Introduction

MAESTRO-NASH is an ongoing 54-month, randomized, double-blind, placebo-controlled Phase 3 trial evaluating the efficacy of resmetirom in patients with biopsy-confirmed MASH and fibrosis. 966 patients with biopsy-confirmed NASH were randomized 1:1:1 to resmetirom 80 mg, resmetirom 100 mg, or placebo once daily. Dual primary endpoints at Week 52 were achieved with both resmetirom 80 mg and 100 mg: NASH resolution with no worsening of fibrosis (NR) or ≥1-stage improvement in fibrosis with no worsening of NAS (FI). Both Week 52 liver biopsy endpoints, NR and FI, were achieved. Resmetirom was recently approved for the treatment of adult patients with noncirrhotic NASH and liver fibrosis consistent with F2 to F3 stages. Expert guidance recommends treatment with resmetirom based on staging fibrosis using Vibration-Controlled Transient Elastography (VCTE). EASL recommends stratifying patients using Fibrosis-4 Index (FIB-4). Most guidelines recommend using VCTE cutoffs lower than 10 to <15 kPa for treatment.

Aims & Methods

We assessed results from baseline noninvasive tests (FIB-4, VCTE) against biopsy results in MAESTRO-NASH to measure how well they diagnosed noncirrhotic patients with NASH (consistent
with F2-F3 stages at baseline). We assessed the utility of a lower VCTE cutoff (8.5 to <10 kPa) in capture of F2 and F3 patients who otherwise would be missed. Also evaluated was the addition of
MRE/MRI-PDFF or ELF to VCTE to assess diagnostic utility.

Results

FIB-4 poorly predicted patients in the non-cirrhotic fibrosis stages: F2 (60% patients fell into low-risk) and F3 (40% fell into low-risk). Including a lower cutoff of VCTE (8.5 to <10 kPa) captured
F1B (34% 8.5 to <10 kPa) and many F2 (25% 8.5 to <10 kPa) and F3 patients (19% 8.5 to <10 kPa). The addition of MRE/MRI-PDFF to VCTE increased diagnostic accuracy for F2/F3 to 68% and
F4 to 81%. The addition of the ELF to the VCTE suggested that a low ELF result paired with high VCTE may warrant a VCTE repeat.

Conclusion

Identification of patients with NASH F2 to F3 was achieved with VCTE. F1B are F2 equivalent (F1B is moderate fibrosis on biopsy). Patients with fibrosis stage F4 were effectively ruled out. In addition to VCTE, practitioners may consider expanded noninvasive criteria (ELF, MRE) to help refine fibrosis staging.

Disclosure

This study was supported by Madrigal Pharmaceuticals, Inc.