Abstract
BackgroundTissue released blood-based biomarkers can provide insight into drug mode of action and response. To understand the changes in extracellular matrix turnover, we analyzed biomarkers associated with joint tissue turnover from a phase 3, randomized, placebo-controlled study of baricitinib in patients with active rheumatoid arthritis (RA).MethodsSerum biomarkers associated with synovial inflammation (C1M, C3M, and C4M), cartilage degradation (C2M), bone resorption (CTX-I), and bone formation (osteocalcin) were analyzed at baseline, and weeks 4 and 12, from a subgroup of patients (n = 240) randomized to placebo or 2-mg or 4-mg baricitinib (RA-BUILD, NCT01721057). Mixed-model repeated measure was used to identify biomarkers altered by baricitinib. The relationship between changes in biomarkers and clinical measures was evaluated using correlation analysis.ResultsTreatment arms were well balanced for baseline biomarkers, demographics, and disease activity. At week 4, baricitinib 4-mg significantly reduced C1M from baseline by 21% compared to placebo (p < 0.01); suppression was sustained at week 12 (27%, p < 0.001). Baricitinib 4-mg reduced C3M and C4M at week 4 by 14% and 12% compared to placebo, respectively (p < 0.001); they remained reduced by 16% and 11% at week 12 (p < 0.001). In a pooled analysis including all treatment arms, patients with the largest reduction (upper 25% quartile) in C1M, C3M, and C4M by week 12 had significantly greater clinical improvement in the Simplified Disease Activity Index at week 12 compared to patients with the smallest reduction (lowest 25% quartile).ConclusionBaricitinib treatment resulted in reduced circulating biomarkers associated with joint tissue destruction as well as concomitant RA clinical improvement.Trial registrationClinicalTrials.gov NCT01721057; date of registration: November 1, 2012
Highlights
Tissue released blood-based biomarkers can provide insight into drug mode of action and response
Study overview Baseline characteristics and disease activity of the 240 patients included in this analysis were similar among treatment groups and had a similar distribution to the overall study population [13]; baseline concentrations and range/distribution of all biomarkers tested were similar between all three groups (Table 1)
Baricitinib induced a drop in C1M, C3M, and C4M compared to the placebo All biomarkers were within the detectable range at each time point
Summary
Tissue released blood-based biomarkers can provide insight into drug mode of action and response. C3M, which is a peptide released following MMP-mediated cleavage of type III collagen, has been associated with inflammation-driven tissue turnover and fibrosis [6, 7]. Another marker associated with synovial inflammation, C4M, is released following MMP-mediated cleavage of type IV collagen, a major constituent in the basement membrane Changes in this marker have previously been associated with inflammation-driven tissue turnover [8, 9]. A number of blood-based biomarkers have been developed that reflect systemic bone turnover status Examples of such biomarkers include CTX-I, a fragment of type I collagen generated by cathepsin K cleavage that reflects the rate of osteoclastmediated bone resorption. Changes in serum biomarkers associated with joint tissue remodeling include synovial inflammation (C1M, C3M, and C4M), cartilage degradation (C2M), and bone resorption (CTX-I) and formation (osteocalcin)
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