura A ，Yokoyama K ，Sakurai T ，Kobayashi M ，Eizuka M ，Yanai S ，Nomura K ，Shibuya T ，Takahara M ，Hiraoka S ，Sako M ，Yoshida A ，Tsuruta K ，Yoshioka S ，Koroku M ，Omori T ，Saruta M ，Matsumoto T ，Okamoto R ，Tsuchiya K ，Fujii T ... -  《-》

Abrocitinib, tralokinumab and upadacitinib for treating moderate-to-severe atopic dermatitis.

Edwards SJ ，Karner C ，Jhita T ，Barton S ，Marceniuk G ，Yiu ZZN ，Wittmann M ... -  《-》