Madrigal Announces Additional Positive Results from the Pivotal Phase 3 MAESTRO-NASH Clinical Trial of Resmetirom

Madrigal Pharmaceuticals

CONSHOHOCKEN, PA — Madrigal Pharmaceuticals, Inc. (NASDAQ: MDGL) recently announced additional results from the pivotal Phase 3 MAESTRO-NASH biopsy clinical trial of resmetirom, a liver-directed selective thyroid hormone receptor agonist. The new MAESTRO-NASH data are being presented at the NASH-TAG Conference, taking place from January 5-7, 2023 in Park City, Utah.

In December 2022, Madrigal announced that MAESTRO-NASH 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 including: 1- NASH resolution (ballooning 0, inflammation 0,1 with ≥2 point improvement in NAFLD activity score (NAS) and no worsening of fibrosis) 2- ≥1-stage reduction in fibrosis with no worsening of NAS. New data to be presented at NASH-TAG using a supportive analysis, a “consensus read” by the central pathologists of digitized biopsy images, supplement the positive topline findings and reinforce the strength of results observed in the primary analysis.

Stephen Harrison, M.D., Chairman for both Pinnacle Clinical Research and Summit Clinical Research, San Antonio, Texas, Visiting Professor of Hepatology, Oxford University, and lead Principal Investigator of the MAESTRO studies, commented, “The magnitude and significance of effect observed for both of the dual primary endpoints was almost identical in the primary analysis and supportive consensus read analysis; this finding reinforces the resmetirom efficacy results. In addition, it is greatly encouraging to see the report of consistent treatment effects across a range of histological measures, including reduction by resmetirom of all components of the NAFLD Activity Score, steatosis, inflammation and ballooning, that measure the severity of NASH. The data demonstrate resmetirom’s potential impact on both the underlying steatohepatitis driving the disease and the fibrosis that is strongly associated with progression to negative clinical outcomes.”

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Rohit Loomba MD, MHSc, Director of the NAFLD Research Center, University of California San Diego, and a Principal Investigator of the MAESTRO-NASH study, added, “The MAESTRO-NASH trial recruited patients with three metabolic risk factors who had a prescreening FibroScan to enrich for a high degree of liver fibrosis. An MRI-PDFF conducted during screening confirmed that patients had NAFLD prior to obtaining a liver biopsy. This strategy supported the enrollment of a highly enriched NASH population with serious liver disease.”

Becky Taub, M.D., Chief Medical Officer and President of Research & Development of Madrigal, stated, “In addition to supporting our regulatory filings in the U.S. and Europe, we believe MAESTRO-NASH and the broader MAESTRO Phase 3 program will provide important learnings to advance NASH drug development and gain insight into the NASH patient population. Importantly, the wealth of biomarker and imaging data from the MAESTRO studies will help identify NASH patients in the real world and provide foundation for monitoring treatment response to resmetirom, if approved.”

Additional MAESTRO-NASH Biopsy Results

All baseline and Week 52 biopsies in MAESTRO-NASH were read independently by two central pathologists (glass slides) for the primary analysis read. Each pathologist’s scores showed a similar statistically significant magnitude of response at both doses for both liver biopsy endpoints. The results were combined statistically to generate a single treatment effect.

As a supportive analysis, a “consensus read” of digitized biopsy images was conducted in cases where the two pathologists scores disagreed as to whether the there was a response for either NASH resolution (ballooning 0,1; ≥2-point NAS reduction and no worsening of fibrosis) OR ≥1 stage fibrosis reduction with no worsening of NAS (primary endpoints). The consensus read by the two central pathologists reinforced the positive results observed in the primary analysis (Tables 1-2).

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Table 1. Dual Primary Endpoints (52 Weeks) – Primary Analysis

Primary Endpoint Resmetirom
80 mg
(n=316)
p-value Resmetirom
100 mg
(n=321)
p-value Placebo

(n=318)

NASH resolution (ballooning 0, inflammation 0,1) with ≥2-point reduction in NAS and no worsening of fibrosis 26 % <0.0001 30 % <0.0001 10 %
≥1-stage improvement in fibrosis with no worsening of NAS 24 % 0.0002 26 % <0.0001 14 %
[/su_table] Table 2. Dual Primary Endpoints (52 Weeks) – Consensus Read Supportive Analysis
Primary Endpoint Resmetirom
80 mg
(n=316)
p-value Resmetirom
100 mg
(n=321)
p-value Placebo

(n=318)

NASH resolution (ballooning 0, inflammation 0,1) with ≥2-point reduction in NAS and no worsening of fibrosis 24 % <0.0001 28 % <0.0001 8 %
≥1-stage improvement in fibrosis with no worsening of NAS 24 % <0.0001 26 % <0.0001 12 %
As previously reported, biopsy endpoints were achieved independent of baseline fibrosis stage or diabetes status, including similar statistical significance and magnitude of response at both doses in subgroups of F2, F3, and F2/F3 biopsies.

Other secondary liver biopsy endpoints were achieved at both doses including ≥2 point reduction in NAS (with ≥1 point improvement in ballooning and/or inflammation) and no worsening of fibrosis; ≥2 point reduction in NAS (with ≥1 point improvement in ballooning and/or inflammation) AND ≥1-stage improvement in fibrosis; NASH resolution (with ≥2 point reduction in NAS) AND ≥1-stage improvement in fibrosis; a 2-stage reduction in fibrosis without worsening of NAS; and reduction in all 3 NAS components (ballooning, inflammation and steatosis) without worsening of fibrosis (the steatosis response included ≥1-point improvement in biopsy steatosis grade and/or, for this endpoint only, a MRI-PDFF reduction of ≥30%).

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.

In the first half of 2023, Madrigal intends to file a new drug application seeking accelerated approval of resmetirom. In addition to the efficacy and safety results from MAESTRO-NASH, the filing will be supported by a robust safety database, which also includes the Phase 3 MAESTRO-NAFLD-1 safety study, and two ongoing outcomes studies designed to confirm clinical benefit.

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