NIS2+TM As a Screening Tool to Optimize Patient Selection in Metabolic Dysfunction-Associated Steatohepatitis Clinical Trials.

Background & Aims Strategies to reduce liver biopsy (LB) screen failures through better patient selection are needed for clinical trials. Standard fibrosis biomarkers were not derived to detect "at-risk" metabolic dysfunction-associated steatohepatitis (MASH; MASH with metabolic dysfunction-associated steatotic liver disease score >= 4 and fibrosis stage >= 2). We compared the performance of screening pathways that incorporate NIS2+(TM), an optimized version of the blood-based NIS4 (R) technology designed to identify at-risk MASH, with those incorporating fibrosis (FIB)-4 within the RESOLVE-IT clinical trial (NCT02704403), aiming for optimized selection of patients for LB. Methods A retrospective simulation analysis was conducted in the RESOLVE-IT screening pathway (RSP) cohort. LB failure rate (LBFR), number of patients needed to screen, and overall cost estimations of different pathways were calculated for a range of NIS2+(TM) and FIB-4 cut-offs and compared with those of the RSP, which relied on investigators' local practices. An analysis of potential recruitment bias based on histology, sex, age, or comorbidities was performed. Results The analysis cohort included 1,929 patients, 765 (40%) with at-risk MASH. The NIS2+(TM) pathway resulted in a significantly lower LBFR (39%) compared with the FIB-4 pathway (58%) or the RSP (60%) when using cost-optimized cut-offs (NIS2+(TM), 0.53; FIB-4, 0.58). For every 1,000 inclusions, NIS2+(TM) significantly reduced unnecessary LBs (632 vs. 1,522; -58%) and screening costs (US$12.7 million vs. US$15.0 million) vs. the RSP, while the number of patients needed to screen increased moderately (3,220 to 4,033). NIS2+(TM) alone is better than FIB-4 alone or combined with FIB-4. Conclusions This analysis demonstrated that patient selection for LB using NIS2+(TM) significantly reduced unnecessary biopsies and screening costs, which could greatly improve the feasibility of MASH clinical trials.