Effect of Sarilumab on Circulating Biomarkers of Bone and Joint Destruction in Patients with Rheumatoid Arthritis with Previous Inadequate Response to Tumor Necrosis Factor Inhibitors

Cem Gabay¹, Jérôme Msihid², Nikki Daskalakis³, Anne Barbot⁴, Moshe Zilberstein³ and Anita Boyapati⁵, ¹University Hospitals of Geneva/SCQM Registry, Geneva, Switzerland, Geneva, Switzerland, ²Sanofi, Chilly-Mazarin, France, Chilly-Mazarin, NJ, France, ³Sanofi Genzyme, Bridgewater, NJ, ⁴Sanofi, Chilly-Mazarin, France, Chilly-Mazarin, France, ⁵Regeneron Pharmaceuticals, Inc., Tarrytown, NY

Meeting: ACR/ARHP Annual Meeting 2016

Date of first publication: September 28, 2016

Keywords: biomarkers and rheumatoid arthritis (RA)

Session Information

Date: Tuesday, November 15, 2016

Title: Rheumatoid Arthritis – Small Molecules, Biologics and Gene Therapy - Poster III

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: Patients with RA develop bone and joint damage due to chronic synovial inflammation that is mediated by specific cytokines.¹ Cytokines (eg, IL-6) recruit activated inflammatory cells and fibroblast-like synoviocytes to generate a pannus that results in bone resorption and cartilage destruction. Here we describe that blockade of IL-6 signaling by sarilumab, a human mAb blocking the IL-6Rα, decreased circulating markers associated with the pannus in adults with active, moderate-to-severe RA and inadequate response to TNF inhibitors (TNFi) from the phase 3 TARGET study (NCT01709578).

Methods: Sera were analyzed using ELISAs at baseline and posttreatment (through week 24) from a subset of patients who received placebo or sarilumab subcutaneously (150 or 200 mg every 2 weeks [q2w]) plus conventional synthetic DMARDs (csDMARDs; n=97/group). Percent change from baseline in biomarkers was analyzed using nonparametric methods (ANOVA-type or rank-based analysis of covariance) to evaluate differences between treatment groups at each time point. For exploratory purposes, percent changes from baseline in biomarkers were also compared, separately by treatment group, between ACR50 responders and nonresponders at week 24 using similar methods. P values <0.05 were considered significant.

Results: Both doses of sarilumab significantly decreased markers of tissue destruction, synovial inflammation, and bone resorption relative to placebo as early as week 2 for several biomarkers assessed, with greater reductions observed at week 24 (Table). For several biomarkers, numerically greater changes from baseline were observed following treatment with sarilumab 200 mg q2w vs sarilumab 150 mg q2w. Numerical increases observed in osteocalcin (OC) after treatment with sarilumab were not statistically significant compared with placebo. When changes from baseline in biomarkers were examined according to ACR50 response at week 24, larger decreases in MMP-3 and increases in OC were observed in patients achieving ACR50 compared with those who did not achieve ACR50; these changes were significant for the sarilumab 150 mg q2w group (Table). Other biomarkers suppressed by sarilumab treatment (eg, chemokine [C-X-C motif] ligand 13 and 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 inadequate response to TNFi. Differences in some biomarker levels observed between ACR50 responders and nonresponders suggest that modulation 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 TARGET
	Week 2^a								Week 24^a
	Placebo + csDMARDs (n=97)			Sarilumab 150 mg q2w + csDMARDs (n=97)		Sarilumab 200 mg q2w + csDMARDs (n=97)			Placebo + csDMARDs (n=97)	Sarilumab 150 mg q2w + csDMARDs (n=97)	Sarilumab 200 mg q2w + csDMARDs (n=97)
Median percent change from baseline in biomarker concentration^b
Acute-phase reactant
CRP^c		9.2	-10.2^§		-67.5^§			13.6		-48.6^§		-85.0^§
Marker of tissue destruction
C1M^c	-6.6			-16.5*		-45.8**			-7.6	-46.1**	-59.5**
Markers of synovial inflammation
C3M^c	-1.4			-9.7**		-21.9**			-7.7	-20.8**	-35.1**
MMP-3^c	-8.0			-5.8		-1.7			-8.5	-34.6**	-48.5**
Markers of bone resorption
Total RANKL^c	—			—		—			-0.4	-20.0**	-20.2**
OPG^c	—			—		—			-2.4	0.1	-5.2
Marker of bone formation
Osteocalcin^d	—			—		—			0.8	5.1	8.0
Marker of lymphoid RA synovial phenotype
CXCL13^c	2.3			-13.2**		-16.0**			-7.1	-28.5**	-38.1**
Marker of myeloid RA synovial phenotype
sICAM-1^d	-0.8			-1.8		-2.4			—	—	—
Median percent change from baseline in biomarker concentration at week 24 in ACR50 responder/nonresponder patients^e
							Sarilumab 150 mg q2w + csDMARDs (n=97)			Sarilumab 200 mg q2w + csDMARDs (n=97)
							ACR50 responder		ACR50 nonresponder	ACR50 responder	AC50 nonresponder
CRP							-88.4		-77.5	-97.1^†	-94.6
MMP-3							-49.3^‡		-28.6	-49.4	-43.5
Osteocalcin							8.3^†		3.1	11.7	2.7
ANCOVA, analysis of covariance; ANOVA, analysis of variance; C1M, collagen type I MMP-cleaved fragment; C3M, collagen type III MMP-cleaved fragment; csDMARD, conventional synthetic DMARD; 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. ^dPercent change from baseline was analyzed using rank-based ANCOVA. ^eChange 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; 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, Barbot A, Zilberstein M, Boyapati A. Effect of Sarilumab on Circulating Biomarkers of Bone and Joint Destruction in Patients with Rheumatoid Arthritis with Previous Inadequate Response to Tumor Necrosis Factor Inhibitors [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-previous-inadequate-response-to-tumor-necrosis-factor-inhibitors/. Accessed .

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