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Harrison SA, Bedossa P, Guy CD, et al. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N Engl J Med. 2024;390(6):497-509. PMID 38324483

One-paragraph summary

An ongoing 54-month phase 3 trial randomised adults with biopsy-confirmed NASH and fibrosis stage F1B, F2 or F3 in a 1:1:1 ratio to once-daily oral resmetirom 80 mg, resmetirom 100 mg, or placebo; 966 patients formed the week-52 primary analysis population (322 / 323 / 321). Resmetirom is a liver-directed, thyroid hormone receptor-β-selective agonist that increases hepatic fat metabolism. Both dual primary endpoints were met at week 52. NASH resolution with no worsening of fibrosis occurred in 25.9% (80 mg) and 29.9% (100 mg) versus 9.7% on placebo, and fibrosis improvement by ≥1 stage with no worsening of the NAFLD activity score in 24.2% and 25.9% versus 14.2% (all p<0.001). LDL-cholesterol fell 13.6% and 16.3% by week 24 versus +0.1% on placebo (p<0.001). Diarrhoea and nausea were more frequent with resmetirom; serious adverse events were similar across groups (10.9%, 12.7%, 11.5%). These results supported accelerated FDA approval in March 2024 for non-cirrhotic MASH with F2–F3 fibrosis.

Key findings

Endpoint at week 52 Placebo 80 mg 100 mg
NASH resolution, no worsening of fibrosis 9.7% 25.9% 29.9%
Fibrosis improvement ≥1 stage, no worsening of NAS 14.2% 24.2% 25.9%
LDL-C change to week 24 +0.1% −13.6% −16.3%
Serious adverse events 11.5% 10.9% 12.7%
  • Absolute fibrosis-improvement difference 10.0–11.7 percentage points; NNT ≈ 9–10.
  • Absolute resolution difference 16.2–20.2 points; NNT ≈ 5–6.
  • The LDL reduction is a genuine secondary benefit in a population whose leading cause of death is cardiovascular.

Limitations

  • Both primary endpoints are histological surrogates, and the trial's clinical-outcome phase runs to 2028. Accelerated approval is conditional on it.
  • One of the two endpoints — NASH resolution — measures the histological feature that carries little independent prognostic weight once fibrosis is known (Angulo 2015, PMID 25935633; Akbari 2024, PMID 38293684).
  • Cirrhosis was excluded (F1B–F3 enrolled), so the highest-event-rate population is untested; a separate outcomes trial in well-compensated MASH cirrhosis is running (NCT05500222).
  • The 9.7% placebo resolution rate is at the low end of the field's range (2% to 34.3% across MASH trials), which inflates the apparent effect relative to trials with high placebo response.
  • Absolute effect sizes are modest against the ≥10% weight-loss lifestyle benchmark (90% NASH resolution in the subgroup achieving it — a non-randomised comparison).

Why it matters

It ended two decades in which no drug was approved for this disease, and it did so on a regulatory model — accelerated approval on a histological surrogate — that the entire subsequent field now depends on. Semaglutide followed the same route in August 2025 (Sanyal 2025, PMID 40305708; Bansal 2026, PMID 41201884), and the phase 3 pipeline of FGF21 analogues, incretin multi-agonists and PPAR agonists is built on the same endpoints. It also created an immediate implementation problem: the label is histological (F2–F3) but the population must be found non-invasively, which generated dedicated expert guidance on identifying the intended population and, more urgently, on excluding patients with cirrhosis in whom the drug is untested (Noureddin 2024, PMID 39038768).

Cited by wiki pages

  • resmetirom-and-thyromimetics.md
  • clinical-trials-landscape.md
  • bariatric-and-metabolic-surgery.md
  • red-flags-and-safety-concerns.md
  • overview.md