Introduction. 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 changes in ALT, FibroScan CAP, and Fibroscan VCTE 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. Both doses of resmetirom significantly reduced ALT approximately 30% relative to placebo. In resmetirom treated patients, higher % reductions in ALT were associated with higher NR and FI on biopsy. For resmetirom treated patients without a reduction in ALT, the NASH resolution and fibrosis improvement responses were predicted to be higher than the mean placebo biopsy responses. CAP improved with resmetirom treatment. CAP improvement in individual resmetirom patients predicted both NR and FI responses; however, even no change in CAP predicted biopsy responses higher than the mean for placebo. A CAP improvement in placebo patients did not predict an FI on biopsy. VCTE was improved over time (1-3 years) years relative to placebo in resmetirom treated patients. Resmetirom treated patients, even those with no VCTE improvement, had higher NASH resolution and fibrosis improvement responses than the mean placebo response rates. VCTE improvement was poorly predictive of a placebo FI or NR response; worsening of VCTE in placebo patients predicted a lower-than-average NASH resolution and fibrosis improvement.
Conclusion. ALT was reduced and CAP and VCTE improved was by resmetirom relative to placebo. However, biopsy responses were not always associated with changes in these markers. Additional analyses, including artificial intelligence (AI)-based assessments of histological response, are ongoing.

Stephen Harrison

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