Healthful Living Rx: MASH Clinical Perspectives

Explore the latest issue of Healthful Living Rx: MASH Clinical Perspectives—a medically reviewed, clinician-focused guide featuring expert insights, peer case studies, evolving clinical guidance, and practical strategies for the evaluation and management of MASH. It has been developed with leading MASH specialists from around the country.

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SUMMER/FALL 2026

MASH Stage & Risk What Matters Now p. 3

SCAN FOR EXPANDED INSIGHTS

Metabolic Liver Disease A Growing Burden p. 10

Beyond ALT & AST Clinical Assessment p. 14

When Severity Shapes Care Clinical Considerations p. 15

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SUMMER/FALL 2026

IN THIS ISSUE

Healthful Living

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MASH The pathway from steatosis to fibrosis to cirrhosis

is a publication of PAC Media Group, Vero Beach, Florida 32963

10 The Growing Burden of Metabolic Liver Disease Epidemiology, metabolic drivers, and implications for patient care

PRESIDENT France Tanguay Kenyon

EDITORIAL DIRECTOR Valerie Latona

CREATIVE DIRECTOR Elle Chan

LEAD MEDICAL WRITER Martica Heaner, PhD

COPY EDITOR Carolyn Waldron

SALES DIRECTOR Renee Tulenko

Patients at Risk: Identifying MASH Early Assessing patients who may benefit from further evaluation

OPERATIONS MANAGER Ellen Reising

MEDICAL ADVISORY BOARD

Fernando Bril, MD Scott Isaacs, MD, FACP, FACE Wajahat Mehal, MD, PhD, DPhil

Beyond ALT & AST Screening and risk assessment for MASLD/MASH

© 2026 PAC Media Group. All rights reserved. This publication is intended for healthcare professionals only. The content is provided for informational purposes and is not a substitute for professional clinical judgment. Although every effort has been made to ensure accuracy, PAC Media Group and its contributors assume no responsibility for errors, omissions, or any outcomes resulting from the use of this information. Clinicians are encouraged to consult current, authoritative resources before making medical decisions. No part of this publication may be reproduced, distributed, or used in any form without prior written permission from PAC Media Group. For inquiries, contact: operations@pacmediagroup.com

When Severity Shapes Care MASH case studies in clinical management

Steatotic liver disease has historically received less attention in metabolic risk evaluation. While HbA1c and cardiovascular risk factors are regularly assessed, more comprehensive evaluation of liver disease has not consistently been incorporated into clinical practice. As a result, many patients may remain undiagnosed until later stages of disease.

Healthful Living Rx 3

Since screening is not routine and the disease process may be mostly asymptomatic, many patients are unaware of the earlier, underlying condition of steatosis. These patients may only learn of it after their disease has advanced to a more severe form. Historically, even in cases when fat in the liver had been spotted through ultrasounds or other scans, the findings have often been considered incidental or of limited clinical significance. 1 “We’ve now learned that what used to be called ‘fatty liver’ or ‘benign steatosis’ is, in fact, not a harmless condition,” says Scott Isaacs, MD, an endocrinologist at Emory University School of Medicine in Georgia and co-author of a 2025 consensus report on the topic for the American Diabetes Association (ADA). “Many of us in endocrinology have cared for patients who were told for years that ‘a little fatty liver’ or mildly abnormal liver enzymes were nothing to worry about until these patients were suddenly presenting with signs of advanced liver disease.” Because liver screenings are not always routine and steatotic liver disease is often asymptomatic, it’s not uncommon for the diagnosis to occur outside the initial point of care. “Many in endocrinology would say, ‘I see plenty of people with type 2 diabetes, but they never complain of a liver problem’ or ‘I’ve never seen anybody with cirrhosis in my clinic,’”

not usually the cause of death. Most people with chronic kidney or liver disease ultimately die from cardiovascular causes, explains Cusi, adding: “The liver disease may never have been diagnosed, despite being present.” All metabolic abnormalities contribute to the overall dysfunction. “Chronic kidney and liver disease promote cardiovascular disease,” says Cusi, “so identifying them and treating them will likely have a positive impact on cardiovascular disease as well.” Evolution of Nomenclature & Staging Research has deepened understanding of the varied pathology of liver disease, clarifying terminology that better describes its etiology and stages. Importantly, advances in disease biology have revealed that steatotic liver disease is about more than just the liver: It’s now understood to reflect systemic metabolic dysfunction that drives progressive liver injury. “When you’re in a state of metabolic unhealthiness, the inflammation and damage that occurs from it are in tissues everywhere,” says Cusi, “from the endothelial layers of your blood vessels to the glomeruli of your kidneys to your liver cells.” nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is now named according to what causes it, rather than what doesn’t (alcohol). In 2023, a multi-organization Delphi What was first known as fatty liver, then coined

explains Kenneth Cusi, MD, FACP, FACE, Chief of the Division of Endocrinology, Diabetes & Metabolism in the Department of Medicine at the University of Florida, in Gainesville, and the lead author of the 2025 ADA consensus report. “But typically, MASLD is asymptomatic—until it’s not. By the time someone gets really sick from liver disease, it happens suddenly.” Care often transitions across specialties as disease progresses, which can limit continuity of care. Another reason for the underdetection of liver disease is that, even though it can be deadly, it is

process dubbed it metabolic-dysfunction-associated steatotic liver disease (MASLD) and, in its more advanced stages, metabolic-dysfunction-associated steatohepatitis (MASH). MetALD is the term now used for patients with MASLD who consume moderate to large amounts of alcohol. 2 The Pathogenesis of MASLD & MASH Because the disease develops over time and there is a known pathway to severe progression, when identified early, MASH may be treatable and, in some cases,

4 Healthful Living Rx

reversible. It starts with steatosis; hepatic triglyceride accumulation initiates the disease continuum. Patients with liver steatosis who have at least one cardiometabolic risk factor (type 2 diabetes, obesity, hypertension, high triglycerides) can be diagnosed with MASLD once other etiologies are excluded. 3 Steatosis leads to fibrosis. The disease progression reflects a complex interaction between metabolic stress, inflammation, and fibrogenesis. MASH is an advanced stage of MASLD that indicates liver cell injury and necrosis that has developed within the broader context of metabolic dysfunction. It reflects the progression from isolated fat accumulation within hepatocytes to the development of inflammation and hepatocyte necrosis (ballooning). There may be minimal to no fibrosis in its earliest stage. 4 Liver disease is increasingly understood as a manifestation of systemic metabolic dysfunction driven by ectopic fat deposition, insulin resistance, and chronic inflammation. Accumulation of toxic lipid species within hepatocytes promotes lipotoxicity, leading to cellular injury through mitochondrial dysfunction and endoplasmic reticulum stress. This sustained metabolic stress triggers inflammatory signaling and hepatocellular damage, with ballooned hepatocytes representing dead and dying cells. Although hepatocytes retain the capacity to regenerate, repeated injury results in maladaptive

the risk of liver failure, liver cancer, and death.” After screening, the rate of fibrosis determines treatment. “The threshold at which to act is when we reach clinically significant fibrosis, or stage F2,” says Cusi, adding that, at this point, if you continue to have metabolic risk factors without intervention, the condition will progress to end-stage liver disease. “But the liver has incredible plasticity,” Cusi says. “So, if you catch a patient when there is moderate scarring, you may be able to reverse it, or freeze it, so it doesn’t advance. MASH with fibrosis staging of F2 or greater is considered to be at-risk MASH.” 6 Prevalence of MASLD & MASH MASLD and MASH are highly prevalent in the U.S.: About 30 percent of adults and 70 percent of adults with type 2 diabetes have MASLD, and around half of those with type 2 diabetes have MASH—and one in five have advanced fibrosis. 3,6 Because this condition is not routinely screened for (and not treated), it represents a growing public health burden and is often identified at more advanced stages of disease. “A common complaint of liver specialists,” says Cusi, “is that by the time a patient is referred to them, they already have cirrhosis.” Importantly, there are opportunities for earlier identification and intervention across the disease continuum. New research has resulted in better

The threshold at which to act is when we reach clinically significant fibrosis, or stage F2. At that point, if you continue to have the typical metabolic risk factors, unless you do something, the condition will progress on a path to end-stage liver disease. —Kenneth Cusi, MD, FACP, FACE

repair with deposition of scar tissue and progressive fibrosis. These processes collectively drive the transition from isolated steatosis to steatohepatitis and advancing hepatic fibrosis. 4,5 Fibrosis progression remains the key determinant of outcomes of MASLD/MASH. Staging (F0–F4) reflects degrees of scarring, synonymous with fibrosis, from no scarring to cirrhosis (F4). As fibrosis advances, so does the risk of liver failure, hepatocellular carcinoma (HCC), and mortality. 6,7 Says Isaacs: “The higher the fibrosis stage, the higher

screening tools (see pp. 12–15) to help identify patients at risk for fibrosis, allowing them to catch it in earlier, and more treatable, stages. As understanding of liver biology evolves, management approaches increasingly address both systemic metabolic drivers, as well as liver-specific disease processes. New therapeutics, in conjunction with more targeted lifestyle interventions, are expanding management options for patients who, if treated earlier, can stop the progression—and sometimes even reverse the disease.

SCAN FOR MASLD, MASH CLINICAL GUIDANCE

Healthful Living Rx 5

Gallbladder-Related Adverse Reactions Cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) were observed more often in Rezdira-treated patients than in placebo-treated patients. The exposure-adjusted incidence rates (EAIRs) for these events were less than 1 per 100 person-years (PY) for all treatment arms. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated. If an acute gallbladder event is suspected, interrupt treatment until the event is resolved. Drug Interaction with Certain Statins An increase in exposure of atorvastatin, pravastatin, rosuvastatin, and simvastatin was observed when concomitantly administered with Rezdira, which may increase the risk of adverse reactions related to these drugs. Dosage adjustment for certain statins is recommended. Monitor for statin-related adverse reactions including, but not limited to, elevation of liver tests, myopathy, The most common adverse reactions with Rezdira (reported in ≥5% of patients and higher compared to placebo) are diarrhea, nausea, pruritus, vomiting, constipation, abdominal pain, and dizziness. Diarrhea and nausea were the most common causes of treatment discontinuation. DRUG INTERACTIONS Clinically Significant Interaction Eects of Strong or Moderate CYP2C8 Inhibitors on Rezdira • Concomitant use with strong CYP2C8 inhibitors (eg, gemfibrozil) is not recommended. Reduce Rezdira dosage if used concomitantly with a moderate CYP2C8 inhibitor (eg, clopidogrel). and rhabdomyolysis. ADVERSE REACTIONS

INDICATION AND IMPORTANT SAFETY INFORMATION INDICATION

Rezdira is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). This indication is approved under accelerated approval based on improvement of MASH and fibrosis. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Limitation of Use: Avoid use in patients with decompensated cirrhosis. WARNINGS AND PRECAUTIONS Hepatotoxicity Hepatotoxicity has been observed with the use of Rezdira. One patient developed substantial elevations of liver biochemistries that resolved when treatment was interrupted. Please see full Prescribing Information for more details on this specific case of Hepatotoxicity [see Warnings and Precautions (5.1)]. Monitor for elevations in liver tests, liver-related adverse reactions, and symptoms/signs of hepatotoxicity (eg, fatigue, nausea, vomiting, right upper quadrant pain or tenderness, jaundice, fever, rash, and/or eosinophilia [>5%]). If hepatotoxicity is suspected, discontinue Rezdira and monitor. If laboratory values return to baseline, weigh the potential risks against the benefits of restarting Rezdira. If laboratory values do not return to baseline, consider drug- induced autoimmune-like hepatitis (DI-ALH) or autoimmune liver disease in the evaluation of elevations in liver tests.

Please see Brief Summary on the following pages and full Prescribing Information at https://www.madrigalpharma.com/Rezdira-us-prescribing-information.

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Visit RezdiraHCP.com to learn more and get patients started.

IMPROVING FIBROSIS & MASH is no longer wishful thinking Rezdira is the first and only treatment for MASH with moderate to advanced fibrosis that activates THR-β directly in the liver 1 For adults with noncirrhotic MASH with moderate to advanced fibrosis, in conjunction with diet and exercise. This indication is approved under accelerated approval based on improvement of MASH and fibrosis. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Limitation of Use: Avoid use in patients with decompensated cirrhosis.

Oral, Once- Daily Dosing 1

Dual E icacy 1

Demonstrated Safety 1

Liver- Directed 1

At Week 52, Rezdira delivers statistically significant fibrosis improvement* with no worsening of steatohepatitis and steatohepatitis resolution † with no worsening of fibrosis. 1

MASH=metabolic dysfunction-associated steatohepatitis.

IMPORTANT SAFETY INFORMATION cont.

Renal Impairment The recommended dosage of Rezdira in patients with mild, moderate, or severe renal impairment is the same as in patients with normal kidney function. Hepatic Impairment Avoid use in patients with decompensated cirrhosis (consistent with moderate to severe hepatic impairment). Moderate or severe hepatic impairment (Child-Pugh Class B or C) may increase the risk of adverse reactions. The safety and eectiveness of Rezdira have not been established in patients with cirrhosis. Trial design: MAESTRO-NASH is an ongoing pivotal Phase 3, multicenter, randomized, double-blind, placebo-controlled trial in 888 patients with biopsy- confirmed MASH with liver fibrosis (F2 or F3). Patients were randomized 1:1:1 to Rezdira (80 mg or 100 mg) or placebo to evaluate the eicacy and safety at 52 weeks. 1,2 *Fibrosis improvement: ≥1-stage improvement in fibrosis with no worsening of steatohepatitis (defined as no increase in score for ballooning, inflammation, or steatosis). 1 † Steatohepatitis resolution: Resolution of steatohepatitis (score of 0-1 for inflammation, 0 for ballooning, and any value for steatosis) with no worsening of fibrosis. 1

Clinically Significant Interactions Aecting Other Drugs • Statins: Limit daily rosuvastatin and simvastatin dosage to 20 mg. Limit pravastatin and atorvastatin dosage to 40 mg. • CYP2C8 Substrates: Monitor patients more frequently for substrate-related adverse reactions if Rezdira is co-administered with CYP2C8 substrates where minimal concentration changes may lead to serious adverse reactions. USE IN SPECIFIC POPULATIONS Pregnancy There are no available data on Rezdira use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Report pregnancies to Madrigal Pharmaceuticals, Inc. Adverse Event Reporting line at 1-800-905-0324 and visit https://pregnancyregistry.madrigalpharma.com for information about a pregnancy safety study. Lactation There is no information regarding the presence of Rezdira in human or animal milk, the eects on the breast-fed infant, or the eects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Rezdira and any potential adverse eects on the breastfed infant from Rezdira or from the underlying maternal condition. Geriatric Use Numerically higher incidence of adverse reactions have been observed in patients ≥65 years of age compared to younger adult patients.

THR- β =thyroid hormone receptor beta. References: 1. Rezdira. Prescribing Information. Madrigal Pharmaceuticals, Inc. 2. Harrison SA et al. N Engl J Med. 2024;390(6):497-509.

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REZDIFFRA ® (resmetirom) Brief Summary of full Prescribing Information INDICATIONS AND USAGE

Adverse Reactions Leading to Discontinuations The exposure-adjusted incidence rates (EAIRs) per 100 person-years (PY) for treatment discontinuation due to any adverse reaction were higher in the REZDIFFRA dosage arms: 4 per 100 PY, 5 per 100 PY, and 8 per 100 PY in placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. Diarrhea and nausea were the most common causes of treatment discontinuation. Common Adverse Reactions Table 1 displays EAIRs per 100 PY for the common adverse reactions that occurred in at least 5% of patients with F2 or F3 fibrosis treated in either drug arm with REZDIFFRA and were greater than that reported for placebo. Table 1: Exposure-Adjusted Incidence Rates (EAIR) of Common Adverse Reactions Reported with REZDIFFRA in Adult Patients with Noncirrhotic NASH (Trial 1) a, b, c Adverse Reactions Leading to Discontinuations The exposure-adjusted incidence rates (EAIRs) per 100 person-years (PY) for treatment discontinuation due to any adverse reaction were higher in the REZDIFFRA dosage arms: 4 per 100 PY, 5 per 100 PY, and 8 per 100 PY in placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. Diarrhea and nausea were the most common causes of treatment discontinuation. Common Adverse Reactions Table 1 displays EAIRs per 100 PY for the common adverse reactions that occurred in at least 5% of patients with F2 or F3 fibrosis treated in either drug arm with REZDIFFRA and were greater than that reported for placebo. Table 1: Exposure-Adjusted Incidence Rates (EAIR) of Common Adverse Reactions Reported with REZDIFFRA in Adult Patients with Noncirrhotic NASH (Trial 1) a, b, c

REZDIFFRA is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). This indication is approved under accelerated approval based on improvement of NASH and fibrosis [see Clinical Studies (14) in the full Prescribing Information] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Limitations of Use Avoid use of REZDIFFRA in patients with decompensated cirrhosis [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3) in the full Prescribing Information] . CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Hepatotoxicity Hepatotoxicity has been observed with use of REZDIFFRA. One patient had normal alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) levels at baseline, who received REZDIFFRA 80 mg daily, developed substantial elevations of liver biochemistries that resolved when treatment was interrupted. After reinitiating REZDIFFRA, the patient had elevations of ALT, AST, and TB. Peak values observed were 58 x upper limit of normal (ULN) for ALT, 66 x ULN for AST, 15 x ULN for TB, with no elevation of alkaline phosphatase (ALP). Elevations in liver enzymes were accompanied by elevations in immunoglobulin G levels, suggesting drug-induced autoimmune-like hepatitis (DI-ALH). The liver tests returned to baseline following hospitalization and discontinuation of REZDIFFRA without any therapeutic intervention. Monitor patients during treatment with REZDIFFRA for elevations in liver tests and for the development of liver-related adverse reactions. Monitor for symptoms and signs of hepatotoxicity (e.g., fatigue, nausea, vomiting, right upper quadrant pain or tenderness, jaundice, fever, rash, and/or eosinophilia [>5%]). If hepatotoxicity is suspected, discontinue REZDIFFRA and continue to monitor the patient. If laboratory values return to baseline, weigh the potential risks against the benefits of restarting REZDIFFRA. If laboratory values do not return to baseline, consider DI-ALH or autoimmune liver disease in the evaluation of elevations in liver tests. Gallbladder-Related Adverse Reactions In clinical trials, cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) were observed more often in REZDIFFRA-treated patients than in placebo- treated patients. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated. If an acute gallbladder event is suspected, interrupt REZDIFFRA treatment until the event is resolved [see Adverse Reactions (6.1) in the full Prescribing Information] . Drug Interaction with Certain Statins An increase in exposure of atorvastatin, pravastatin, rosuvastatin and simvastatin was observed when concomitantly administered with REZDIFFRA [see Clinical Pharmacology (12.3) in the full Prescribing Information] , which may increase the risk of adverse reactions related to these drugs. Dosage adjustment for certain statins is recommended [see Drug Interactions (7.2) in the full Prescribing Information] . Monitor for statin-related adverse reactions including but not limited to elevation of liver tests, myopathy, and rhabdomyolysis. ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: • Hepatotoxicity [see Warnings and Precautions (5.1) in the full Prescribing Information] • Gallbladder-Related Adverse Reactions [see Warnings and Precautions (5.2) in the full Prescribing Information] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of REZDIFFRA was evaluated in two randomized, double-blind, placebo- controlled trials that enrolled a total of 2019 patients. Trial 1 Trial 1 included patients who had noncirrhotic NASH with stages F2 and F3 fibrosis at eligibility (n=888) [see Clinical Studies (14) in the full Prescribing Information] . Trial 1 included patients who had noncirrhotic NASH with stages F2 and F3 fibrosis at eligibility (n=888) [see Clinical Studies (14) in the full Prescribing Information] . An increase in exposure of atorvastatin, pravastatin, rosuvastatin and simvastatin was observed when concomitantly administered with REZDIFFRA [see Clinical Pharmacology (12.3) in the full Prescribing Information] , which may increase the risk of adverse reactions related to these drugs. Dosage adjustment for certain statins is recommended [see Drug Interactions (7.2) in the full Prescribing Information] . Monitor for statin-related adverse reactions including but not limited to elevation of liver tests, myopathy, and rhabdomyolysis. ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: • Hepatotoxicity [see Warnings and Precautions (5.1) in the full Prescribing Information] • Gallbladder-Related Adverse Reactions [see Warnings and Precautions (5.2) in the full Prescribing Information] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions,adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in clinical trials of another drug and may not reflect the rates observed in clinical practice. The safety of REZDIFFRA was evaluated in two randomized, double-blind, placebo- controlled trials that enrolled a total of 2019 patients. Trial 1 Monitor patients during treatment with REZDIFFRA for elevations in liver tests and for the development of liver-related adverse reactions. Monitor for symptoms and signs of hepatotoxicity (e.g., fatigue, nausea, vomiting, right upper quadrant pain or tenderness, jaundice, fever, rash, and/or eosinophilia [>5%]). If hepatotoxicity is suspected, discontinue REZDIFFRA and continue to monitor the patient. If laboratory values return to baseline, weigh the potential risks against the benefits of restarting REZDIFFRA. If laboratory values do not return to baseline, consider DI-ALH or autoimmune liver disease in the evaluation of elevations in liver tests. Gallbladder-Related Adverse Reactions In clinical trials, cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) were observed more often in REZDIFFRA-treated patients than in placebo- treated patients. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated. If an acute gallbladder event is suspected, interrupt REZDIFFRA treatment until the event is resolved [see Adverse Reactions (6.1) in the full Prescribing Information] . Drug Interaction with Certain Statins REZDIFFRA is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). This indication is approved under accelerated approval based on improvement of NASH and fibrosis [see Clinical Studies (14) in the full Prescribing Information] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Limitations of Use Avoid use of REZDIFFRA in patients with decompensated cirrhosis [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3) in the full Prescribing Information] . CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Hepatotoxicity Hepatotoxicity has been observed with use of REZDIFFRA.One patient had normal alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) levels at baseline, who received REZDIFFRA 80 mg daily, developed substantial elevations of liver biochemistries that resolved when treatment was interrupted.After reinitiating REZDIFFRA, the patient had elevations of ALT,AST, and TB. Peak values observed were 58 x upper limit of normal (ULN) for ALT, 66 x ULN for AST, 15 x ULN for TB, with no elevation of alkaline phosphatase (ALP). Elevations in liver enzymes were accompanied by elevations in immunoglobulin G levels,suggesting drug-induced autoimmune-like hepatitis (DI-ALH).The liver tests returned to baseline following hospitalization and discontinuation of REZDIFFRA without any therapeutic intervention.

REZDIFFRA 80 mg Once Daily N=298 n (EAIR d )

REZDIFFRA 100 mg Once Daily N=296 n (EAIR d )

Placebo N=294 n (EAIR d )

Adverse Reaction

Diarrhea Nausea Pruritus Vomiting

52 (14)

78 (23) 65 (18)

98 (33) 51 (15) 36 (10)

36 (9) 18 (4) 15 (4) 18 (4) 18 (4)

24 (6) 27 (7) 20 (5) 22 (5)

24 (6) 27 (7) 20 (5) 22 (5) 17 (4)

30 (8) 28 (8) 27 (7)

Constipation

Abdominal pain

Gastrointestinal Adverse Reactions The incidence of gastrointestinal adverse reactions was higher for the REZDIFFRA drug arms compared to placebo. The EAIRs for gastrointestinal adverse reactions were 57 per 100 PY, 73 per 100 PY, and 89 per 100 PY in the placebo, REZDIFFRA 80 mg once daily, REZDIFFRA 100 mg once daily arms, respectively. Diarrhea typically began early in treatment initiation and was mild to moderate in severity. The median time (Q1 to Q3) to a diarrheal event was 39 (2 to 195) days, 17 (3 to 70) days, and 6 (2 to 54) days in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. Diarrhea typically began early in treatment initiation and was mild to moderate in severity.The median time (Q1 to Q3) to a diarrheal event was 39 (2 to 195) days, 17 (3 to 70) days, and 6 (2 to 54) days in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. Median duration of diarrhea was 9 days for placebo compared to 20 days for both REZDIFFRA 80 mg once daily and REZDIFFRA 100 mg once daily dosage arms. Nausea also began early in treatment and was mild to moderate in severity. Among patients with nausea, the median time (Q1 to Q3) to a nausea event was 85 (24 to 347) days, 28 (2 to 162) days, and 5 (2 to 40) days in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respec- tively. Median duration of nausea was 17 days, 26 days, and 28 days for patients in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. Vomiting and abdominal pain adverse reactions were mild to moderate in severity. Hypersensitivity Reactions Reactions such as urticaria and rash, which may reflect drug hypersensitivity, were observed in patients receiving REZDIFFRA. The EAIRs for urticaria were 0.2 per 100 PY, 0.7 per 100 PY, and 1.5 per 100 PY in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. The EAIRs for rash were 3 per 100 PY in the placebo and REZDIFFRA 80 mg once daily arms compared to 5 per 100 PY in the REZDIFFRA 100 mg once daily arm. Gallbladder-Related Adverse Reactions A higher incidence of cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) was observed in the treatment arms compared to placebo. However, the EAIRs for these events were less than 1 per 100 PY for all treatment arms. Less Common Adverse Reactions Additional adverse reactions that occurred more frequently in the REZDIFFRA arms compared to placebo, in less than 5% of patients, included decreased appetite, flatulence, abnormal feces, dysgeusia, vertigo, arrhythmia, palpitations, depression, erythema, hypoglycemia, tendinopathy, abnormal uterine bleeding. Dizziness 17 (4) a Population includes adult patients with noncirrhotic NASH with liver fibrosis (stages F2 and F3 at eligibility). b Median exposure duration was 68 weeks for placebo, 74 weeks for REZDIFFRA 80 mg once daily, and 66 weeks for REZDIFFRA 100 mg once daily. c EAIRs are per 100 person-years (PY) where total PYs were 435, 435, and 407 for placebo, 80 mg once daily, and 100 mg once daily arms, respectively. 6 (1) 17 (4) a Population includes adult patients with noncirrhotic NASH with liver fibrosis (stages F2 and F3 at eligibility). b Median exposure duration was 68 weeks for placebo, 74 weeks for REZDIFFRA 80 mg once daily, and 66 weeks for REZDIFFRA 100 mg once daily. c EAIRs are per 100 person-years (PY) where total PYs were 435, 435, and 407 for placebo, 80 mg once daily, and 100 mg once daily arms, respectively. 17 (4) d The EAIR per 100 PY can be interpreted as an estimated number of first occur- rences of the adverse reaction of interest if 100 patients are treated for one year. Abbreviations: EAIR, exposure-adjusted incidence rate; PY, person-years; NASH, nonalcoholic steatohepatitis d The EAIR per 100 PY can be interpreted as an estimated number of first occur- rences of the adverse reaction of interest if 100 patients are treated for one year. Abbreviations: EAIR, exposure-adjusted incidence rate; PY, person-years; NASH, nonalcoholic steatohepatitis Gastrointestinal Adverse Reactions The incidence of gastrointestinal adverse reactions was higher for the REZDIFFRA drug arms compared to placebo.The EAIRs for gastrointestinal adverse reactions were 57 per 100 PY, 73 per 100 PY, and 89 per 100 PY in the placebo, REZDIFFRA 80 mg once daily, REZDIFFRA 100 mg once daily arms, respectively. Median duration of diarrhea was 9 days for placebo compared to 20 days for both REZDIFFRA 80 mg once daily and REZDIFFRA 100 mg once daily dosage arms. Nausea also began early in treatment and was mild to moderate in severity. Among patients with nausea, the median time (Q1 to Q3) to a nausea event was 85 (24 to 347) days, 28 (2 to 162) days, and 5 (2 to 40) days in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respec- tively. Median duration of nausea was 17 days, 26 days, and 28 days for patients in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively.Vomiting and abdominal pain adverse reactions were mild to moderate in severity. Hypersensitivity Reactions Reactions such as urticaria and rash, which may reflect drug hypersensitivity, were observed in patients receiving REZDIFFRA.The EAIRs for urticaria were 0.2 per 100 PY, 0.7 per 100 PY, and 1.5 per 100 PY in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively.The EAIRs for rash were 3 per 100 PY in the placebo and REZDIFFRA 80 mg once daily arms compared to 5 per 100 PY in the REZDIFFRA 100 mg once daily arm. Gallbladder-Related Adverse Reactions A higher incidence of cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) was observed in the treatment arms compared to placebo. However, the EAIRs for these events were less than 1 per 100 PY for all treatment arms. Less Common Adverse Reactions Additional adverse reactions that occurred more frequently in the REZDIFFRA arms compared to placebo, in less than 5% of patients, included decreased appetite, flatulence, abnormal feces, dysgeusia, vertigo, arrhythmia, palpitations, depression, erythema, hypoglycemia, tendinopathy, abnormal uterine bleeding. Dizziness 6 (1)

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Data Animal Data

Laboratory Abnormalities Liver Tests

Increases in mean alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were observed in the first 4 weeks after initiating treatment with REZDIFFRA. In both REZDIFFRA dosage arms, the mean elevation in ALT and AST values was less than 1.5 times baseline at 4 weeks after treatment initiation.These values returned to baseline around 8 weeks after initiating treatment. Table 2 presents the frequency of liver test elevations during Trial 1. Increases in mean alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were observed in the first 4 weeks after initiating treatment with REZDIFFRA. In both REZDIFFRA dosage arms, the mean elevation in ALT and AST values was less than 1.5 times baseline at 4 weeks after treatment initiation. These values returned to baseline around 8 weeks after initiating treatment. Table 2 presents the frequency of liver test elevations during Trial 1.

No effects on embryo-fetal development were observed in pregnant rats treated orally with up to 100 mg/kg/day (21 times the maximum recommended dose based on AUC [area under the plasma concentration-time curve]) or in pregnant rabbits treated orally with up to 30 mg/kg/day (2.8 times the maximum recommended dose based on AUC) during the period of organogenesis. Oral administration of 75 mg/kg/day in pregnant rabbits (3.5 times the maximum recommended dose based on AUC) produced an increase in post-implantation loss and decreases in viable fetuses and fetal weight.These effects were likely due to maternal toxicity (i.e., marked reductions in weight gain and food consumption). A pre- and postnatal development study was performed using oral administration of 3, 30, or 100 mg/kg/day in female rats during organogenesis through lactation. Treatment with 100 mg/kg/day (37 times the maximum recommended dose based on AUC) produced increases in number of stillborn, pup deaths during postnatal days 1-4, and pups with absence of milk in stomach. Birthweight was decreased by 10% in this dose group, with recovery to normal body weight thereafter.The effects in offspring were associated with marked reductions in maternal plasma levels of T4 (88% decrease),T3 (79% decrease), and TSH (44% decrease). No effects on postnatal development were observed at doses up to 30 mg/kg/day (7.2 times the maximum recommended dose based on AUC).This study lacked a complete evaluation of physical and neurobehavioral development in offspring; however, no effects of resmetirom were noted in tests of learning and memory. The metabolite MGL-3623 was tested for its effects on embryo-fetal development. No effects were observed in pregnant rats treated orally with up to 100 mg/kg/day MGL-3623 (4.7 times the maximum recommended dose based on AUC for MGL- 3623) during the period of organogenesis. Lactation Risk Summary There is no information regarding the presence of REZDIFFRA in human or animal milk, the effects on the breast-fed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be consid- ered along with the mother’s clinical need for REZDIFFRA and any potential adverse effects on the breastfed infant from REZDIFFRA or from the underlying maternal condition. Pediatric Use The safety and effectiveness of REZDIFFRA have not been established in pediatric patients. Geriatric Use In Trial 1, of the 594 patients with NASH who received at least one dose of REZDIFFRA, 149 (25%) were 65 years of age and older and 13 (2%) were 75 years of age and older [see Clinical Studies (14) in the full Prescribing Information] . No overall differences in effectiveness but numerically higher incidence of adverse reactions have been observed in patients 65 years of age and older compared to In Trial 1, of the 594 patients with NASH who received at least one dose of REZDIFFRA, 149 (25%) were 65 years of age and older and 13 (2%) were 75 years of age and older [see Clinical Studies (14) in the full Prescribing Information] . No overall differences in effectiveness but numerically higher incidence of adverse reactions have been observed in patients 65 years of age and older compared to The recommended dosage of REZDIFFRA in patients with mild, moderate, or severe renal impairment is the same as in patients with normal kidney function [see Clinical Pharmacology (12.3) in the full Prescribing Information] . Hepatic Impairment Avoid use of REZDIFFRA in patients with decompensated cirrhosis (consistent with moderate to severe hepatic impairment). Moderate or severe hepatic impairment (Child-Pugh Class B or C) increases resmetirom C max and AUC [see Clinical Pharmacology (12.3) in the full Prescribing Information] , which may increase the risk of adverse reactions. Avoid use of REZDIFFRA in patients with decompensated cirrhosis (consistent with moderate to severe hepatic impairment). Moderate or severe hepatic impairment (Child-Pugh Class B or C) increases resmetirom C max and AUC [see Clinical Pharmacology (12.3) in the full Prescribing Information] , which may increase the risk of adverse reactions. No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A) [see Clinical Pharmacology (12.3) in the full Prescribing Information] . The safety and effectiveness of REZDIFFRA have not been established in patients with NASH cirrhosis. For more detailed information, please read the full Prescribing Information. Manufactured for and Distributed by: Madrigal Pharmaceuticals, Inc. West Conshohocken, PA REZDIFFRA ® (resmetirom) Rezdiffra ® and its related logo are registered trademarks of Madrigal Pharmaceuticals, Inc. © 2026 Madrigal Pharmaceuticals, Inc. Issued: 12/25 US-PP-RES-00148 v4 No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A) [see Clinical Pharmacology (12.3) in the full Prescribing Information] . The safety and effectiveness of REZDIFFRA have not been established in patients with NASH cirrhosis. For more detailed information, please read the full Prescribing Information. Manufactured for and Distributed by: Madrigal Pharmaceuticals, Inc. West Conshohocken, PA REZDIFFRA ® (resmetirom) Rezdiffra ® and its related logo are registered trademarks of Madrigal Pharmaceuticals, Inc. © 2026 Madrigal Pharmaceuticals, Inc. Issued: 12/25 US-PP-RES-00148 v4 The recommended dosage of REZDIFFRA in patients with mild, moderate, or severe renal impairment is the same as in patients with normal kidney function [see Clinical Pharmacology (12.3) in the full Prescribing Information] . Hepatic Impairment younger adult patients. Renal Impairment No effects on embryo-fetal development were observed in pregnant rats treated orally with up to 100 mg/kg/day (21 times the maximum recommended dose based on AUC [area under the plasma concentration-time curve]) or in pregnant rabbits treated orally with up to 30 mg/kg/day (2.8 times the maximum recommended dose based on AUC) during the period of organogenesis. Oral administration of 75 mg/kg/day in pregnant rabbits (3.5 times the maximum recommended dose based on AUC) produced an increase in post-implantation loss and decreases in viable fetuses and fetal weight. These effects were likely due to maternal toxicity (i.e., marked reductions in weight gain and food consumption). A pre- and postnatal development study was performed using oral administration of 3, 30, or 100 mg/kg/day in female rats during organogenesis through lactation. Treatment with 100 mg/kg/day (37 times the maximum recommended dose based on AUC) produced increases in number of stillborn, pup deaths during postnatal days 1-4, and pups with absence of milk in stomach. Birthweight was decreased by 10% in this dose group, with recovery to normal body weight thereafter. The effects in offspring were associated with marked reductions in maternal plasma levels of T4 (88% decrease), T3 (79% decrease), and TSH (44% decrease). No effects on postnatal development were observed at doses up to 30 mg/kg/day (7.2 times the maximum recommended dose based on AUC). This study lacked a complete evaluation of physical and neurobehavioral development in offspring; however, no effects of resmetirom were noted in tests of learning and memory. The metabolite MGL-3623 was tested for its effects on embryo-fetal development. No effects were observed in pregnant rats treated orally with up to 100 mg/kg/day MGL-3623 (4.7 times the maximum recommended dose based on AUC for MGL- 3623) during the period of organogenesis. Lactation Risk Summary There is no information regarding the presence of REZDIFFRA in human or animal milk, the effects on the breast-fed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be consid- ered along with the mother’s clinical need for REZDIFFRA and any potential adverse effects on the breastfed infant from REZDIFFRA or from the underlying maternal condition. Pediatric Use The safety and effectiveness of REZDIFFRA have not been established in pediatric patients. Geriatric Use younger adult patients. Renal Impairment

Table 2: Frequency of Liver Test Elevations in Trial 1

REZDIFFRA 80 mg Once Daily (%)

REZDIFFRA 100 mg Once Daily (%)

REZDIFFRA 80 mg Once Daily (%)

REZDIFFRA 100 mg Once Daily (%)

Placebo (%)

ALT > 3x ULN ALT > 5x ULN AST > 3x ULN AST > 5x ULN TB a > 2x ULN

2 9 1 1

2 2

4 3

2 2

4 3

a TB elevations include patients with Gilbert syndrome.

Thyroid Function Tests A decrease in levels of prohormone free T4 (FT4) of mean 2%, 13%, and 17% was seen at 12 months in patients treated with placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily, respectively, with minimal changes in active hormone T3 or in TSH.There were no clinical findings associated with FT4 decreases. Additional Safety Data The safety evaluation of REZDIFFRA also included an analysis of an additional randomized placebo-controlled safety trial which included 969 patients from a relevant patient population (placebo [n=318], REZDIFFRA 80 mg once daily [n=327], and REZDIFFRA 100 mg once daily [n=324]). Thyroid Function Tests A decrease in levels of prohormone free T4 (FT4) of mean 2%, 13%, and 17% was seen at 12 months in patients treated with placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily, respectively, with minimal changes in active hormone T3 or in TSH. There were no clinical findings associated with FT4 decreases. Additional Safety Data The safety evaluation of REZDIFFRA also included an analysis of an additional randomized placebo-controlled safety trial which included 969 patients from a relevant patient population (placebo [n=318], REZDIFFRA 80 mg once daily [n=327], and REZDIFFRA 100 mg once daily [n=324]). Data from the safety trial was combined with data from NASH patients with F2 and F3 fibrosis at eligibility (n=888) and data from an additional 162 patients from a relevant patient population enrolled in Trial 1. In the combined safety population (n=2019), the median (Q1 to Q3) age of patients at baseline was 58 (50 to 65) years; 55% were female, 28% were Hispanic, 89% were White, 2% were Asian, and 4% were Black or African American. The safety profile from this combined analysis was similar to that in Trial 1, other than the one case of hepatotoxicity in the safety trial [see Warnings and Precautions The safety profile from this combined analysis was similar to that in Trial 1, other than the one case of hepatotoxicity in the safety trial [see Warnings and Precautions Data from the safety trial was combined with data from NASH patients with F2 and F3 fibrosis at eligibility (n=888) and data from an additional 162 patients from a relevant patient population enrolled in Trial 1. In the combined safety population (n=2019), the median (Q1 to Q3) age of patients at baseline was 58 (50 to 65) years; 55% were female, 28% were Hispanic, 89% were White, 2% were Asian, and 4% were Black or African American. There are no available data on REZDIFFRA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.There are risks to the mother and fetus related to underlying NASH with liver fibrosis (see Clinical Considerations) . In animal reproduction studies, adverse effects on embryo-fetal development occurred in pregnant rabbits treated with resmetirom at 3.5 times the maximum recom- mended dose during organogenesis.These effects were associated with maternal toxicity, whereas no embryo-fetal effects were observed at lower dose levels with better tolerance in pregnant rabbits. No embryo-fetal developmental effects occurred in pregnant rats treated with resmetirom or the metabolite MGL-3623.A pre- and postnatal development study in rats with maternal dosing of resmetirom during organogenesis through lactation showed a decrease in birthweight and increased incidence of stillbirths and mortality (postnatal days 1-4) at 37 times the maximum recommended dose (see Data) .These effects were associated with marked suppression of maternal T4,T3, and TSH levels. The background risk of major birth defects and miscarriage for the indicated population is unknown.All pregnancies have a background risk of birth defect, loss, and other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. There are no available data on REZDIFFRA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus related to underlying NASH with liver fibrosis (see Clinical Considerations) . In animal reproduction studies, adverse effects on embryo-fetal development occurred in pregnant rabbits treated with resmetirom at 3.5 times the maximum recom- mended dose during organogenesis. These effects were associated with maternal toxicity, whereas no embryo-fetal effects were observed at lower dose levels with better tolerance in pregnant rabbits. No embryo-fetal developmental effects occurred in pregnant rats treated with resmetirom or the metabolite MGL-3623. A pre- and postnatal development study in rats with maternal dosing of resmetirom during organogenesis through lactation showed a decrease in birthweight and increased incidence of stillbirths and mortality (postnatal days 1-4) at 37 times the maximum recommended dose (see Data) . These effects were associated with marked suppression of maternal T4, T3, and TSH levels. Report pregnancies to Madrigal Pharmaceuticals, Inc.Adverse Event reporting line at 1-800-905-0324 or https://pregnancyregistry.madrigalpharma.com. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk There are risks to the mother and fetus related to underlying maternal NASH with liver fibrosis, such as increased risks of gestational diabetes, hypertensive complications, preterm birth, and postpartum hemorrhage. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, and other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Report pregnancies to Madrigal Pharmaceuticals, Inc. Adverse Event reporting line at 1-800-905-0324 or https://pregnancyregistry.madrigalpharma.com. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk There are risks to the mother and fetus related to underlying maternal NASH with liver fibrosis, such as increased risks of gestational diabetes, hypertensive complications, preterm birth, and postpartum hemorrhage. (5.1) in the full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary (5.1) in the full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary

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