Resmetirom and the First Approved MASH Drug: Reading an Accelerated Approval

In March 2024 the U.S. Food and Drug Administration granted accelerated approval to resmetirom, marketed as Rezdiffra, for adults with noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) who have moderate to advanced liver fibrosis. It is the first drug ever approved for this disease, and the decision rested on two biopsy-based surrogate endpoints rather than on evidence that patients live longer or avoid cirrhosis. According to the FDA's approval announcement, the agency cleared the drug on a surrogate measured at month 12 within a still-running 54-month trial, and required the sponsor to finish that trial to verify clinical benefit. Reading this approval correctly means holding one idea in mind: an accelerated approval says a drug's effect on a surrogate is reasonably likely to predict benefit, not that the benefit has been shown.

A note on names first. The older labels NAFLD and NASH were renamed in a 2023 multi-society consensus to MASLD and MASH. The pivotal trial and much of the regulatory paperwork still say NASH; the terms describe the same fatty-liver-driven inflammation and scarring.

What accelerated approval actually is

The accelerated approval pathway, in place since the early 1990s, lets the FDA clear a drug for a serious condition with unmet need on the basis of a surrogate endpoint that is reasonably likely to predict clinical benefit. In exchange, the sponsor must run a confirmatory trial to show the benefit is real, and the law permits the agency to withdraw approval if that trial fails or is not completed. Before resmetirom, no medicine was approved for MASH at all, so the unmet need was genuine. The pathway is a deliberate trade: earlier access now, verification later.

The word "surrogate" carries the weight here. A surrogate endpoint is a laboratory or imaging or, in this case, histologic marker that stands in for the outcomes people actually care about. Those outcomes in liver disease are progression to cirrhosis, hepatic decompensation, liver cancer, transplant, and death. The bet embedded in an accelerated approval is that moving the surrogate will move those harder endpoints too.

What MAESTRO-NASH measured

The pivotal study, MAESTRO-NASH, was published in the New England Journal of Medicine in February 2024. It randomly assigned patients with biopsy-confirmed MASH and fibrosis stage F1B, F2, or F3 to once-daily oral resmetirom at one of two doses or to placebo, with 966 patients forming the primary analysis population. Resmetirom is a liver-directed thyroid hormone receptor beta agonist, a mechanism aimed at reducing liver fat and the downstream inflammation that drives scarring.

Two primary endpoints were read from liver biopsy at week 52. The first was resolution of MASH with no worsening of fibrosis. The second was improvement of fibrosis by at least one stage with no worsening of the disease-activity score. Both endpoints are histologic. Neither counts a single clinical event.

Reading the numbers

MASH resolution occurred in roughly 26 percent of patients on the lower dose and about 30 percent on the higher dose, compared with about 10 percent on placebo. Fibrosis improved by at least one stage in roughly 24 and 26 percent of the two dose groups, versus about 14 percent on placebo. Each comparison was statistically significant.

Two things are worth reading carefully. The absolute difference over placebo is real but modest, roughly ten to twenty percentage points depending on the endpoint and dose, which means most treated patients did not meet the endpoint. And liver biopsy is a noisy ruler: a needle samples a tiny fraction of the organ, and pathologists reading the same slide can disagree on stage. Histologic endpoints improve confidence when they move in the right direction across a large randomized trial, yet they carry measurement variability that a hard outcome like death does not.

What a surrogate does and does not prove

The reason the FDA accepted these biopsy endpoints is that fibrosis stage tracks with long-term liver-related risk in natural-history studies. Higher stage predicts more cirrhosis, more decompensation, more death. That relationship is what makes histologic improvement "reasonably likely" to predict clinical benefit. But reasonably likely is a probabilistic judgment, not a demonstrated result. A surrogate can move without the outcome following, either because the marker was an imperfect stand-in or because the biological path from marker to event is longer and more complicated than expected.

So what remains open after this approval is the question that matters most to a patient: does taking this drug lower the chance of progressing to cirrhosis, needing a transplant, or dying of liver disease? That question is being tested. The same 54-month MAESTRO-NASH trial continues toward its clinical-outcome readout, and a separate study, MAESTRO-NASH-OUTCOMES (NCT05500222), is evaluating liver-related events in people with compensated MASH cirrhosis. Until those results are in, the honest reading is that the biopsy improved and the hard outcomes are unproven.

Why the trade-off can still be reasonable

None of this is a verdict on the drug. The logic of the approval is defensible: a serious, progressive disease, no prior treatment, a surrogate with biological plausibility and natural-history support, and a binding requirement to confirm benefit. Accelerated approval exists for exactly this situation. The failure mode is not the pathway. It is forgetting what the pathway means, treating "approved" as a synonym for "proven to change outcomes" when the two are distinct legal and scientific claims.

For a reader trying to make sense of a new liver drug, the durable skill is to ask what endpoint the approval was built on. If the answer is a surrogate, the follow-up questions are how tightly that surrogate predicts real outcomes and whether the confirmatory trial has reported yet. This article is educational and not medical advice; decisions about any therapy belong with a qualified clinician who knows the individual case.