Effect of Sarilumab on Circulating Biomarkers of Bone and Joint Destruction in Patients with Rheumatoid Arthritis with Inadequate Response to Methotrexate

Cem Gabay¹, Jérôme Msihid², Nikki Daskalakis³, Neil Graham⁴, Anne Barbot⁵, Moshe Zilberstein³ and Anita Boyapati⁴, ¹University Hospitals of Geneva/SCQM Registry, Geneva, Switzerland, Geneva, Switzerland, ²Sanofi, Chilly-Mazarin, France, Chilly-Mazarin, NJ, France, ³Sanofi Genzyme, Bridgewater, NJ, ⁴Regeneron Pharmaceuticals, Inc., Tarrytown, NY, ⁵Sanofi, Chilly-Mazarin, France, Chilly-Mazarin, France

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Biomarkers, methotrexate (MTX) and rheumatoid arthritis (RA)

Session Information

Date: Tuesday, November 15, 2016

Title: Rheumatoid Arthritis – Small Molecules, Biologics and Gene Therapy IV: Biomarkers

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Patients with RA develop bone and joint damage due to chronic inflammation that is mediated by a destructive synovial pannus.¹ The pannus is composed of inflammatory cell types that act in concert with resident activated fibroblast-like synoviocytes to trigger bone and joint damage. Here we describe that blockade of IL-6 signaling by sarilumab, a human mAb blocking the IL-6Rα, decreased circulating markers associated with synovial inflammation and tissue damage in patients with active, moderate-to-severe RA with inadequate response to MTX from MOBILITY (NCT01061736).

Methods: Sera were analyzed using ELISAs at baseline and posttreatment through week 52 from a subset of patients (N=384) receiving placebo or subcutaneous sarilumab (150 or 200 mg every 2 weeks [q2w]) plus weekly MTX. Percent change from baseline in biomarkers was analyzed using nonparametric methods (ANOVA-type) to evaluate differences between treatment groups at each time point. For exploratory purposes, percent changes from baseline in biomarkers were also compared between ACR50 responders at week 24 using similar methods, separately by treatment group. P values <0.05 were considered significant.

Results: Both doses of sarilumab significantly decreased markers of tissue destruction and synovial inflammation relative to placebo as early as week 2, with greater reductions observed at week 24 (Table). For most biomarkers, numerically greater differences from baseline were observed in the sarilumab 200 mg q2w group vs the sarilumab 150 mg q2w group. When changes from baseline in biomarkers were examined according to ACR50 response at week 24, significantly greater reductions in chemokine (C-X-C motif) ligand 13, a marker of lymphoid RA synovial phenotype, and MMP-3, a marker of synovial inflammation, were observed in ACR50 responders relative to nonresponders in the sarilumab 150 mg q2w group. Additionally, ACR50 responders demonstrated greater posttreatment reductions in collagen type I MMP-cleaved fragment (sarilumab 200 mg q2w group) and CRP (sarilumab 150 mg q2w group) compared with ACR50 nonresponders. Other biomarkers suppressed by sarilumab treatment (eg, RANK ligand) did not significantly differ by ACR50 response (not shown).

Conclusion: Sarilumab significantly reduced biomarkers of bone resorption and joint damage in patients with RA and an inadequate response to MTX. Differences in some biomarker levels observed between ACR50 responders and nonresponders suggest that the suppression of these biomarkers may contribute to a decrease in disease activity. Reference: 1. Srirangan et al. Ther Adv Musculoskelet Dis. 2010;2:247-256.

Table. Posttreatment Changes in Serum Concentrations of Circulating Biomarkers in Patients With RA From MOBILITY
	Week 2^a							Week 24^a
	Placebo + MTX (n=126)		Sarilumab 150 mg q2w + MTX (n=128)			Sarilumab 200 mg q2w + MTX (n=130)		Placebo + MTX (n=126)	Sarilumab 150 mg q2w + MTX (n=128)	Sarilumab 200 mg q2w + MTX (n=130)
Median percent change from baseline in biomarker concentration^b,c
Acute-phase reactant
CRP		-0.5		-69.9^§			-91.8^§	-12.2	-93.3^§	-95.4^§
Marker of tissue destruction
C1M	0.5		-24.4**			-38.1**		-16.4	-39.3**	-50.1**
Markers of synovial inflammation
C3M	-2.8		-15.9**			-20.0**		-4.2	-25.8**	-30.9**
MMP-3	-1.7		-15.0**			-5.5*		-6.7	-37.8**	-47.8**
Markers of bone resorption
Total RANKL	—		—			—		-10.6	-20.4	-25.7*
OPG	—		—			—		2.2	1.2	-2.4
Marker of lymphoid RA synovial phenotype
CXCL13	-1.3		-13.7**			-18.4**		-3.1	-16.8**	-32.1**
Marker of myeloid RA synovial phenotype
sICAM-1	-0.7		-2.8			-3.5		0.1	-7.9**	-7.5**
Median percent change from baseline in biomarker concentration at week 24 in ACR50 responder/nonresponder patients^d
					Sarilumab 150 mg q2w + MTX (n=128)				Sarilumab 200 mg q2w + MTX (n=130)
					ACR50 responder			ACR50 nonresponder	ACR50 responder	AC50 nonresponder
CRP					-95.1^†			-88.7	-96.3	-93.7
C1M					-40.9			-38.0	-54.2^†	-42.1
MMP-3					-45.2^†			-36.8	-48.8	-40.3
CXCL13					-34.1^‡			-13.4	-37.1	-26.1
ANOVA, analysis of variance; C1M, collagen type I MMP-cleaved fragment; C3M, collagen type III MMP-cleaved fragment; CXCL13, chemokine (C-X-C motif) ligand 13; OPG, osteoprotegerin; q2w, every 2 weeks; RANKL, RANK ligand; sICAM-1, soluble intercellular adhesion molecule 1. Adjusted P<0.05 and ≥0.01 vs placebo. *Adjusted P<0.01 vs placebo. ^†Unadjusted P<0.05 and ≥0.01 vs nonresponders. ^‡Unadjusted P<0.01 vs nonresponders. ^§Unadjusted P<0.01 vs placebo. ^aPatient numbers reflect maximum number of patients included in each group. Fewer samples may have been analyzed at a given time point because of missing or non-evaluable samples. ^bThe Benjamini-Hochberg procedure was used to correct for multiplicity and control false discovery rateusing all comparisons for most biomarkers tested; unadjusted P values are presented for CRP. Note that only selected comparisons are shown here. ^cPercent change from baseline was analyzed using ANOVA-type method and adjusted P values of the comparisons vs placebo are reported. ^dChange in biomarker concentrations in ACR50 responders vs nonresponders was compared in active treatment groups at week 24 using ANOVA-type method, separately by group. Unadjusted P values are reported.

Disclosure: C. Gabay, Roche, Merck, AbbVie, Pfizer, Bristol-Myers Squibb, Sanofi, and AB2 Bio, 5; J. Msihid, Sanofi, 1,Sanofi, 3; N. Daskalakis, Sanofi Genzyme, 1,Sanofi Genzyme, 3; N. Graham, Regeneron Pharmaceuticals, Inc, 1,Regeneron Pharmaceuticals, Inc, 3; A. Barbot, Sanofi, 1,Sanofi, 3; M. Zilberstein, Sanofi Genzyme, 1,Sanofi Genzyme, 3; A. Boyapati, Regeneron Pharmaceuticals, Inc, 1,Regeneron Pharmaceuticals, Inc, 3.

To cite this abstract in AMA style:

Gabay C, Msihid J, Daskalakis N, Graham N, Barbot A, Zilberstein M, Boyapati A. Effect of Sarilumab on Circulating Biomarkers of Bone and Joint Destruction in Patients with Rheumatoid Arthritis with Inadequate Response to Methotrexate [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/effect-of-sarilumab-on-circulating-biomarkers-of-bone-and-joint-destruction-in-patients-with-rheumatoid-arthritis-with-inadequate-response-to-methotrexate/. Accessed .

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