Rezdiffra 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.

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Dual efficacy: Rezdiffra delivers statistically significant fibrosis improvement* and steatohepatitis resolution† at Week 521

There were no differences in response to Rezdiffra for both primary endpoints based on age, gender, type 2 diabetes status, GLP‑1 therapy, or fibrosis stage (F2 or F3)1,2

Fibrosis improvement with no worsening of steatohepatitis

  Placebo
(n=294)		 Rezdiffra 80 mg
(n=298)		 Rezdiffra 100 mg
(n=296)
Response rate,
Pathologist A (%) 		15 23 28
Difference in response rate vs placebo (95% CI)   8 (2, 14) 13 (7, 20)
Response rate,
Pathologist B (%) 		13 23 24
Difference in response rate vs placebo (95% CI)   11 (5, 17) 11 (5, 17)

Rezdiffra achieved statistically significant results for fibrosis improvement for both doses in a statistical analysis incorporating both pathologists' independent readings.1,‡

Fibrosis improvement combined analysis Fibrosis improvement combined analysis
Fibrosis improvement paired biopsy imputed analysis Fibrosis improvement paired biopsy imputed analysis
Paired Biopsy/Imputed Analysis Details

In MAESTRO-NASH, patients without a Week 52 liver biopsy were considered an “endpoint non-responder” in the primary endpoint analysis for the intent-to-treat population (N=888).1 Given these “endpoint non-responders” were each randomized to a treatment group and could have potentially responded, the FDA conducted an independent sensitivity analysis, imputing all missing values with a logistic regression model, which adjusted for treatment group, baseline type 2 diabetes (presence or absence), baseline fibrosis stage (F2 or F3), and pathologist.4 Based on Madrigal data, 695 (78.3% of the 888) patients had paired biopsy data at both baseline and Week 52 (n=246, placebo; n=234, 80 mg; n=215, 100 mg), resulting in 193 (21.7%) patients without paired biopsy data (n=48, placebo; n=64, 80 mg; n=81, 100 mg).3

*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 with no worsening of fibrosis

  Placebo
(n=294)		 Rezdiffra 80 mg
(n=298)		 Rezdiffra 100 mg
(n=296)
Response rate,
Pathologist A (%) 		13 27 36
Difference in response rate vs placebo (95% CI)   14 (8, 20) 23 (16, 30)
Response rate,
Pathologist B (%) 		9 26 24
Difference in response rate vs placebo (95% CI)   17 (11, 23) 15 (9, 21)

Rezdiffra achieved statistically significant results for steatohepatitis resolution for both doses in a statistical analysis incorporating both pathologists’ independent readings.1,‡

Steatohepatitis resolution combined analysis Steatohepatitis resolution combined analysis
Steatohepatitis resolution paired biopsy imputed analysis Steatohepatitis resolution paired biopsy imputed analysis
Paired Biopsy/Imputed Analysis Details

In MAESTRO-NASH, patients without a Week 52 liver biopsy were considered an “endpoint non-responder” in the primary endpoint analysis for the intent-to-treat population (N=888).1 Given these “endpoint non-responders” were each randomized to a treatment group and could have potentially responded, the FDA conducted an independent sensitivity analysis, imputing all missing values with a logistic regression model, which adjusted for treatment group, baseline type 2 diabetes (presence or absence), baseline fibrosis stage (F2 or F3), and pathologist.4 Based on Madrigal data, 695 (78.3% of the 888) patients had paired biopsy data at both baseline and Week 52 (n=246, placebo; n=234, 80 mg; n=215, 100 mg), resulting in 193 (21.7%) patients without paired biopsy data (n=48, placebo; n=64, 80 mg; n=81, 100 mg).3

†Steatohepatitis resolution: Resolution of steatohepatitis (score of 0-1 for inflammation, 0 for ballooning, and any value for steatosis) with no worsening of liver fibrosis.1
‡Patients with missing liver biopsy at Week 52 were considered non-responders.1
§Combined pathologist results estimated using the Mantel-Haenszel method stratified by baseline type 2 diabetes status (presence or absence) and fibrosis stage (F2 or F3).2
Learn more about the MAESTRO-NASH trial design.

Learn how to identify appropriate patients for Rezdiffra

See Characteristics

Learn about the demonstrated safety and tolerability profile of Rezdiffra1

See Safety Information
GLP-1=glucagon-like peptide-1; MASH=metabolic dysfunction-associated steatohepatitis, formerly known as NASH or nonalcoholic steatohepatitis.
References:
  1. Rezdiffra. Prescribing Information. Madrigal Pharmaceuticals, Inc.
  2. Harrison SA et al. N Engl J Med. 2024;390(6)(article and suppl):497-509.
  3. Data on file. REF-00630. Madrigal Pharmaceuticals, Inc.; June 2024.
  4. Data on file. REF-00923. Madrigal Pharmaceuticals, Inc.; November 2024.

IMPORTANT SAFETY INFORMATION AND INDICATION

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COLLAPSE COLLAPSE

WARNINGS AND PRECAUTIONS

Hepatotoxicity

Hepatotoxicity has been observed with the use of Rezdiffra. 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 Rezdiffra and monitor. 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 drug-induced autoimmune-like hepatitis (DI-ALH) or autoimmune liver disease in the evaluation of elevations in liver tests.

Gallbladder-Related Adverse Reactions

Cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) were observed more often in Rezdiffra-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 Rezdiffra, 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, and rhabdomyolysis. Please see the upcoming Drug Interactions section of the Important Safety Information for more details.

ADVERSE REACTIONS

The most common adverse reactions with Rezdiffra (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 Interactions Affecting Rezdiffra

Clinically Significant Interactions Affecting Other Drugs

USE IN SPECIFIC POPULATIONS

Pregnancy

There are no available data on Rezdiffra use in pregnant women. Report pregnancies to Madrigal Pharmaceuticals, Inc.’s Adverse Event reporting line at 1-800-905-0324 and https://www.madrigalpharma.com/contact/.

Lactation

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 considered 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.

Geriatric Use

Numerically higher incidence of adverse reactions have been observed in patients ≥65 years of age compared to younger adult patients.

Renal Impairment

Rezdiffra has not been studied in patients with severe renal impairment.

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 effectiveness have not been established in patients with cirrhosis.

INDICATION

Rezdiffra 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.

Please see full Prescribing Information for Rezdiffra.

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