Rezdiffra Phase 3 Trial (MAESTRO-NASH) for NASH F2-F3

Is resmetirom approved for MASH with F2-F3 fibrosis?

Yes. The Rezdiffra label covers adults with noncirrhotic MASH, formerly known as NASH, with moderate to advanced liver fibrosis consistent with stages F2 to F3, used in addition to diet and exercise [1]. The FDA approved it on March 14, 2024 under NDA 217785 [2], describing it as the first treatment approved for patients with liver scarring due to fatty liver disease [3].

The approval is accelerated. It rests on improvement of MASH and fibrosis seen on biopsy rather than on liver-related outcomes, and continued approval may be contingent on confirmatory trials verifying clinical benefit [1]. The label carries two limitations: avoid use in decompensated cirrhosis, and safety and effectiveness have not been established in MASH cirrhosis or in children [1].

What MAESTRO-NASH found at week 52

The primary week-52 analysis included 966 adults with biopsy-confirmed NASH and F1B, F2 or F3 fibrosis, randomized 1:1:1 to resmetirom 80 mg, 100 mg or placebo once daily: 322, 323 and 321 patients respectively [4]. Two co-primary endpoints were read from paired biopsies at week 52:

• MASH resolution with no worsening of fibrosis: 25.9% on 80 mg and 29.9% on 100 mg versus 9.7% on placebo (P<0.001 for both comparisons) [4].
• Fibrosis improvement of at least one stage with no worsening of the NAFLD activity score: 24.2% on 80 mg and 25.9% on 100 mg versus 14.2% on placebo (P<0.001) [4].

In absolute terms the difference from placebo was about 16 to 20 percentage points for MASH resolution and about 10 to 12 points for fibrosis improvement. The trial itself is a 54-month study, and the biopsy endpoints come from its month-12 analysis [1].

Why the label's response rates look different from the published ones

The published week-52 results include 966 patients with F1B, F2 or F3 fibrosis [4]. Rezdiffra's label reports a separate efficacy analysis of 888 patients with F2 or F3 fibrosis at eligibility (294 on placebo, 298 on 80 mg, 296 on 100 mg), with results from two pathologists [1]. For resolution of steatohepatitis with no worsening of fibrosis, Pathologist A read 13% on placebo, 27% on 80 mg and 36% on 100 mg; Pathologist B read 9%, 26% and 24% [1]. For one-stage fibrosis improvement with no worsening of steatohepatitis, Pathologist A read 15%, 23% and 28%; Pathologist B read 13%, 23% and 24% [1]. Both doses were statistically significant on both endpoints when the two pathologists' reads were combined [1].

The FDA's approval announcement describes the same spread: 26% to 27% on 80 mg and 24% to 36% on 100 mg for NASH resolution versus 9% to 13% on placebo, and 23% on 80 mg and 24% to 28% on 100 mg for fibrosis improvement versus 13% to 15% on placebo, depending on the pathologist [3].

The 29.9% published result and the 36% label result both come from MAESTRO-NASH, but they differ in analysis population (966 patients with F1B to F3 versus 888 with F2 to F3) and in how the biopsies were read [1][4].

Who was in the trial

In the 888-patient F2/F3 population: median age 58, 56% female, median BMI 35, 68% with type 2 diabetes, and 63% with F3 fibrosis [1]. Forty-nine percent were taking a statin at baseline [1].

What changed beyond the biopsy

From baseline to week 24, LDL cholesterol changed by -13.6% on 80 mg and -16.3% on 100 mg [4]. Free T4 fell by a mean of 2% on placebo, 13% on 80 mg and 17% on 100 mg at 12 months, with minimal change in T3 or TSH and no clinical findings associated with the decrease [1].

A separate 52-week safety trial, MAESTRO-NAFLD-1, enrolled adults with NAFLD and presumed NASH: 100 mg (n=325), 80 mg (n=327), placebo (n=320), plus an open-label 100 mg arm (n=171) [5]. At 16 weeks, hepatic fat differed from placebo by -34.9% on 80 mg and -38.6% on 100 mg [5]. That is a different population from the biopsy-confirmed F2-F3 cohort in MAESTRO-NASH.

How resmetirom is dosed

Weight-based, once daily, with or without food: 80 mg for patients under 100 kg and 100 mg for patients at 100 kg or more [1]. Tablets are swallowed whole and not split, crushed or chewed; a missed dose is skipped and the next scheduled dose resumed [1]. Mild, moderate or severe renal impairment and mild hepatic impairment (Child-Pugh A) need no dose adjustment [1]. With a moderate CYP2C8 inhibitor such as clopidogrel the dose drops to 60 mg or 80 mg depending on weight, and gemfibrozil, a strong CYP2C8 inhibitor, is not recommended [1].

Resmetirom is a partial agonist of thyroid hormone receptor-beta, the main thyroid hormone receptor in the liver, where stimulation reduces intrahepatic triglycerides; the heart and bone effects of thyroid hormone are largely mediated through receptor-alpha [1]. It is not a GLP-1 drug and not thyroid hormone replacement [1].

What the label says to watch for

The label has no boxed warning and lists no contraindications [1]. On hepatotoxicity, it records one patient on 80 mg daily with normal baseline liver tests who reached ALT 58 times, AST 66 times and total bilirubin 15 times the upper limit of normal with raised IgG, suggesting drug-induced autoimmune-like hepatitis; the tests returned to baseline after hospitalization and stopping the drug, and rose again on rechallenge [1]. The label directs monitoring of liver tests and liver-related symptoms during treatment and discontinuation if hepatotoxicity is suspected [1].

Gallstone disease, acute cholecystitis and obstructive pancreatitis from gallstones occurred more often than on placebo, with rates under 1 per 100 person-years in all arms; the label says to interrupt treatment for a suspected acute gallbladder event [1]. For statins, resmetirom raises exposure to rosuvastatin, simvastatin, pravastatin and atorvastatin, and the label limits the daily statin dose to 20 mg for rosuvastatin and simvastatin and 40 mg for pravastatin and atorvastatin, with monitoring for liver test elevation, myopathy and rhabdomyolysis [1].

Common adverse reactions in Trial 1, as exposure-adjusted incidence per 100 person-years (placebo / 80 mg / 100 mg): diarrhea 14 / 23 / 33, nausea 9 / 18 / 15, pruritus 4 / 6 / 10, vomiting 4 / 7 / 8 [1]. Diarrhea began early, with a median time to a diarrheal event of 39 days on placebo, 17 days on 80 mg and 6 days on 100 mg, and was mild to moderate, with a median duration of 20 days on resmetirom versus 9 days on placebo [1]. Discontinuation for adverse reactions ran 4 / 5 / 8 per 100 person-years, most often for diarrhea and nausea [1]. ALT above 3 times the upper limit of normal occurred in 10% on placebo, 11% on 80 mg and 13% on 100 mg [1].