Madrigal Pharmaceuticals announces results from Phase 3 MAESTRO-NASH trial

Madrigal Pharmaceuticals announced positive topline results from the pivotal Phase 3 MAESTRO-NASH biopsy clinical trial of resmetirom, a liver-directed selective thyroid hormone receptor agonist. MAESTRO-NASH, a registrational Phase 3 trial, has achieved both liver histological improvement endpoints that FDA proposed as reasonably likely to predict clinical benefit to support accelerated approval for the treatment NASH with liver fibrosis. MAESTRO-NASH Week 52 Results: MAESTRO-NASH is an ongoing blinded Phase 3 clinical trial, and enrolled patients continue on therapy after the Week 52 liver biopsy for up to a total of 54 months to accrue hepatic clinical outcome events including histologic conversion to cirrhosis and hepatic decompensation events. Efficacy Results: Patients meeting eligibility requirements for MAESTRO-NASH were randomized 1:1:1 to receive resmetirom 80 mg, resmetirom 100 mg, or placebo taken orally once daily. Baseline characteristics in the 966 randomized patients in the primary analysis NASH population were balanced across treatment arms. Medications included 49% on statins, 14% on GLP-1 agonists, 14% on SGLT2 inhibitors. A second biopsy was conducted after 52 weeks of treatment for assessment of the dual primary endpoints. The primary efficacy analysis assessed histological response at 52 weeks in 955 patients with biopsy-confirmed NASH with fibrosis that excluded 11 ITT patients who had their Week 52 biopsy after Week 60 due to COVID-related reasons per regulatory guidelines. Patients without a second biopsy due to early study discontinuation or missing liver biopsy were included and considered as non-responders in the primary efficacy analyses. The compliance to treatment was high and minimally impacted by COVID pandemic restrictions. Biopsy endpoints were achieved independent of baseline fibrosis stage or diabetes status, including similar statistical significance and magnitude of effect at both doses in subgroups of F2, F3, and F2/F3 patients. Other secondary liver biopsy endpoints that were achieved at both doses include greater than or equal to2 point reduction in NAS with no worsening of fibrosis, greater than or equal to2 point reduction in NAS with greater than or equal to1-stage improvement in fibrosis, NASH resolution with greater than or equal to1-stage improvement in fibrosis, and a 2-stage reduction in fibrosis without worsening of NAS. Multiple secondary endpoints were achieved, including statistically significant reduction from baseline in liver enzymes. Reductions in atherogenic lipids and lipoproteins, fibrosis biomarkers and imaging tests were observed in resmetirom treatment arms as compared with placebo. Safety Results: Resmetirom was safe and well-tolerated at both the 80 mg and 100 mg doses. The frequency of serious adverse events was similar across treatment arms: 11.8%, 12.7% and 12.1% for the 80 mg, 100 mg, and placebo groups, respectively. The rate of study discontinuation for adverse events was low: 2.8%, 7.7% and 3.7% for the 80 mg, 100 mg and placebo groups, respectively. SAEs occurred at expected rates based on the patient population.