Date: Monday, November 9, 2015
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Among the 4 Janus kinase (JAK) family members, JAK1 often has a dominant role in the intracellular signaling for cytokines involved in auto-immune and inflammatory diseases, such as rheumatoid arthritis (RA). We therefore hypothesized that inhibiting JAK1 only would provide an efficacious treatment for RA, and may avoid potential side effects associated with inhibition of other JAKs. Filgotinib (GLPG0634) displays a strong selectivity for inhibition of JAK1 over JAK2, JAK3 and TYK2. In phase 2a clinical trials, filgotinib rapidly improved signs and symptoms of RA with good tolerability and safety. The data reported here present the changes in serum pharmacodynamic markers observed in RA patients after 4 weeks of treatment with filgotinib.
RA patients (n=91) with insufficient response to MTX were randomized to receive placebo or 30, 75, 150, or 300 mg filgotinib once-daily orally for 4 weeks as add-on to MTX in a double-blind phase 2a study. Blood was sampled pre-dose and on the last day of treatment. Concentrations of the biomarkers chitinase-3 L1 (CHI3L1)/YKL-40 and SAA were quantified using an ELISA assay from R&D Systems. All other biomarker concentrations were evaluated at Myriad RBM Inc. using the InflammationMAP© assay. For each parameter, data are reported in percentage relative to the baseline value of each individual.
After 4 weeks of treatment with filgotinib, levels of the acute phase proteins CRP and haptoglobin dose-dependently decreased in RA patients. IL-18 and SAA, two markers of inflammation, and sTNFR2 whose expression is increased in RA patients, also displayed a significant decrease. The plasma concentration of ICAM-1 and VCAM-1, both known to play a major role in the adhesion and recruitment of leukocytes, was also decreased. The concentration of the metalloprotease MMP3, involved in tissue remodelling and induced in inflammation, decreased following treatment with 150 and 300 mg QD. Both CHI3L1 and VEGF, whose expressions are controlled by JAK1-activating gp130 receptors and STAT transcription factors, were decreased at all doses of filgotinib.
|PLACEBO||94 +/- 15||101 +/- 15||1034 +/- 4||88 +/- 14||94 +/- 4||97 +/- 6||99 +/- 3||92 +/- 10||120 +/- 5||138 +/- 23|
|75 mg||72 +/- 13||91 +/- 7||96 +/- 5||86 +/- 20||111 +/- 10||97 +/- 3||110 +/- 6||116 +/- 20||76 +/- 9 ***||106 +/-5|
|150 mg||38 +/- 10 **||71 +/- 9||83 +/- 6 *||43 +/- 10||80 +/- 6 **||87 +/- 6||85 +/- 3 **||66 +/- 10||74 +/- 8 **||111 +/-6|
|300mg||22 +/- 5 ***||50 +/- 6 **||82 +/- 3 **||38 +/- 8 *||79 +/- 4 *||79 +/- 3 *||89 +/- 2||54 +/- 6 *||56 +/-8 ***||
97 +/- 8 *
Percent change from baseline in biomarkers after 4 weeks of filgotinib treatment (Mean +/- SEM – Kruskal – Wallis + Dunn’s post hoc tests *: p<0.05; **: p<0.01; ***: p<0.001, compared to baseline)
Within 4 weeks of treatment with the JAK1-selective inhibitor filgotinib in RA patients, plasma markers of inflammation and joint damage significantly decreased. Markers linked to JAK1-dependent signalling were also significantly impacted. Overall, together with the previously reported clinical efficacy of filgotinib, these results support that inhibition of JAK1 is sufficient to correct inflammation in RA patients, and may offer a treatment strategy that avoids side effects associated with inhibition of other JAKs.
To cite this abstract in AMA style:Galien R, Van der Aa A, Blanque R, Darquenne S, Harrison P, Tasset C. Selective JAK1 Inhibition with Filgotinib (GLPG0634) Decreases Plasma Markers of Inflammation and Joint Damage in Patients with Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/selective-jak1-inhibition-with-filgotinib-glpg0634-decreases-plasma-markers-of-inflammation-and-joint-damage-in-patients-with-rheumatoid-arthritis/. Accessed July 23, 2019.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/selective-jak1-inhibition-with-filgotinib-glpg0634-decreases-plasma-markers-of-inflammation-and-joint-damage-in-patients-with-rheumatoid-arthritis/