Drug Update · Gastroenterology

Resmetirom (REZDIFFRA) Approved for Adults with Noncirrhotic MASH (F2–F3) After Month 12 Histology Gains

August 27, 2026

Approved indication

Adults with noncirrhotic MASH (F2 to F3 fibrosis)

Approval pathway

Accelerated approval (based on improvement of MASH and fibrosis)

Recommended dosages

<100 kg: 80 mg once daily; ≥100 kg: 100 mg once daily

Month 12 histology (Pathologist A) resolution rates

Placebo 13%; REZDIFFRA 80 mg 27%; REZDIFFRA 100 mg 36% [12]

Safety population size

2,019 patients evaluated for safety [2]

Clinical Perspective

Clinicians treating adults with noncirrhotic MASH with stage F2 to F3 fibrosis should be aware that REZDIFFRA is an FDA‑approved, oral THR‑beta agonist indicated in conjunction with diet and exercise for this population ^[2]^[4]. The approval and recent label revisions rest on Month 12 histopathology improvements in resolution of steatohepatitis and fibrosis on post‑baseline liver biopsy from the randomized Trial 1 analysis, and labeling notes that continued approval may be contingent on verification of clinical benefit in the required confirmatory trial ^[7]^[5]. Will the ongoing 54‑month confirmatory trial verify clinical benefit on the planned clinical outcomes of progression to cirrhosis, hepatic decompensation, liver transplant, and mortality?

Dr. Sanjay Iyer, MBBS, MD (General Medicine), DM (Gastroenterology) · Gastroenterology

REZDIFFRA (resmetirom) is FDA-approved in conjunction with diet and exercise for adults with noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced liver fibrosis (stages F2 to F3 fibrosis) under an accelerated approval granted March 14, 2024; labeling revisions updating disease terminology and noninvasive marker language were approved July 24, 2026 ^[2]^[3]^[4]. Approval was based on a Month 12 histopathology analysis from a 54-month randomized, double-blind, placebo-controlled trial (Trial 1 / MGL-3196-11 / NCT03900429) showing improvement in resolution of steatohepatitis and improvement in fibrosis on post-baseline liver biopsy at Month 12 versus placebo ^[7]^[2].

Clinical Context

Resmetirom (REZDIFFRA) is a thyroid hormone receptor‑beta (THR‑beta) agonist developed by Madrigal Pharmaceuticals and approved to treat adults with noncirrhotic MASH with stage F2 to F3 fibrosis when used with diet and exercise ^[2]^[4]. The approval used accelerated approval based on surrogate histologic endpoints (improvement of MASH and fibrosis) with a required confirmatory postapproval trial to verify clinical benefit ^[5]^[7]. The therapeutic landscape for MASH includes liver‑directed approaches such as THR‑beta agonists (resmetirom) and fatty acid synthase inhibitors, and systemic metabolism‑targeting approaches including incretin analogues (e.g., semaglutide) discussed in recent review literature ^[1]. Labeling changes in a July 24, 2026 supplemental approval updated disease terminology from NASH to MASH and added descriptive effects on transient elastography and ELF score in Clinical Pharmacology ^[3].

Key Findings

The Month 12 analysis from Trial 1 (MGL-3196-11 / NCT03900429) compared placebo (n=294) with REZDIFFRA 80 mg once daily (n=298) and REZDIFFRA 100 mg once daily (n=296) and assessed two histopathology co‑endpoints on post‑baseline liver biopsies: 1) resolution of steatohepatitis and no worsening of fibrosis, and 2) at least one stage improvement in fibrosis and no worsening of steatohepatitis ^[7].
Clinicians should consult current prescribing information for full dosing guidance.
For resolution of steatohepatitis and no worsening of fibrosis (Pathologist A reads), response rates were 13% for placebo, 27% for REZDIFFRA 80 mg, and 36% for REZDIFFRA 100 mg; differences versus placebo (Pathologist A) were 14% (95% CI 8, 20) for 80 mg and 23% (95% CI 16, 30) for 100 mg ^[7].
For improvement in liver fibrosis and no worsening of steatohepatitis (Pathologist A reads), response rates were 15% for placebo, 23% for REZDIFFRA 80 mg, and 28% for REZDIFFRA 100 mg; differences versus placebo (Pathologist A) were 8% (95% CI 2, 14) for 80 mg and 13% (95% CI 7, 20) for 100 mg ^[7].
The efficacy determination used independent readings from two pathologists (Pathologist A and Pathologist B) and a statistical analysis that incorporated both independent readings; both doses demonstrated improvement on the Month 12 histopathology endpoints versus placebo in that analysis ^[7].

Safety & Tolerability

Hepatotoxicity, including drug‑induced autoimmune‑like hepatitis and marked elevations in liver biochemistries, has been observed; monitoring of liver tests and clinical signs/symptoms of hepatotoxicity is recommended and discontinuation advised if hepatotoxicity is suspected ^[2]^[6].
Cholelithiasis was observed more often in REZDIFFRA‑treated patients than in placebo‑treated patients ^[2]^[6].
Acute cholecystitis was observed more often in REZDIFFRA‑treated patients than in placebo‑treated patients ^[2]^[6].
Obstructive pancreatitis (gallstone) was observed more often in REZDIFFRA‑treated patients than in placebo‑treated patients ^[2]^[6].
Diarrhea was listed among the most common adverse reactions (reported in at least 5% and higher than placebo) ^[2]^[6].
Nausea was listed among the most common adverse reactions (reported in at least 5% and higher than placebo) ^[2]^[6].
Pruritus was listed among the most common adverse reactions (reported in at least 5% and higher than placebo) ^[2]^[6].
Vomiting was listed among the most common adverse reactions (reported in at least 5% and higher than placebo) ^[2]^[6].
Constipation was listed among the most common adverse reactions (reported in at least 5% and higher than placebo) ^[2]^[6].
Abdominal pain was listed among the most common adverse reactions (reported in at least 5% and higher than placebo) ^[2]^[6].
Dizziness was listed among the most common adverse reactions (reported in at least 5% and higher than placebo) ^[2]^[6].

Study Design

The efficacy determination used Trial 1 (MGL‑3196‑11; NCT03900429), a 54‑month, randomized, double‑blind, placebo‑controlled trial enrolling patients with baseline or recent liver biopsy showing MASH and fibrosis stage 2 or 3 and a NAFLD Activity Score ≥4; the Month 12 analysis included 888 F2/F3 patients randomized 1:1:1 to placebo (n=294), REZDIFFRA 80 mg once daily (n=298), or REZDIFFRA 100 mg once daily (n=296) plus lifestyle counseling ^[7]. Clinicians should consult current prescribing information for full dosing guidance. The Month 12 co‑endpoints were resolution of steatohepatitis with no worsening of fibrosis and one stage improvement in fibrosis with no worsening of steatohepatitis on post‑baseline liver biopsies; missing biopsies at Month 12 were considered non‑responders ^[7]. The combined safety population across trials included 2,019 patients ^[2]^[6].

FAQ

What is resmetirom (REZDIFFRA) approved for?

REZDIFFRA (resmetirom) is approved in conjunction with diet and exercise for the treatment of adults with noncirrhotic metabolic dysfunction‑associated steatohepatitis (MASH), formerly termed NASH, with moderate to advanced liver fibrosis consistent with stages F2 to F3 fibrosis. This indication received accelerated approval based on histologic improvement of MASH and fibrosis, and continued approval may depend on verification of clinical benefit in confirmatory trials. Clinicians should consult current prescribing information for complete dosing guidance.

How does resmetirom work?

Resmetirom is described in the prescribing information as a thyroid hormone receptor‑beta (THR‑beta) agonist that acts as a partial activator of this receptor, with activation in the liver reducing liver fat accumulation. Clinical pharmacology sections and label content note effects on noninvasive liver disease markers including transient elastography (liver stiffness) and ELF score as described in updated labeling. Clinicians should consult current prescribing information for complete dosing guidance.

What is the recommended dose of resmetirom (REZDIFFRA)?

The recommended dosage of REZDIFFRA is weight‑based: for patients weighing <100 kg the recommended dosage is 80 mg orally once daily, and for patients weighing ≥100 kg the recommended dosage is 100 mg orally once daily. The label provides specific guidance for dosage modifications with concomitant use of moderate CYP2C8 inhibitors and recommends avoiding concomitant use with strong CYP2C8 inhibitors; clinicians should consult current prescribing information for complete dosing guidance.

What are the most common side effects of resmetirom?

The most common adverse reactions reported in at least 5% of patients and at higher rates than placebo include diarrhea, nausea, pruritus, vomiting, constipation, abdominal pain, and dizziness. The label also warns about hepatotoxicity, cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) observed more often in treated patients, plus clinically significant drug interactions with CYP2C8 inhibitors and increased exposure to some statins that require statin dose limits; clinicians should consult current prescribing information for complete dosing guidance.

Clinicians should consult current prescribing information for complete dosing guidance.

Resmetirom (REZDIFFRA) Approved for Adults with Noncirrhotic MASH (F2–F3) After Month 12 Histology Gains

Direct Clinical Takeaway & Evidence Summary

Resmetirom (REZDIFFRA) Approved for Adults with Noncirrhotic MASH (F2–F3) After Month 12 Histology Gains

Clinical Perspective

Clinical Context

Key Findings

Safety & Tolerability

Study Design

FAQ

References

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