Biotech Values

[biotech jim]

GILD: Interesting abstract and data from GILD with selonsertib on mi RNAs and correlation with fibrotic state, presented at EASL.

FRI-463
The association of circulating microRNAs (miRs) with liver fibrosis stage and the impact of selonsertib treatment in patients with NASH

Michael Charlton1, Anna Mae Diehl2, Nandita Sarkar3, Biao LI4, Lulu Wang3, Andrew Billin3, Stephen Djedjos3, Mani Subramanian3, Rob Myers3, Nezam Afdhal5, Stephen Caldwell6, Zachary Goodman7, Rohit Loomba8 1University of Chicago, Chicago, United States; 2Duke Clinical Research Institute, Durham, United States; 3Gilead Sciences, Foster City, United States; 4Gilead Sciences, Gilead Sciences, Foster City, United States; 5Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, United States; 6University of Virginia, Charlottesville, United States; 7Inova Fairfax Hospital, Falls Church, United States; 8University of California at San Diego, Division of Gastroenterology, Department of Medicine, San Diego, United States
Email: [e-mail]

Background and Aims: Circulating miRs have been studied as potential biomarkers of NASH. We assessed: 1) associations between miRs and liver fibrosis and 2) the modulation of miR expression in response to selonsertib (SEL) treatment in patients with NASH enrolled in a Phase 2 trial.

Method: Plasma samples were collected from 72 subjects with biopsy-confirmed NASH (NASH CRN F2-3 fibrosis and NAFLD Activity Score [NAS] ≥5). Subjects were treated with SEL alone or in combination with simtuzumab (SIM) or SIM alone for 24 weeks. Liver biopsies were performed at baseline (BL) and week 24 (W24). Selected miRs (n=301) were measured at BL, W12, and W24 by qPCR. Differential expression analysis using the Linear Models for Microarray Data (limma) method and Spearman correlations (rs) were performed. The utility of miRs alone or in combination with other markers to discriminate advanced fibrosis (F3-4 vs. F1-2) or fibrosis response (≥1-stage reduction in fibrosis vs. no improvement at W24 vs. BL) was determined using areas under receiver operating characteristics (AUROC) curves.

Results: At BL, miR-136-5p was 1.58 fold lower in patients with F2 compared to F3 fibrosis (p=0.046). At W24, 10 miRs, including miR-136-5p, showed modest AUROCs (0.63-0.71) for distinguishing patients with advanced vs. mild fibrosis (F3-4 vs. F1-2; Table). Changes in expression of 12 miRs from BL to W24 were significantly correlated with change in fibrosis stage (all p<0.05; Table). Expression of miR-136-5p alone or with CK18-M30 and MRE at W24 most accurately distinguished fibrosis responders from non-responders with AUROCs of 0.73 (95% CI 0.58, 0.89) and 0.89 (95% CI 0.79, 0.98), respectively. Twelve miRs were modulated by SEL treatment. Among them, miR-122-5p, miR- 215-5p, miR-505-3p, miR-885-5p, and miR-34a-5p were down-regulated by SEL treatment with miR- 885-5p having the largest fold change of -1.56 (p=0.005).

Conclusion: In this Phase 2 trial, we identified a panel of miRs associated with hepatic fibrosis and changes in fibrosis following SEL treatment. The accuracy of a miR to determine fibrosis response was enhanced when combined with other biomarkers. These observations require validation in future studies.