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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Rezdiffra was evaluated in MAESTRO-NASH: a comprehensive Phase 3 trial in noncirrhotic MASH patients with moderate to advanced fibrosis1,2

MAESTRO-NASH is an ongoing Phase 3, randomized, double-blind, placebo-controlled trial. Efficacy and safety were evaluated in 888 adults with biopsy-confirmed MASH with stage F2 or F3 liver fibrosis (at eligibility).1

Trial design schema for MAESTRO-NASH

Efficacy1

Week 52 dual primary endpoints

  • Fibrosis improvement: ≥1-stage improvement in fibrosis with no worsening of steatohepatitis (defined as no increase in score for ballooning, inflammation, or steatosis)*
  • 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
  • Pathologist A and Pathologist B independently read the liver biopsies for each patient
  • Patients with missing liver biopsy at Week 52 were considered non-responders in the primary analysis

Stratification1

  • Patients were stratified by baseline type 2 diabetes status (present/absent) and fibrosis stage (F2 or F3)

Key inclusion and exclusion criteria1,2

Inclusion

  • ≥18 years of age
  • Presence of ≥3 metabolic risk factors†
  • Liver biopsy confirmed fibrosis stage: F2 or F3‡
  • NAS ≥4
  • VCTE ≥8.5 kPa; CAP ≥280 dB/m§
  • MRI-PDFF ≥8%||

Exclusion

  • Moderate to severe hepatic impairment (Child-Pugh B or C)
  • Cirrhosis
  • Liver decompensation
  • Chronic liver diseases, autoimmune hepatitis, hepatocellular carcinoma
  • History of significant alcohol consumption#
  • Platelet count <140,000/mm3
  • MELD score ≥12**

Learn how to identify appropriate patients for Rezdiffra

See Characteristics
*Liver fibrosis was evaluated on the NASH Clinical Research Network (CRN) fibrosis score as 0 to 4.1
†Includes obesity, type 2 diabetes, dyslipidemia, and hypertension.2
‡If a patient had a biopsy ≤6 months before enrollment, it was considered a qualifying biopsy.2
§For patients with a historic liver biopsy <2 years old, baseline VCTE and CAP could be <8.5 kPa and <280 dB/m, respectively.2
||CAP ≥280 dB/m was allowed if MRI-PDFF was unavailable.2
Primary biliary cholangitis, primary sclerosing cholangitis, hepatitis B, hepatitis C.2
#History of significant alcohol consumption for more than 3 consecutive months within 1 year prior to screening. Significant alcohol consumption is defined as equal to or greater than approximately 2 alcoholic drinks per day for males, and approximately 1.5 alcoholic drinks per day for females.2
**As determined at screening, unless due to therapeutic anti-coagulation.2
AR=adverse reaction; CAP=controlled attenuation parameter; dB/m=decibels per meter; kPa=kilopascal; MASH=metabolic dysfunction-associated steatohepatitis, formerly known as NASH or nonalcoholic steatohepatitis; MELD=Model for end-stage liver disease; MRI-PDFF=magnetic resonance imaging proton density fat fraction; NAS=nonalcoholic fatty liver disease (NAFLD) activity score; NIT=noninvasive test; VCTE=vibration‑controlled transient elastography.
References:
  1. Rezdiffra. Prescribing Information. Madrigal Pharmaceuticals, Inc.
  2. Harrison SA et al. N Engl J Med. 2024;390(6):497-509 (article, suppl, and protocol).

IMPORTANT SAFETY INFORMATION AND INDICATION

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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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