Monotherapy with Filgotinib, a JAK1-Selective Inhibitor, Reduces Disease-Related Biomarkers in Rheumatoid Arthritis Patients

Peter C. Taylor¹, René Galien², Annegret Van der Aa³, Corinne Jamoul³, Pille Harrison³, Chantal Tasset³, Yang Pan⁴, Lovely Goyal⁴, Wanying Li⁴ and Jacqueline Tarrant⁴, ¹Kennedy Institute of Rheumatology, London, United Kingdom, ²Galapagos SASU, Romainville, France, ³Galapagos NV, Mechelen, Belgium, ⁴Gilead Sciences, Foster City, CA

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: biomarkers and rheumatoid arthritis (RA), Janus kinase (JAK)

Session Information

Date: Sunday, November 5, 2017

Title: Rheumatoid Arthritis – Small Molecules, Biologics and Gene Therapy Poster I: Comorbidities and Adverse Events; Efficacy and Safety of Small Molecules

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 T_H17/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 T_H1 (IL-2, IFN-γ, IL-12), T_H2 (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.

Disclosure: P. C. Taylor, UCB, 2,GlaxoSmithKline, 2,Galapagos NV, 2,Eli Lilly and Company, 2,UCB, 5,Eli Lilly and Company, 5,Pfizer Inc, 5,Galapagos NV, 5,Merck Pharmaceuticals, 5,GlaxoSmithKline, 5,Abbvie, 5,Bristol-Myers Squibb, 5,Janssen Pharmaceutica Product, L.P., 5,Novartis Pharmaceutical Corporation, 5,Sandoz, 5,Biogen Idec, 5; R. Galien, Galapagos SASU, 3; A. Van der Aa, Galapagos NV, 1,Galapagos NV, 3; C. Jamoul, Galapagos NV, 3; P. Harrison, Galapagos NV, 1,Galapagos NV, 3; C. Tasset, Galapagos NV, 1,Galapagos NV, 3; Y. Pan, Gilead Sciences, 3; L. Goyal, Gilead Sciences, 3; W. Li, Gilead Science, 3; J. Tarrant, Gilead Sciences, 3.

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 .

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