P653 Impact of ozanimod on type III collagen turnover biomarkers and the association with ozanimod efficacy in patients with moderately to severely active ulcerative colitis: Results from the phase 3 True North study

Abstract

Abstract Background Ozanimod (OZA), an oral sphingosine 1-phosphate 1 and 5 receptor modulator, was efficacious and well tolerated for up to 52 wk in adults with moderately to severely active ulcerative colitis (UC) in the phase 3 True North study (NCT02435992). Alterations in the degradation and formation of type III collagens, a major component of the extracellular matrix of the intestinal wall, may play a role in the pathogenesis of UC. The objective of this analysis was to assess the effect of OZA on type III collagen levels and turnover and the association of type III collagen levels with OZA efficacy in the True North study. Methods In a 10-wk induction period, patients (pts) in Cohort 1 were randomised to receive oral OZA 0.92 mg (n=429) or placebo (PBO) once daily (n=216) in a double-blind manner and pts in Cohort 2 received open-label OZA at the same daily dose (n=367). At Week (W) 10, pts with a clinical response to OZA in either cohort underwent rerandomisation to receive double-blind OZA (n=457) or PBO (n=69) for 52 wk (maintenance period). Type III collagen biomarker plasma levels were assessed at baseline (BL), W10, and W52. Associations between type III collagen levels and disease activity or efficacy outcomes were assessed using Spearman’s rho correlation and logistic regression, respectively. Results At W10, treatment with OZA resulted in significantly decreased collagen type III degradation (C3M) (Figure 1A), increased collagen formation (PRO-C3) (Figure 1B), and decreased collagen turnover (C3M/PRO-C3) (Figure 1C). Significant reductions in C3M and C3M/PRO-C3 were observed in pts with vs without a clinical response in all treatment groups (P<0.001), while significant increases in PRO-C3 were observed in responders vs nonresponders (P<0.001; Cohort 1 only). The significantly greater reductions in C3M/PRO-C3 were observed with OZA vs PBO regardless of prior exposure to biologics or tumour necrosis factor inhibitors. Changes in C3M, PRO-C3, and C3M/PRO-C3 levels from BL to W10 were significantly correlated with improvements in all disease activity scores from BL to W10 with OZA and PBO. These changes in C3M, PRO-C3, and C3M/PRO-C3 continued through W52 (Figure 1D–F) in pts who continued OZA. At W52, significantly greater reductions in C3M/PRO-C3 ratios were observed in responders vs non-responders in pts who continued OZA. Conclusion These data show that pts with UC who were treated with OZA had decreased plasma type III collagen degradation and turnover, with greater reductions in OZA responders than nonresponders. This further supports the evaluation of collagen type III fragments as potential markers of treatment response in pts with UC.