The Cholate Challenge Test Quantified Baseline Functional Heterogeneity and Improvement in Response to Resmetirom in...

In this study of metabolic dysfunction-associated steatohepatitis (MASH)-related Child-Pugh A cirrhosis (MASH cirrhosis), we used the cholate challenge test to quantify baseline disease severity and the subsequent impact of resmetirom treatment.

Thirty-two subjects enrolled in the Phase 3 open-label MAESTRO-NAFLD-1 trial with MASH cirrhosis underwent baseline dual cholate shunt testing, and 25 had subsequent retesting at 28 and 48 weeks. Blood was sampled from 0 to 90 minutes, serum concentrations measured, and parameters of function (disease severity index [DSI]), portal-systemic shunting (SHUNT%), and clinical risk (RISK ACE) were calculated. Responders were defined by > 2-point decrease in DSI, stable subjects by a ΔDSI within ±2, and nonresponders by > 2-point increase.

Baseline DSI (22 ± 7) and SHUNT% (36% ± 16%) were consistent with significant functional impairment and portal-systemic shunting. Responder rates were 14% by 28 weeks and 38% by 48 weeks (P = .0254). After 28 weeks, 87% of subjects were either stable or showed improvement. After 48 weeks, 83% of subjects were either stable or showed improvement, with a significant reduction in mean RISK ACE from baseline (-4.0%, P = .041). Subjects with the greatest hepatic impairment (n = 12, baseline DSI >23) showed the greatest reduction in RISK ACE (-7.5%, P = .053).

MASH cirrhosis is characterized by a broad spectrum of hepatic impairment and portal-systemic shunting. DSI, SHUNT%, and RISK ACE may provide early estimates of potential clinical benefit with resmetirom treatment. MAESTRO-NAFLD-1 was registered at ClinicalTrials.gov (NCT04197479).