Topline Phase 3 Data for NASH Candidate Resmetirom Set Promising Stage

Patients receiving the investigational drug resmetirom achieved significant and clinically relevant reductions in liver fat and atherogenic lipids according to new data from the phase 3 MAESTRO-NAFLD safety study.

According to a statement from Madrigal Pharmaceuticals, the 52-week double-blind placebo-controlled study in patients with presumed nonalcoholic fatty liver disease met primary endpoints, demonstrating resmetirom was safe and well-tolerated at both the 80 mg and top dose of 100 mg, and delivered positiving findings on key cardiometabolic secondary endpoints.

“This positive readout from MAESTRO-NAFLD-1 is a significant milestone for the field. As the first Phase 3 study in NASH that does not rely on liver biopsy to identify patients and measure treatment response, MAESTRO-NAFLD-1 will help accelerate the role of non-invasive imaging and biomarkers in NASH drug development," said MAESTRO principal investigator Stephen Harrison, MD, medical director for Pinnacle Clinical Research, San Antonio, Texas, and visiting professor of hepatologat at Oxford University.

Data "from the first of our two Phase III MAESTRO trials support our conviction that resmetirom has the potential to be the first medication approved for the treatment of patients with NASH and liver fibrosis," said Madrigal CEO Paul Friedman, in the statement." Resmetirom is a liver-directed, thyroid hormone receptor (THR)-β agonist designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity.

Safety and ITT populations

In MAESTRO-NAFLD-1, 972 patients were randomized in the double-blind arms of the study: 969 were included in the safety population (primary outcome) while 943 were included in the modified intent-to-treat (ITT) population, the latter arm desinged to evaluate key secondary endpoints. For inclusion patients were required to demonstrate 3 risk factors for metabolic syndrome, a level of liver fibrosis (measured by FibroScan) consistent with a range of stages of liver fibrosis, and liver fat ≥8% as measured by magnetic resonance imaging proton density fat-fraction (MRIPDFF).

Reporting on the primary outcome measure--serious adverse events (SAEs)--the company said frequency was similar across treatment arms over the 52-week study period. For treatment-emergent AEs (TEAEs) the rate of patients experiencing at least one ranged from 81.8% for placebo, to 88.4% in the 80mg resmetirom group. The rate of TEAEs greater/equal grade 3 also was

Madrigal states that the AEs reported most frequently among resmetirom-treated patients were typically mild diarrhea or increased stool frequency at the beginning of therapy, which occurred at 9% and 17% over the placebo rate in the 80mg and 100mg dose groups, respectively.

comparable across the 3 groups, the highest seen in those treated with placebo (9.1%) and the lowest among those treated with the 80mg active study drug. The overall discontinuation rate, according to the statement, was 2.17%.

Secondary endpoints were assessed in the 943-patient modified ITT group and were characterized by "significant reductions" from baseline in liver fat as well as a decline in levels of LDL-C, ApoB, and triglycerides.

Specifically, reduction on MRI-PDFF at week 16 for the 80mg dose group was -41% and for the 100 mg group, -48%, both p<.001, compared with -6% for patients receiving placebo. The results showed, moreover, that the 100mg dose was associated with a -14.4% decline in cholesterol and -16.6% drop in ApoB at week 24, also both p<.001. Observed declines in those measures for the 80mg dose group were somewhat less pronounced.

Safety evaluation is imperative

“These positive results from the first of our two Phase 3 MAESTRO trials support our conviction that resmetirom has the potential to be the first medication approved for the treatment of patients with NASH and liver fibrosis," said CEO Friedman. He added that these blinded and placebo-controlled findings reinforce phase 2 and open-label phase 3 safety data from an even larger study population followed for more than 1 year. Friedman further emphasized the imperative for rigorous safety evaluation in development of NASH medications because the potential population for treatment with an approved drug is so large.

"We see a safety and tolerability profile for resmetirom in this study of nearly one thousand patients treated for 52 weeks that, similar to earlier studies, leads to very low adverse event discontinuation rates. We look forward to presenting additional analyses of safety and efficacy data from MAESTRO-NAFLD-1 at future scientific congresses.”