Two-year open-label data from the MAESTRO-NAFLD-1 compensated cirrhosis arm (F4c) reported a mean reduction in liver stiffness by VCTE of 7.9 kPa in patients with baseline platelets below 100,000/µL and 6.4 kPa in those above 100,000/µL. Among the lower-platelet cohort, Baveno risk categories for clinically significant portal hypertension shifted favorably over two years: CSPH declined from 50% to 35%, probable CSPH from 43% to 26%, and no/low CSPH increased from 7% to 39%, with two-thirds of all treated patients moving to lower-risk categories. Treatment interruption between years one and two (mean 77 days) attenuated gains that generally returned upon re-initiation. Across MAESTRO, patients reported sustained improvements in disease-specific quality-of-life domains; safety remained consistent with prior studies, with low discontinuation and no changes in bone mineral density.
The core development is Madrigal’s readout from the compensated MASH cirrhosis population in MAESTRO-NAFLD-1, including a high-risk subgroup often excluded from F4c trials (platelets <100,000/µL), and new analyses from the open-label extension showing that pauses in therapy (mean 111 days) reversed earlier biomarker improvements, which were restored with resumed treatment. The company also presented pooled HRQoL findings showing sustained benefit in cirrhotic and non-cirrhotic cohorts. Rezdiffra is already approved in the U.S. and Europe for noncirrhotic MASH with moderate to advanced fibrosis (F2–F3) under an accelerated pathway; it is not approved in cirrhosis. Madrigal’s confirmatory outcomes program in compensated cirrhosis (MAESTRO-NASH OUTCOMES) is fully enrolled and includes patients with low platelets. Strategically, this is a flank move to extend Rezdiffra’s footprint into F4c, where the medical need is high and no therapy is approved. By foregrounding noninvasive fibrosis, portal hypertension risk scores, and HRQoL alongside tolerability, Madrigal is building a cohesive narrative for regulators and payers that connects surrogate improvements to clinical trajectory. The treatment-interruption analyses are also doing double duty: clinically, they frame MASH as a chronic condition requiring continuous therapy; commercially, they set expectations for ongoing use and adherence. The tension is that these data are open-label and biomarker-driven in a population where regulators will prioritize hard outcomes (decompensation, transplant-free survival). The company is signaling confidence, but the conversion from signal to label expansion will hinge on the trial’s outcomes. For sites and CROs, the operational read-through is clear. F4c development with low-platelet inclusion will push trials into hepatology centers with elastography capacity, endoscopy linkage, and routine application of Baveno criteria—raising the bar on imaging standardization and longitudinal risk scoring. The interruption effect elevates adherence management from a commercial concern to a protocol-critical element; expect sponsors to tighten visit cadence, deploy adherence tech, and fortify patient support to minimize therapeutic gaps. Imaging vendors and central readers stand to see increased demand as noninvasive endpoints further entrench in cirrhosis programs. Payers will watch HRQoL signals and CSPH risk migration for health-economic relevance, but will likely reserve judgment until outcomes data clarify event reduction. Next, attention shifts to MAESTRO-NASH OUTCOMES: timing of first adjudicated decompensation events, subgroup performance in patients with low platelet counts, and concordance between VCTE/Baveno shifts and clinical endpoints. If event curves separate, Madrigal can credibly pursue label expansion into compensated cirrhosis and pressure-test noninvasive measures as supportive evidence. If not, the field may pivot to combination strategies with FGF21 or incretin-based agents to drive more profound antifibrotic effects. Operationally, watch for protocol amendments that harden adherence controls and for broader site networks to accommodate elastography throughput. The unresolved questions are durability beyond 2 years, real-world adherence in patients with metabolic comorbidity, and whether biomarker improvements translate into reduced portal hypertension complications at a level that satisfies regulators and payers.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
