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 patient types typically seen in practice, including those with common comorbidities1,2

Baseline data in MAESTRO-NASH

Demographics and
comorbidities 		Placebo
(n=294) 		Rezdiffra
80 mg
(n=298) 		Rezdiffra
100 mg (n=296) 		Overall
(N=888)
Age, years, median (Q1, Q3)* 58 (51, 65) 57 (49, 64) 59 (52, 65) 58 (51, 65)
BMI, kg/m2, median (Q1, Q3)* 34 (31, 40) 35 (31, 39) 35 (31, 40) 35 (31, 40)
Female, % 55 56 57 56
Hispanic, % 16 21 26 21
White, % 87 90 90 89
Type 2 diabetes, % 67 70 68 68
Hypertension, % 81 76 80 79
Dyslipidemia, % 70 71 73 71
Thyroxine use, %† 15 12 15 14
Statin use, % 49 47 51 49
ALT, U/L, median (Q1, Q3)* 46 (31, 70) 48 (32, 67) 48 (34, 69) 48 (33, 68)
AST, U/L, median (Q1, Q3)* 36 (25, 48) 34 (26, 46) 36 (25, 52) 36 (26, 49)
Demographics and
comorbidities 		Placebo
(n=294) 		Rezdiffra 80 mg
(n=298) 		Rezdiffra 100 mg (n=296) Overall
(N=888)
Age, years, median (Q1, Q3)* 58 (51, 65) 57 (49, 64) 59 (52, 65) 58 (51, 65)
BMI, kg/m2, median (Q1, Q3)* 34 (31, 40) 35 (31, 39) 35 (31, 40) 35 (31, 40)
Female, % 55 56 57 56
Hispanic, % 16 21 26 21
White, % 87 90 90 89
Type 2 diabetes, % 67 70 68 68
Hypertension, % 81 76 80 79
Dyslipidemia, % 70 71 73 71
Thyroxine use, %† 15 12 15 14
Statin use, % 49 47 51 49
ALT, U/L, median (Q1, Q3)* 46 (31, 70) 48 (32, 67) 48 (34, 69) 48 (33, 68)
AST, U/L, median (Q1, Q3)* 36 (25, 48) 34 (26, 46) 36 (25, 52) 36 (26, 49)

Patients were allowed to be on stable doses of concomitant medications for diabetes (including 15% of patients on GLP‑1 therapy), dyslipidemia (including 49% of patients on statins), and hypertension.1,2

Assessment of baseline disease parameters Placebo
(n=294) 		Rezdiffra
80 mg
(n=298) 		Rezdiffra
100 mg
(n=296) 		Overall
(N=888)
NITs VCTE, kPa, median (Q1, Q3)* 12 (10, 15) 12 (10, 15) 12 (10, 16) 12 (10, 15)
CAP, dB/m, median (Q1, Q3)* 350 (321, 379) 348 (317, 375) 350 (324, 381) 349 (320, 378)
FIB-4, median (Q1, Q3)* 1.3 (1, 1.8) 1.3 (0.9, 1.7) 1.4 (1, 1.9) 1.3 (1, 1.8)
ELF, median (Q1, Q3)* 9.7 (9.2, 10.3) 9.7 (9.2, 10.3) 9.8 (9.3, 10.4) 9.7 (9.2, 10.4)
Liver Biopsy Fibrosis stage F2, % 38 37 36 37
Fibrosis stage F3, % 62 63 64 63
Assessment of baseline disease parameters Placebo
(n=294) 		Rezdiffra 80 mg
(n=298) 		Rezdiffra 100 mg (n=296) Overall
(N=888)
NITs VCTE, kPa, median (Q1, Q3)* 12 (10, 15) 12 (10, 15) 12 (10, 16) 12 (10, 15)
CAP, dB/m, median (Q1, Q3)* 350 (321, 379) 348 (317, 375) 350 (324, 381) 349 (320, 378)
FIB-4, median (Q1, Q3)* 1.3 (1, 1.8) 1.3 (0.9, 1.7) 1.4 (1, 1.9) 1.3 (1, 1.8)
ELF, median (Q1, Q3)* 9.7 (9.2, 10.3) 9.7 (9.2, 10.3) 9.8 (9.3, 10.4) 9.7 (9.2, 10.4)
Liver Biopsy Fibrosis stage F2, % 38 37 36 37
Fibrosis stage F3, % 62 63 64 63

Patients in the study had a NAFLD Activity Score (NAS) ≥4 at baseline.2

*This represents the middle 50% (Q1, Q3). 25% of the data fall below Q1 and 25% of the data lie above Q3.3

AASLD Practice Guidance: Patient Identification for Rezdiffra

The latest guidance from AASLD recommends Rezdiffra for appropriate patients with noncirrhotic MASH with moderate to advanced fibrosis.4,†

Rezdiffra recommended

Rezdiffra recommended

Imaging-based NILDA:

  • VCTE: LSM 8 kPa-15 kPa‡
  • MRE: LSM 3.1 kPa-4.4 kPa‡

Liver histology:

  • MASH with F2-F3§

Rezdiffra
may be used

Rezdiffra
may be used

Individualized decisions by a specialist experienced in liver fibrosis for:

  • LSM values outside the recommended ranges
  • Other NILDA data consistent with F2-F3||

Rezdiffra is
not recommended

Rezdiffra is
not recommended

  • Cirrhosis, including LSM via VCTE >20 kPa or MRE >5 kPa
  • Concomitant active liver disease
  • Excessive alcohol use (>20/30 g/d in women/men)
  • Active thyroid disease
There are no FDA-approved noninvasive tests to diagnose MASH with fibrosis stage F2-F3 or to monitor response to pharmacotherapy.
†Adapted from Figure 1 in the AASLD Practice Guidance: October 2024 Updates.
‡Modified from the AASLD NILDA guidelines.5
§Liver biopsy is not routinely recommended for staging of MASH.4
||Imaging-based NILDA is preferred, eg, shear wave elastography (applying local standards for F2-F3), versus enhanced liver fibrosis score (9.2-10.4). The latter range is based on the interquartile range from the MAESTRO trial data; no recommendations are available from the AASLD NILDA guidelines.1,6
Persons with active hyperthyroidism or untreated hypothyroidism (ie, TSH >10 mIU/L without symptoms, or TSH >7 mIU/L with symptoms) were excluded from the MAESTRO-NASH study.4

Rezdiffra delivered statistically significant results for both primary endpoints in MAESTRO-NASH2

See Dual Efficacy

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AASLD=American Association for the Study of Liver Diseases; ALT=alanine transaminase; AST=aspartate aminotransferase; BMI=body mass index; CAP=controlled attenuation parameter; dB/m=decibels per meter; ELF=enhanced liver fibrosis; FIB‑4=Fibrosis-4; GLP-1=glucagon-like peptide-1; kPa=kilopascal; LSM=liver stiffness measure; MASH=metabolic dysfunction-associated steatohepatitis, formerly known as NASH or nonalcoholic steatohepatitis; MRE=magnetic resonance elastography; NAFLD=nonalcoholic fatty liver disease; NILDA=noninvasive liver disease assessment; NIT=noninvasive test; Q=quartile; TSH=thyroid-stimulating hormone; U/L=units per liter; VCTE=vibration-controlled transient elastography.
References:
  1. Data on file. REF-00630. Madrigal Pharmaceuticals, Inc.; June 2024.
  2. Rezdiffra. Prescribing Information. Madrigal Pharmaceuticals, Inc.
  3. Thomas S. https://articles.outlier.org/what-are-quartiles-in-statistics. March 26, 2023.
  4. Chen VL et al. Hepatology. 2025;81(1):312-320.
  5. Sterling RK et al. Hepatology. Published online March 15, 2024.
  6. Sterling RK et al. Hepatology. 2024;81(1):321-357.

IMPORTANT SAFETY INFORMATION AND INDICATION

EXPAND EXPAND

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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