Abstract

Background: MAESTRO-NASH (NCT03900429) is an ongoing 54-month, randomized, double-blind, placebo-controlled Phase 3 trial evaluating the efficacy of resmetirom in patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) and fibrosis. 966 patients with biopsy-confirmed NASH were randomized 1:1:1 to resmetirom 80mg, resmetirom 100mg, or placebo administered once daily. Histologic endpoints were assessed after 52 weeks. Dual primary endpoints at Week 52 were achieved with both resmetirom 80mg and 100mg: NASH resolution with no worsening of fibrosis (NR) or ≥1-stage reduction in fibrosis with no worsening of NAS (FR).

Methods: Adults with ≥3 metabolic risk factors, liver stiffness ≥8.5 kPa, hepatic fat ≥8%, biopsy-confirmed NASH with F1B-F3 fibrosis, and NAS ≥4 were eligible to participate in MAESTRO-NASH. The relationship of non-invasive measures with histological response (NR and/or FR) in the resmetirom 80mg, resmetirom 100mg, and placebo groups was assessed.

Results: Patients with biopsy-confirmed NASH with fibrosis had high metabolic risk including obesity (mean BMI=36), type 2 diabetes (70%), hypertension (78%), and 10-year ASCVD risk score >14. Baseline mean (SD) FibroScan VCTE was 13.3 (6.8), 13.6 (7.1), and 12.9 (5.6) kPa for the resmetirom 80mg, resmetirom 100mg, and placebo groups. Baseline ELF across all fibrosis groups was 9.8 (0.87). FIB-4 across all dose groups was 1.3. Median reduction in MRI-PDFF was 42% and 52% in the paired biopsy population at resmetirom 80mg and 100mg. Among patients treated with resmetirom 80mg or 100mg who achieved a ≥30% reduction from baseline in MRI-PDFF, NR was observed in 28% and 38% and FR in 17% and 18% more patients than placebo. Among resmetirom-treated patients with a ≥120% increase in SHBG (marker of drug exposure), NR was seen in 34% and 37% and FR in 22% and 20% more resmetirom 80mg and 100mg patients than placebo. A ≥30% PDFF response was observed in 96%, 88%, and 92% of resmetirom 100mg NR, FR, and NR and/or FR responders. Half of the resmetirom ≥30% PDFF responders without NR or FR showed ≥2-point NAS reduction. On biopsy, NR correlated with FR (r²=0.30). Additional correlates of NR and FR at resmetirom 100mg included reduction in PDFF (r²=0.39, 0.23); ALT (r²=0.20, 0.24); and liver volume (r²=0.25, 0.18). Weaker correlations were observed with AST and FibroScan CAP. Correlations at resmetirom 80mg were similar. LDL-C lowering did not correlate with either NR or FR. Although MRE (kPa), Fibroscan VCTE, and ELF were reduced with resmetirom treatment, the reduction in these non-invasive measures did not correlate with NR or FR.

Conclusion: Achievement of NASH resolution and fibrosis reduction was associated with a ≥30% reduction from baseline in MRI-PDFF and ≥120% increase in SHBG at both resmetirom doses (80 and 100mg). Additional analyses, including artificial intelligence (AI)-based assessments of histological response, are ongoing.