Abstract

Background: MAESTRO-MASH (NCT03900429), an ongoing, randomized, double-blind, placebo-controlled Phase 3 serial liver biopsy study, achieved both primary endpoints on liver biopsy (MASH resolution and fibrosis reduction) at Week 52 with both resmetirom doses, including a ≥1-stage reduction in fibrosis without worsening of MASH of 24%, 26% (mITT) at 80 and 100 mg resmetirom compared with placebo (14%). As an exploratory endpoint, artificial intelligence slide reading technologies were employed to measure the effect of resmetirom on fibrosis on serial liver biopsy using both continuous and quantitative scoring.

Methods: Fibrosis was estimated as a continuous and categorical score using second harmonic generation (qFibrosis)/two photon excited fluorescence of 768 paired biopsy samples from MAESTRO-MASH. A separate unstained slide was analyzed for qFibrosis (normalized by tissue area and then corrected for qSteatosis (tissue area-steatosis area)). Relative changes in 184 fibrosis parameters were determined.

Results: The analyses were based on a total of 768 slide pairs including a baseline and Week 52 slide that were received and met criteria for quality (<10% missing pairs; <3% excluded for quality). Based on a continuous qSteatosis score, the percent change from baseline in steatosis was 80 mg resmetirom, -36%; 100 mg resmetirom, -46%; placebo, -10%; p<0.0001 for both resmetirom doses. The continuous change from baseline in corrected qFibrosis score was 80 mg resmetirom, -22%; 100 mg resmetirom, -20%; placebo, 3%; p<0.0001 for both resmetirom doses. The categorical qFibrosis stage aligned with the stage assigned by the central pathologists (F1, F2, F3) with the exception that qFibrosis estimated a high fraction (~20%) as F4 at baseline (F4 scored at baseline by the central pathologists were excluded from this study). Based on categorical change in qFibrosis score, there was a significant improvement in fibrosis stage (1-stage or 2-stage improvement) at 80 and 100 mg resmetirom relative to placebo, and less worsening of fibrosis in the resmetirom groups compared with placebo (Table). The percentage showing improvement in qFibrosis (≥1-stage) was higher than scored by the central pathologists and identified 90% of resmetirom responders determined by the central pathologists. Significant correlations were observed between reduction in qFibrosis and reduction in PDFF, ALT, AST, and ELF.

Conclusion: Measurements of fibrosis change using qFibrosis on either a continuous or categorical scale demonstrated a clear improvement and less worsening in fibrosis among resmetirom-treated patients with MASH as compared with placebo-treated patients after 52 weeks.