Madrigal Pharmaceuticals, Inc. 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. 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.

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; a2-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 anew 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. About the Resmetirom Phase 3 Registration Program for the Treatment of NASH: Madrigal is currently conducting four Phase 3 clinical trials to demonstrate the safety and efficacy of resmetirom for the treatment of NASH: MAESTRO-NASH, MAESTRO-NAFLD-1, MAESTRO-NAFLD-OLE, and MAESTRO-NASH-OUTCOMES.

MAESTRO-NASH is a multicenter, randomized, double-blind, placebo-controlled Phase 3 study of resmetirom in patients with liver biopsy-confirmed NASH and was initiated in March 2019. The subpart H portion of the study enrolled more than 1,000 patients with biopsy-proven NASH (at least half with F3 (advanced) fibrosis, the remainder F2 or F1B (moderate fibrosis) with a few earlier F1 patients, randomized 1:1:1 to receive once-daily resmetirom 80 mg, resmetirom 100 mg, or placebo). After 52 weeks of treatment, asecond liver biopsy is performed.

The dual primary surrogate endpoints on biopsy were NASH resolution with =2-point reduction in NAS (NAFLD Activity Score), and with no worsening of fibrosis OR a1-point decrease in fibrosis with no worsening of NAS. Achievement of either primary endpoint was considered a successful trial outcome. A key secondary endpoint was lowering of LDL-C. Patients enrolled in the MAESTRO-NASH study (up to 2,000 in total) continue on therapy after the initial 52-week treatment period for up to 54 months to accrue and measure hepatic clinical outcome events including progression to cirrhosis on biopsy (52 weeks and 54 months) and hepatic decompensation events, as well as all-cause mortality.

An additional open-label active treatment arm in patients with early (well-compensated) NASH cirrhosis is ongoing. The primary endpoint was to evaluate the safety and tolerability of resmetirom. A separate 52 week Phase 3 clinical trial, an open-label extension study of MAESTRO-NAFLD-1 (MAESTRO-NAFLD-OLE), is ongoing.

Patients in the 52-week Phase 3 MAESTRO-NAFLD-1 study were randomized 1:1:1:1 to receive once-daily resmetirom 80 mg, resmetirom 100 mg, placebo in double-blind arms or resmetirom 100 mg in an open-label arm. MAESTRO-NAFLD-1 (unlike MAESTRO-NASH), did not include a liver biopsy and represents a “real-life” NASH study. Patients with 3 metabolic risk factors were documented with NASH or NAFLD by historical liver biopsy or noninvasive techniques.

Using noninvasive measures, MAESTRO-NAFLD-1 was designed to provide incremental safety information to support the NASH indication as well as provide additional data regarding clinically relevant key secondary efficacy endpoints to better characterize the potential clinical benefits of resmetirom on cardiovascular- and liver-related endpoints. The primary safety endpoint and several key secondary endpoints were met, including LDL-C, apolipoprotein B, and triglyceride lowering and reduction of liver fat as determined by MRI-PDFF. Additional secondary and exploratory endpoints were assessed including reduction in liver enzymes, FibroScan, and MRE scores, and other NASH biomarkers.

Data from the 52-week first1,000 patient portion of MAESTRO-NASH, together with data from MAESTRO-NAFLD-1, MAESTRO-NAFLD-OLE, Phase 2 and Phase 1 data, including safety parameters, will form the basis for a potential subpart H submission to FDA for accelerated approval of resmetirom for treatment of NASH.