Date: Monday, November 6, 2017
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Anabasum (JBT-101) is a non-immunosuppressive, synthetic, CB2 agonist that resolves inflammation and fibrosis in animal models of SSc and reduces TGF-β and collagen production by dcSSc fibroblasts. It showed evidence of clinical benefit in dcSSc in the Phase 2 trial JBT101-SSc-001 (NCT02465437). To provide additional data on the impact of anabasum on SSc, gene expression was analyzed in skin biopsies from trial subjects.
Gene expression data at baseline and end of treatment (Day 85) were used for differential gene expression, pathway enrichment and intrinsic subset assignment, comparing paired skin biopsies from anabasum-treated (N=23) and placebo-treated (N=13) subjects. Overall response was an ACR Composite Response Index in dcSSc (CRISS) score of ≥ 0.2 and skin response was a decrease in modified Rodnan Skin Score (mRSS) ≥ 5 points.
1937 genes were differentially expressed in anabasum arm (False Discovery Rate ≤ 5%) from baseline to Day 85. Genes downregulated from baseline at Day 85 were enriched in inflammatory response, extracellular matrix (ECM) organization, collagen metabolism, response to cytokine and angiogenesis (Bonferroni-corrected p ≤ 0.05). Genes upregulated from baseline at Day 85 were involved in lipid metabolism. These changes were not observed in the placebo arm.
Inflammatory response and ECM organization pathways included many genes important in SSc (e.g. CCL2, CTGF, FN1, ICAM1, IL4R, PDGFB, TGFB1, THBS1, TIMP1 and TNC). Inflammatory response genes decreased in the anabasum arm (Figure 1A, p < 0.0001) but not the placebo arm (Figure 1B, p = 0.3054). Similar reduction was also observed for ECM organization genes (p = 0.0002 for anabasum vs. p = 0.4840 for placebo).
Most CRISS (83%) and all mRSS improvers in the placebo arm were assigned to normal-like intrinsic gene expression subset whereas in the anabasum arm most CRISS (75%) and mRSS (79%) improvers were classified as inflammatory or fibroproliferative (Figure 1C and 1D). Scleroderma Disease Severity Score (SDSS), a gene expression-based mRSS surrogate, decreased at Day 85 in anabasum-treated (Figure 1E, p = 0.0029) but not placebo-treated subjects (Figure 1F, p = 0.9576).
Anabasum induced clinically relevant molecular responses by modulating inflammatory and fibrotic genes and pathways consistent with the resolution of innate immune signaling. Changes in gene expression in the skin of anabasum-treated subjects were accompanied by improvement in CRISS, mRSS and SDSS. Majority of anabasum improvers had increased baseline inflammatory or fibroproliferative gene expression in skin whereas placebo improvers nearly all had increased normal-like gene expression at baseline. This suggests that the normal-like subset identifies subjects that are more likely to improve spontaneously. This report supports further clinical testing of efficacy of anabasum in dcSSc.
To cite this abstract in AMA style:Martyanov V, Nesbeth Y, Cai G, Wood TA, Reder J, Constantine S, White B, Spiera RF, Whitfield ML. Effect of Anabasum (JBT-101) on Gene Expression in Skin Biopsies from Subjects with Diffuse Cutaneous Systemic Sclerosis (dcSSc) and the Relationship of Baseline Molecular Subsets to Clinical Benefit in the Phase 2 Trial [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). http://acrabstracts.org/abstract/effect-of-anabasum-jbt-101-on-gene-expression-in-skin-biopsies-from-subjects-with-diffuse-cutaneous-systemic-sclerosis-dcssc-and-the-relationship-of-baseline-molecular-subsets-to-clinical-benefit/. Accessed May 20, 2018.
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