ESPEYB21 15. Editors’ Choice New Treatments (4 abstracts)
15.2. A phase 3, randomized, controlled trial of resmetirom in NASH with liver fibrosis
Harrison SA , Bedossa P , Guy CD , Schattenberg JM , Loomba R , Taub R , Labriola D , Moussa SE , Neff GW , Rinella ME , Anstee QM , Abdelmalek MF , Younossi Z , Baum SJ , Francque S , Charlton MR , Newsome PN , Lanthier N , Schiefke I , Mangia A , Pericas JM , Patil R , Sanyal AJ , Noureddin M , Bansal MB , Alkhouri N , Castera L , Rudraraju M , Ratziu V & the MAESTRO-NASH Investigators.
N Engl J Med 390(6): 497–509 (2024). PubMed: 38324483
In Brief This phase 3 trial including 966 adults with biopsy-confirmed non-alcoholic steatohepatitis (NASH) with fibrosis were randomly assigned (1:1:1 ratio) to once-daily resmetirom 80 mg or 100 mg or placebo. Resmetirom, both 80 and 100 mg daily, were superior to placebo with respect to NASH resolution and improvement in liver fibrosis.
NASH resolution occurred more frequently in patients on 80-mg (25.9%) and 100-mg resmetirom (29.9%) than on placebo (9.7%) ( P <0.001 for both). The main side-effects of resmetirom were (generally self-limiting) diarrhea and nausea at treatment initiation.
Despite being one of the most common comorbidities of obesity, there are no licenced effective treatments for NASH - although resolution of NASH and associated fibrosis does occur with successful lifestyle weight management. Due to the absence of effective treatments, the US Food and Drug Ad-ministration (FDA) has agreed an accelerated approval pathway for Resmetirom, which is an oral, liver-directed, thyroid hormone receptor (THR) beta-selective agonist.
Previous research showed impaired THR-beta function in the liver in NASH, leading to reduced mito-chondrial function and fatty acid beta-oxidation. This mechanism also explains why some patients with severe untreated hypothyroidism have markedly raised liver enzyme levels and steatohepatitis, which promptly resolves following appropriate thyroid hormone replacement therapy. Resmetirom appears to be a very promising new treatment for NASH with liver fibrosis.
Of note, the Yearbook editors welcome the new name change for NASH to now ‘ metabolic dysfunction – associated steatohepatitis ’ (MASH) – previously, having to explain to parents and children that they had a ‘non-alcoholic’ condition was always puzzling!
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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