Serial measurements of NIS2+® enable monitoring disease evolution in patients with MASH: A retrospective cohort analysis

Background: There are no approved non-invasive tests for monitoring disease evolution in patients with MASH. We evaluated the potential of NIS2+ ® as a monitoring biomarker to track disease evolution and detect significant improvement in liver histology among patients with at-risk MASH. Methods: All patients enrolled in the RESOLVE-IT phase 3 clinical trial with biopsy-proven at-risk MASH at baseline and NIS2+ ® scores available on all 8 study visits were selected (N=614). Mean follow-up was 19 months. The ability of NIS2+ ® to detect achievement of FDA-recommended histological endpoints (MASH resolution, fibrosis improvement) was evaluated by calculating the AUCs and monitoring performances (sensitivity, specificity, PPV, NPV) at specific thresholds of different NIS2+ ® -based metrics (delta, percentage change, mean). Results: NIS2+ ® changes over time were significantly associated with disease activity evolution and fibrosis regression. A reduction of 0.10 unit in NIS2+ ® score led to a 31% and 14% increase in the odds of MASLD activity score (MAS) improvement and fibrosis regression, respectively, and a 25% decrease in the odds of MAS worsening ( p <0.001 for all). NIS2+ ® -based metrics achieved larger AUC values than ALT-based metrics for detecting MASH resolution and FIB-4–based metrics for fibrosis improvement. Among the 3 metrics, the mean NIS2+ ® scores per patient over 4 visits achieved the highest AUC for MASH resolution (0.758) and fibrosis improvement (0.700). A 24% decrease in NIS2+ ® scores was associated with high specificity (≥0.80) and a sensitivity of 0.53 for the detection of MASH resolution and 0.45 for fibrosis improvement. Conclusions: NIS2+ ® has the potential to effectively monitor MAS and fibrosis changes in patients with MASH, allowing detection of contrasting patterns of histological change in the clinic and histological endpoints in clinical trials.