Session Information
Date: Sunday, November 5, 2017
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: The JAK1 selective inhibitor filgotinib (GLPG0634, GS-6034) has been evaluated in a 24-week phase 2B study (DARWIN 2) as monotherapy in active rheumatoid arthritis (RA) patients who were methotrexate inadequate responders and has shown a good safety and efficacy profile1. A broad range of serum biomarkers were measured to characterize the mode of action of filgotinib.
Methods: Serum samples from RA patients who received either placebo (PBO), or filgotinib monotherapy at 100mg or 200mg once daily (QD) were collected at baseline, weeks 4 and 12 and analyzed for 35 biomarkers by validated single- or multi-plex immunoassays. Median % changes from baseline for biomarkers are reported. Wilcoxon rank-sum test assessed the significance of the difference between filgotinib treated groups and PBO.
Results: Filgotinib monotherapy was associated with significant reductions in a broad panel of immune- and tissue-related biomarkers relevant to RA, compared to placebo (27/35 markers). The largest reductions were in the pro-inflammatory markers IL-6, SAA, and CRP (58-68% median reduction from baseline to week 12, p<0.01). Other top-ranked biomarkers by effect size were related to joint degradation (MMP1, 3, YKL-40), immune cell recruitment (CXCL10, CXCL13), and TH17/reg cells (IL-23 and IL-10) (reductions of 28-31%, p<0.05 for all). These effects were present from week 4 and were maintained at week 12. Other biomarker changes also support down-modulation of TH1 (IL-2, IFN-γ, IL-12), TH2 (IL-4, IL-5, IL-13), B cell (CXCL13, IL-7, IL-21), and myeloid cells (GM-CSF, MIP-1α). Filgotinib monotherapy did not increase leptin above PBO-levels.
Table: Median percent change from baseline of biomarkers at week 12
|
|
PBO (N=61) |
FILGO 200mg QD (N=65) |
|
PBO (N=61) |
FILGO 200mg QD (N=65) |
|
PBO (N=61) |
FILGO 200mg QD (N=65) |
|
BAFF |
-3 |
-1 NS |
IL-6 |
2 |
-58 ** |
MIP-1β |
3 |
3 NS |
|
CRP |
-27 |
-68 ** |
IL-7 |
0 |
-21 ** |
MMP1 |
5 |
-28 * |
|
CXCL10 |
-4 |
-31 * |
IL-8 |
-7 |
-8 NS |
MMP3 |
6 |
-31 *** |
|
CXCL13 |
-4 |
-30 ** |
IL-10 |
13 |
-26 *** |
RESISTIN |
1 |
-16 ** |
|
EGF |
11 |
21 NS |
IL-12 |
6 |
-23 *** |
SAA |
0 |
-68 *** |
|
GM-CSF |
6 |
-21 *** |
IL-13 |
13 |
-20 *** |
sgp130 |
-2 |
0 NS |
|
ICAM-1 |
-4 |
-8 NS |
IL-17A |
1 |
-16 ** |
TNFα |
5 |
-14 ** |
|
IFN-γ |
6 |
-23 *** |
IL-21 |
4 |
-23 *** |
TNF-RI |
0 |
-18 *** |
|
IL-1β |
8 |
-16 *** |
IL-23 |
-4 |
-31 *** |
VCAM-1 |
0 |
-9 *** |
|
IL-2 |
10 |
-21 *** |
LEPTIN |
20 |
26 NS |
VEGF |
0 |
-22 ** |
|
IL-4 |
21 |
-22 *** |
MCP-1 |
-5 |
-13 NS |
YKL-40 |
-4 |
-31 ** |
|
IL-5 |
3 |
-14 *** |
MIP-1α |
3 |
-6 ** |
|
||
p-values comparing % changes between filgotinib and PBO groups: NS, p>0.05; *p<0.05; **p<0.01; ***p<0.001
Conclusion: Filgotinib reduces the systemic levels of pro-inflammatory and RA-associated tissue-derived biomarkers. These effects on biomarkers in multiple disease processes and immune cell subsets provide insight into the efficacy shown by filgotinib evaluated as monotherapy in the Phase 2B study1.
References: 1Kavanaugh A, et al. Ann Rheum Dis 2017; 76: 1009–1019.
To cite this abstract in AMA style:
Taylor PC, Galien R, Van der Aa A, Jamoul C, Harrison P, Tasset C, Pan Y, Goyal L, Li W, Tarrant J. Monotherapy with Filgotinib, a JAK1-Selective Inhibitor, Reduces Disease-Related Biomarkers in Rheumatoid Arthritis Patients [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/monotherapy-with-filgotinib-a-jak1-selective-inhibitor-reduces-disease-related-biomarkers-in-rheumatoid-arthritis-patients/. Accessed .ACR Meeting Abstracts - https://acrabstracts.org/abstract/monotherapy-with-filgotinib-a-jak1-selective-inhibitor-reduces-disease-related-biomarkers-in-rheumatoid-arthritis-patients/