Longitudinal correlations between MRE, MRI-PDFF, and liver histology in patients with non-alcoholic steatohepatitis: Analysis of data from a phase II trial of selonsertib.

BACKGROUND & AIMS: Non-invasive tools for monitoring treatment response and disease progression in non-alcoholic steatohepatitis (NASH) are needed. Our objective was to evaluate the utility of magnetic resonance (MR)-based hepatic imaging measures for the assessment of liver histology in patients with NASH. METHODS: We analyzed data from patients with NASH and stage 2 or 3 fibrosis enrolled in a phase II study of selonsertib. Pre- and post-treatment assessments included centrally read MR elastography (MRE)-estimated liver stiffness, MR imaging-estimated proton density fat fraction (MRI-PDFF), and liver biopsies evaluated according to the NASH Clinical Research Network classification and the non-alcoholic fatty liver disease activity score (NAS). RESULTS: Among 54 patients with MRE and biopsies at baseline and week 24, 18 (33%) had fibrosis improvement (≥1-stage reduction) after undergoing 24 weeks of treatment with the study drug. The area under the receiver operating characteristic curve (AUROC) of MRE-stiffness to predict fibrosis improvement was 0.62 (95% CI 0.46-0.78) and the optimal threshold was a ≥0% relative reduction. At this threshold, MRE had 67% sensitivity, 64% specificity, 48% positive predictive value, 79% negative predictive value. Among 65 patients with MRI-PDFF and biopsies at baseline and week 24, a ≥1-grade reduction in steatosis was observed in 18 (28%). The AUROC of MRI-PDFF to predict steatosis response was 0.70 (95% CI 0.57-0.83) and the optimal threshold was a ≥0% relative reduction. At this threshold, MRI-PDFF had 89% sensitivity and 47% specificity, 39% positive predictive value, and 92% negative predictive value. CONCLUSIONS: These preliminary data support the further evaluation of MRE-stiffness and MRI-PDFF for the longitudinal assessment of histologic response in patients with NASH. LAY SUMMARY: Liver biopsy is a potentially painful and risky method to assess damage to the liver due to non-alcoholic steatohepatitis (NASH). We analyzed data from a clinical trial to determine if 2 methods of magnetic resonance imaging - 1 to measure liver fat and 1 to measure liver fibrosis (scarring) - could potentially replace liver biopsy in evaluating NASH-related liver injury. Both imaging methods were correlated with biopsy in showing the effects of NASH on the liver.

Evolocumab lowers LDL-C safely and effectively when self-administered in the at-home setting.

Evolocumab has been shown to consistently reduce low-density lipoprotein cholesterol (LDL-C) across populations. The phase 3 studies included administration in the home-use and in-clinic settings but did not specifically evaluate the feasibility of home-use administration. Two clinical studies enrolled patients with hypercholesterolemia or mixed dyslipidemia on statin therapy and with/without ezetimibe received evolocumab in the home-use setting. Patients were randomized to self-administer evolocumab using one of two injection devices biweekly over 6 weeks (autoinjector or prefilled syringe; n = 149; ClinicalTrials.gov, NCT01849497) or monthly over 12 weeks (autoinjector or automated minidoser; n = 164; NCT01879319). The first self-administration occurred in the in-clinic setting, and two more were performed in the at-home setting. Patients were successful in self-administering evolocumab in the home-use setting in approximately 95 % of attempts and experienced LDL-C reductions from baseline to week 6 or the mean of weeks 10 and 12 of approximately 65 %. Rates of successful self-administration and LDL-C reduction were similar across dosing schedules and study devices. Adverse events were similar between randomized groups and generally mild in severity. In two clinical studies, therefore, patients were able to successfully self-administer evolocumab in both the in-clinic and at-home settings regardless of which dosing schedule or device they used.