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.

Sarilumab and adalimumab differential effects on bone remodelling and cardiovascular risk biomarkers, and predictions of treatment outcomes

“…These effects were generally observed early and persisted through to week 24. This was particularly evident with CRP and is consistent with previous observations [13,14,18,19]. In addition, a greater proportion of patients treated with sarilumab vs. adalimumab monotherapy demonstrated normalization of serum biomarkers at week 24, which was greatest for biomarkers of the acute-phase response (CRP and SAA).…”

“…The pharmacodynamic effects of sarilumab Table S3 for tertile ranges). CI, confidence interval; CXCL13, chemokine (C-X-C motif) ligand 13; HAQ-DI, Health Assessment Questionnaire-Disability Index; LS, least squares; MMP-3, matrix metalloproteinase-3; NS, not significant at 5%; P1NP, procollagen type 1 N-terminal propeptide; SAA, serum amyloid A; VAS, visual analogue scale monotherapy observed in MONARCH are generally consistent with those reported after 24 weeks treatment in the MOBILITY (MTX-IR patients treated with sarilumab 150 mg/200 mg q2w + MTX vs. placebo + MTX) and TARGET (TNF-IR patients treated with sarilumab 150 mg/200 mg q2w + csDMARDs vs. placebo + csDMARDs) biomarker populations, where sarilumab treatment reduced biomarkers of bone resorption and synovial inflammation [18,19]. P1NP was significantly increased after sarilumab monotherapy compared with adalimumab, but in other studies, TNF inhibition has been associated with significant increases in P1NP posttreatment [22].…”

“…Biomarkers were analysed retrospectively (except CRP) at one or two post-baseline timepoints through week 24 (Table S1). Timepoints selected for analysis were based on either previous data following sarilumab treatment [18,19] or on literature suggesting either acute or latent effects of RA therapy on specific markers. The assay characteristics for most biomarkers have been described previously [18].…”

Filgotinib, a JAK1 Inhibitor, Modulates Disease-Related Biomarkers in Rheumatoid Arthritis: Results from Two Randomized, Controlled Phase 2b Trials

“…We observed decreases in several immune cell recruitment biomarkers (CXCL10, CXCL13, VCAM, and ICAM1). Reduced serum CXCL10 [23,24] and CXCL13 [24,25] levels were reported following treatment with other RA therapeutics, and CXCL10 was also reduced locally in the synovium of RA patients in response to the pan-JAK inhibitor, tofacitinib [23]. Reductions in biomarkers previously associated with the stromal response (ICAM1, VCAM, MMP1, and MMP3) have been demonstrated in the synovium after treatment with other effective RA therapies [23,26].…”

Levels of CXCL13 and sICAM-1 correlate with disease activity score in patients with rheumatoid arthritis treated with tocilizumab

“…More patients in the present study received TCZ + MTX (n = 297) than TCZ monotherapy (n = 157). However, a study of patients with inadequate response to tumor necrosis factor inhibitors who received sarilumab + DMARDs was also unable to fully replicate the biomarker results from ADACTA [12].…”