Identification of sarilumab pharmacodynamic and predictive markers in patients with inadequate response to TNF inhibition: a biomarker substudy of the phase 3 TARGET study

Abstract

Introduction: Interleukin-6 (IL-6) orchestrates formation of an inflammatory pannus, leading to joint damage in rheumatoid arthritis (RA). Sarilumab is a human monoclonal antibody blocking the IL-6Rα. In TARGET (NCT01709578), a phase 3 study in adults with moderate-to-severe RA and inadequate response or intolerance to tumour necrosis factor inhibitors, subcutaneous sarilumab 200 mg or 150 mg every 2 weeks (q2w) plus conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) significantly reduced disease activity versus placebo plus csDMARDs.

Methods: Circulating levels of biomarkers associated with synovial inflammation (matrix metalloproteinase 3 (MMP-3), collagen type I MMP-cleaved fragment (C1M), collagen type III MMP-cleaved fragment (C3M)), myeloid (soluble intercellular adhesion molecule 1 (sICAM-1), IL-8 and calprotectin) and lymphoid activation (chemokine, CXC motif, ligand 13 (CXCL13), CXCL10, B cell-activating factor) and bone remodelling (receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin and osteocalcin) were evaluated in patients from a TARGET substudy.

Results: Sarilumab significantly decreased C1M, C3M, CXCL13, MMP-3 and total RANKL levels at week 24 versus placebo; some markers were significantly suppressed at week 2 and normalised to levels in healthy controls. Levels of sICAM-1 were predictive of disease activity score by C-reactive protein and clinical disease activity index low disease activity (LDA) response in the sarilumab 200 mg q2w group at week 12. A trend was observed in which patients with lower sICAM-1 levels at baseline had better response compared with patients with higher sICAM-1.

Conclusions: Sarilumab plus csDMARDs decreased circulating biomarkers of synovial inflammation and bone resorption; sICAM-1 was predictive of achieving LDA with sarilumab.

Trial registration number: NCT01709578; Post-results.

Keywords: dmards (biologic); rheumatoid arthritis; treatment.

Figure 1

Median per cent change (error bars represent the quartile ranges Q1–Q3) from baseline in biomarkers of (A) acute-phase response (CRP), (B and C) synovial inflammation (C3M and MMP-3), (D) tissue destruction (C1M), (E) bone resorption (tRANKL) and (F) lymphoid RA synovial phenotype (CXCL13). ANOVA-type method was implemented. *Adjusted P<0.05 versus placebo; **adjusted P<0.01 versus placebo; †adjusted P<0.01 versus sarilumab 150 mg q2w (Benjamini-Hochberg procedure); ‡nominal P<0.0001 versus placebo (CRP only); §nominal P<0.0001 versus sarilumab 150 mg q2w (CRP only). ANOVA, analysis of variance; C1M, collagen type I MMP-cleaved fragment; C3M, collagen type III MMP-cleaved fragment; CRP, C-reactive protein; csDMARD, conventional synthetic disease-modifying antirheumatic drug; CXCL13, chemokine, CXC motif, ligand 13; MMP, matrix metalloproteinase; q2w, every 2 weeks; RA, rheumatoid arthritis; tRANKL, total receptor activator of nuclear factor-κB ligand.

Figure 2

Percentage of patients in each treatment group whose biomarker values returned to normal reference ranges at week 24. C1M, collagen type I MMP-cleaved fragment; C3M, collagen type III MMP-cleaved fragment; CRP, C reactive protein; csDMARD, conventional synthetic disease-modifying antirheumatic drug; CXCL13, chemokine, CXC motif, ligand 13; MMP, matrix metalloproteinase; q2w, every 2 weeks; RANKL, receptor activator of nuclear factor-κB ligand. *P<0.05 versus placebo; †P<0.01 versus placebo; ‡P<0.0001 versus placebo (χ² test, unadjusted P values).

Figure 3

Odds ratios for achieving ACR50 response, ACR70 response, DAS28-CRP LDA, DAS28-CRP remission and CDAI LDA at weeks 12 and 24. High, >median value in overall treatment groups; low, ≤median value in overall treatment groups. Median concentrations of biomarkers are 83.42 ng/mL (C1M), 49.70 ng/mL (MMP-3), 301.84 pg/mL (CXCL10), 19.90 pg/mL (IL-8), 132.33 pg/mL (CXCL13), 0.14 pmol/L (free RANKL), 1071.90 pg/mL (BAFF), 5.47 pmol/L (OPG) and 291.0 ng/mL (sICAM-1). ACR50/70, American College of Rheumatology 50%/70% improvement; BAFF, B cell-activating factor; CDAI, clinical disease activity index; C1M, collagen type I MMP-cleaved fragment; CXCL, chemokine, CXC motif, ligand; CDAI, clinical disease activity index; CRP, C-reactive protein; DAS28-CRP, 28-joint disease activity by CRP; LDA, low disease activity; MMP-3, matrix metalloproteinase 3; np, number of responders with placebo treatment; nt, number of responders with sarilumab treatment; OPG, osteoprotegerin; RANKL, receptor activator of nuclear factor-κB ligand; sICAM-1, soluble intercellular adhesion molecule 1.