Design of the phase 3 MAESTRO clinical program to evaluate resmetirom for the treatment of nonalcoholic steatohepatitis

Summary Background Non‐alcoholic steatohepatitis (NASH) is a progressive form of non‐alcoholic fatty liver disease (NAFLD) associated with steatosis, hepatocellular injury, inflammation and fibrosis. In a Phase 2 trial in adults with NASH (NCT02912260), resmetirom, an orally administered, liver‐targeted thyroid hormone receptor‐β selective agonist, significantly reduced hepatic fat (via imaging) and resolved NASH without worsening fibrosis (via liver biopsy) in a significant number of patients compared with placebo. Aims To present the design of the Phase 3 MAESTRO clinical programme evaluating resmetirom for treatment of NASH (MAESTRO‐NAFLD‐1 [NCT04197479], MAESTRO‐NAFLD‐OLE [NCT04951219], MAESTRO‐NASH [NCT03900429], MAESTRO‐NASH‐OUTCOMES [NCT05500222]). Methods MAESTRO‐NASH is a pivotal serial biopsy trial in up to 2000 adults with biopsy‐confirmed at‐risk NASH. Patients are randomised to a once‐daily oral placebo, 80 mg resmetirom, or 100 mg resmetirom. Liver biopsies are conducted at screening, week 52 and month 54. MAESTRO‐NAFLD‐1 is a 52‐week safety trial in ~1400 adults with NAFLD/presumed NASH (based on non‐invasive testing); ~700 patients from MAESTRO‐NAFLD‐1 are enrolled in MAESTRO‐NAFLD‐OLE, a 52‐week active treatment extension to further evaluate safety. MAESTRO‐NASH‐OUTCOMES is enrolling 700 adults with well‐compensated NASH cirrhosis to evaluate the potential for resmetirom to slow progression to hepatic decompensation events. Non‐invasive tests (biomarkers, imaging) are assessed longitudinally throughout, in addition to validated patient‐reported outcomes. Conclusion The MAESTRO clinical programme was designed in conjunction with regulatory authorities to support approval of resmetirom for treatment of NASH. The surrogate endpoints, based on week 52 liver biopsy, serum biomarkers and imaging, are confirmed by long‐term clinical liver‐related outcomes in MAESTRO‐NASH (month 54) and MAESTRO‐NASH‐OUTCOMES (time to event).