Therapeutic: resmetirom for non-alcoholic steatohepatitis


Patients with non-alcoholic steatohepatitis (NASH) have a build-up of fat in the liver with no obvious cause (such as alcohol consumption). It can lead to cirrhosis, liver cancer or liver failure and can also result in cardiovascular disease

It is the world’s the most common liver disorder and is particularly common in developed nations: the vast majority of obese people will develop the disease, as will more than 50% of diabetics.

No drugs to specifically treat NASH have yet been approved, but there has been an enormous amount of effort from the pharmaceutical industry.

One drug in the pipeline from Madrigal Pharmaceuticals is resmetirom.1 This is a liver-directed, orally available selective thyroid hormone receptor-beta agonist, which is designed to increase hepatic fat metabolism and reduce lipotoxicity.

In a Phase II trial in patients with NASH confirmed by biopsy, with stage 1–3 fibrosis and a hepatic fat fraction of at least 10% assessed by MRI, 125 subjects were given daily oral doses of 80 mg of resmetirom or a placebo for 36 weeks.2

Hepatic fat measurements were made at weeks 12 and 36, with a second liver biopsy taken at the end. Those given the drug had a relative reduction of hepatic fat (down 32.9%) compared with the placebo (down 10.4%) at week 12.

At the end of the trial, the gap had widened to a 37.3% drop for the treated group compared with 9.5% in the placebo group. Adverse events were mostly mild or moderate and similar for both groups, aside from a higher incidence of mild transient nausea and diarrhoea with the drug.

Another trial found that hepatic fat reduction with resmetirom is associated with an improvement in quality of life for NASH patients.3

In the Phase II double-blind, randomised, placebo-controlled trial, 125 patients with biopsy confirmed non-cirrhotic NASH with a hepatic fat fraction of at least 10% (as assessed by MRI) were given 80 mg of resmetirom or a placebo daily for 36 weeks. By week 12, treated patients had improvements in Bodily Pain and Short Form-6D utility scores, with no quality of life improvements observed in the placebo group.

Results of a Phase III trial to evaluate its safety and tolerability by measuring the incidence of adverse events have also been reported.4

In the randomised, double-blind, placebo-controlled study, 972 patients with non-alcoholic fatty liver disease, as assessed by metabolic risk and non-invasive imaging, were given 80 or 100 mg doses of resmetirom or a placebo, and a further 171 were enrolled in a 100 mg open label arm.

Overall, adverse events led to discontinuation in 2.3% of those given 80 mg, 2.8% with 100 mg and 1.3% in the placebo group. The most common adverse events were diarrhoea in 23.5%, 31.2% and 13.8% of patients, respectively, and nausea in 11.9%, 18.2% and 7.9%. The primary objective was therefore met, as were key secondary endpoints, including LDL-C, ApoB and triglyceride levels.

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  1. M.J. Kelly, et al., J. Med. Chem. 57, 3912 (2014).
  2. S.A. Harrison, Lancet 394, 2012 (2019).
  3. Z.M. Younossi, et al., Clin. Gastroenterol. Hepatol. 20, 1354 (2022).
  4. S. Harrison, et al., EASL Intl Liver Conf. (London, UK, 22–26 June 2022): Abstr. LB005.