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P516 Serological biomarkers of tissue remodeling are associated with endoscopic remission in Crohn’s disease patients treated with GED-0301 (mongersen)

Mortensen, J.(1);Feagan, B.(2);Bay-Jensen, A.C.(1);Karsdal, M.A.(1);Horan, G.(3);Harris, S.(4);Usikin, K.(3);

(1)Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark;(2)Alimentiv, Clinical Trials, San Diego, United States;(3)Bristol-Myers Squibb, Translational Medicine, Princeton, United States;(4)Bristol-Myers Squibb, Translational Medicine, San Diego, United States

Background

In Crohn’s disease (CD) Smad7 is overexpressed in the intestinal mucosa, where it contributes to a sustained production of inflammatory cytokines, increased matrix metalloproteinase (MMP) activity and chronic inflammation through inhibition of the anti-inflammatory actions of TGF-beta. GED-0301, an anti-sense oligodeoxynucleaotide complementary to the mRNA of Smad7, inhibits the translation and synthesis of the Smad7 protein. We investigated exploratory biomarkers of collagen degradation by MMPs (C1M, C3M, C4M) and collagen formation (PRO-C3, PRO-C4 and PRO-C5) and their association with endoscopic remission in CD patients treated with GED-0301.

Methods

63 CD patients were randomized (1:1:1) to 4, 8 or 12 weeks oral, blinded GED-0301 160 mg daily (ClinicalTrials.gov no: NCT02367183). Simple endoscopic score for CD (SES-CD) (centrally read) was used to evaluate disease activity. Remission was defined as a SES-CD≤4 score at week 12. 54 CD patients completed the 12-week induction phase.  Serum biomarkers measured by competitive ELISA se included C1M, C3M, C4M, PRO-C3, PRO-C4, PRO-C5 at baseline, week 4, week 8 and week 12. Spearman rho correlation was applied to evaluate the association with biomarkers and SES-CD score.

Results

Seven patients (11%) achieved a SES-CD≤4 at week 12.  At baseline and at week 12 the biomarkers, C1M (baseline: r=0.36, P=0.005; wk12: r=0.47, P=0.0007), C3M (baseline: r=0.46, P=0.0002; wk12: r=0.28, P=0.047), C4M (baseline: r=0.40, P=0.002; wk12: r=0.36, P=0.011)  PRO-C4 (baseline: r=0.36, P=0.004; wk12: r=0.35, P=0.013), and PRO-C5 (baseline: r=0.30, P=0.022) correlated with SES-CD (table 1). Remitters at baseline showed a numerically lower serum levels of C1M (54ng/mL vs. 65ng/mL), C3M (14.7ng/mL vs. 16.5ng/mL), PRO-C4 (241ng/mL vs. 299ng/mL) and PRO-C5 (442ng/mL vs. 660ng/mL) compared to non-remitters. The biomarkers C1M (P<0.05), C4M (P<0.05) and PRO-C5 (P<0.05) were significantly suppressed in remitters at week 12 compared to non-remitters (figure 1). The same biomarkers also demonstrated sustained suppression  of serum concentrations  at week 4, 8 and 12 (C1M: 21.6% decrease from baseline at week 12; C4M: 15% decrease from baseline at week 12; PRO-C5: 26.6% decrease from baseline at week 12) in remitters compared to non-remitters.

Figure 1: C1M, C4M, PRO-C5 serum levels in endoscopic remitters vs non-remitters and absolute values and percentage change from baseline. Asterisks (*) depicts statistical significant difference between remitters and non-remitters, *p<0.05.

Conclusion

Biomarkers of tissue remodeling correlated with the SES-CD scores of CD patients treated with mongersen. Patients s who achieved remission based on endoscopic criteria showing greater suppression of these biomarkers relative to non-remitters. Collectively, these data suggest that biomarkers of tissue remodeling may be useful to monitoring disease activity and mucosal changes in CD patients.

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