Madrigal Updates on Rezdiffra: Positive Two-Year Data from MAESTRO-NAFLD-1 Trial

(MASH), today announced encouraging two-year results from the open-label compensated MASH cirrhosis (F4c) segment of the Phase 3 MAESTRO-NAFLD-1 trial. In this study, 122 patients experienced significant improvements from baseline in liver stiffness, liver fat, fibrosis biomarkers, liver volume, and risk scores for clinically significant portal hypertension (CSPH).

Dr. Naim Alkhouri, Chief Academic Officer at Summit Clinical Research and Director of the Steatotic Liver Disease Program at the Clinical Research Institute of Ohio, stated, “Rezdiffra demonstrated broad, sustained efficacy across multiple noninvasive parameters at two years of treatment. A high, statistically significant percentage of patients with CSPH or probable CSPH at baseline shifted to lower risk categories.” He also emphasized that a larger placebo-controlled study is necessary to confirm the benefits of Rezdiffra in F4c patients, but current data is promising, particularly for high-risk individuals nearing liver decompensation as they await the ongoing Phase 3 MAESTRO-NASH OUTCOMES trial results.

Understanding CSPH and Its Impact

CSPH is a significant consequence of cirrhosis, leading to severe complications such as ascites, variceal bleeding, and hepatic encephalopathy. Patients with MASH who progress to cirrhosis have a 42 times higher risk of liver-related mortality.

Trial Design and Key Findings

The MAESTRO-NAFLD-1 trial included an open-label active treatment arm for patients with compensated MASH cirrhosis. Following one year of treatment, 122 patients had the option to enroll in an open-label extension, with 113 completing two years of treatment. At baseline, 35% of patients met the Baveno criteria for CSPH, 14% for probable CSPH, and 51% for no/low CSPH. The Baveno criteria assess CSPH risk through a combination of vibration-controlled transient elastography (VCTE) and platelet count.

By year two, 65% of patients with CSPH at baseline moved into lower risk categories, with 42% shifting to no/low CSPH and 23% to probable CSPH. Among those with probable CSPH initially, 57% moved into the no/low CSPH category. This improvement was statistically significant compared to baseline. Similar trends were noted using a modified Baveno criteria that included magnetic resonance elastography (MRE) and Enhanced Liver Fibrosis (ELF) tests.

As previously reported, there was a mean reduction of 6.7 kPa in liver stiffness at the two-year mark, which was statistically significant. In a responder analysis, 51% of patients showed at least a 25% improvement in liver stiffness, a change linked to a lower risk of end-stage liver disease. Notably, 35% of patients achieved liver stiffness measurements that indicate F3 fibrosis, suggesting potential reversal of cirrhosis.

Safety Profile

Safety data remained consistent with previous studies, showing that Rezdiffra was well-tolerated with a low rate of discontinuation due to adverse effects. The most commonly reported adverse events included diarrhea, COVID-19, and nausea, with two deaths not attributable to Rezdiffra.

Dr. David Soergel, Chief Medical Officer of Madrigal, noted, “Lower thyroid-hormone receptor-beta (THR-β) activity in the liver is predictive of hepatic decompensation in patients with MASH. This provides a mechanistic rationale for Rezdiffra’s potential to improve outcomes in patients with compensated MASH cirrhosis.” He expressed confidence in the ongoing Phase 3 outcomes trial of Rezdiffra for this patient population.

Upcoming Investor Webcast

On May 13, 2025, at 8 a.m. EDT, Madrigal will host a webcast to discuss the detailed two-year data from the compensated MASH cirrhosis (F4c) arm of the MAESTRO-NAFLD-1 trial. Interested individuals can access the webcast through the investor relations section of the Madrigal website.

About MASH

Metabolic dysfunction-associated steatohepatitis (MASH), previously known as nonalcoholic steatohepatitis (NASH), is a serious liver disease that can progress to cirrhosis, liver failure, and liver cancer. MASH is projected to become the leading cause of liver transplantation in the U.S., especially among women. Patients with MASH who develop moderate to advanced liver fibrosis face a significantly increased risk of liver-related mortality, making early intervention critical.

Currently, around 1.5 million people in the U.S. have been diagnosed with MASH. Madrigal is focused on reaching approximately 315,000 patients with moderate to advanced fibrosis under the care of liver specialists, as awareness and prevalence of MASH grow.

About Rezdiffra

Rezdiffra is a once-daily, oral, liver-directed THR-β agonist targeting key factors associated with MASH. Approved in the U.S., it is indicated for adults with noncirrhotic MASH with moderate to advanced liver fibrosis, in conjunction with diet and exercise. The ongoing MAESTRO-NASH OUTCOMES trial will evaluate Rezdiffra’s efficacy in treated patients compared to placebo.

Current studies seek to confirm Rezdiffra’s clinical benefits, particularly in broader patient populations, including those with compensated MASH cirrhosis. This ongoing research aims to expand treatment indications for Rezdiffra.

# Key Information and Safety Guidelines for Rezdiffra

Prior to starting Rezdiffra, discuss your medical history with your healthcare provider, especially if you have the following conditions:

• Any liver issues besides NASH.
• Gallbladder issues, including gallstones.
• Pregnancy or plans to become pregnant; it’s uncertain if Rezdiffra affects unborn children.
• Breastfeeding; consult your healthcare provider about the safest feeding options if you take Rezdiffra.

Inform your healthcare provider about all medications you take,

including prescription drugs, over-the-counter products, vitamins, and herbal supplements.

• Drug interactions may occur; Rezdiffra can influence how other medications work and vice versa.
• Specifically inform your healthcare provider if you take gemfibrozil for triglyceride management or cyclosporine for immune suppression, as these are not recommended alongside Rezdiffra.
• Additionally, disclose if you’re taking blood thinners like clopidogrel or statin medications for cholesterol management.
• Keep a comprehensive list of your medications to share with your healthcare provider and pharmacist when starting a new treatment.

Potential Side Effects of Rezdiffra

Rezdiffra may lead to severe side effects, including:

• Hepatotoxicity: If you observe symptoms like tiredness, nausea, vomiting, fever, rash, yellowing skin or eyes (jaundice), or upper abdominal pain, stop taking Rezdiffra and contact your healthcare provider immediately.
• Gallbladder issues: Symptoms such as nausea, vomiting, fever, or severe abdominal pain could indicate gallbladder problems, especially if they radiate to your back. Seek immediate medical attention if these arise.

The most common side effects of Rezdiffra include:

diarrhea, nausea, itching, abdominal pain, vomiting, dizziness, and constipation. This list is not exhaustive; consult your healthcare provider or pharmacist for more information.

For medical advice regarding side effects, contact your doctor. You may report side effects to the FDA at 1-800-FDA-1088 or at

www.fda.gov/medwatch

. Additionally, side effects can also be reported to Madrigal at 1-800-905-0324.

For comprehensive prescribing information, including patient details for Rezdiffra, please refer to the relevant documentation.

About Madrigal Pharmaceuticals

Madrigal Pharmaceuticals, Inc. (Nasdaq: MDGL) specializes in developing innovative therapies for metabolic dysfunction-associated steatohepatitis (MASH), a liver disease with significant treatment gaps. The company’s product, Rezdiffra (resmetirom), is an oral THR-β agonist taken once daily, targeting the underlying issues of MASH. It is the first medication approved by the FDA for MASH treatment with moderate to advanced fibrosis (stages F2 to F3). Currently, a Phase 3 trial is assessing Rezdiffra’s efficacy for compensated MASH cirrhosis (stage F4c). For further details, please visit

www.madrigalpharma.com

.

Forward-Looking Statements

This document includes forward-looking statements under the Private Securities Litigation Reform Act of 1995. These statements involve risks and uncertainties, including but not limited to regulatory approval risks, potential delays, competitive market challenges, and financial uncertainties. Reliance should not be placed on these statements as they are applicable only as of their date of issuance. Madrigal does not undertake to update these statements and encourages reviewing SEC filings for related risks and uncertainties, particularly those detailed in the company’s annual report on Form 10-K for the year ending December 31, 2024.

1. Lin H, Lee HW, Yip TC, et al. Vibration-Controlled Transient Elastography Scores to Predict Liver-Related Events in Steatotic Liver Disease.

JAMA

. 2024;331(15):1287–1297.

2. Kendall TJ, Jimenez-Ramos M, Turner F, et al. An integrated gene-to-outcome multimodal database for metabolic dysfunction-associated steatotic liver disease.

Nat Med

. 2023 Nov;29(11):2939-2953.

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