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Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial
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PDF - Resmetirom (MGL-3196) for the treatment of non-alcoholic
steatohepatitis: a multicentre, randomised, double-blind,
placebo-controlled, phase 2 trial
NAFLD and NASH are both associated with a group of comorbid conditions that include metabolic syndrome, obesity, type 2 diabetes, hypertension, dyslipidaemia, and hypothyroidism. As with other metabolic conditions, NASH is associated with increased cardiovascular risk, including cardiovascular death.
Patients with more advanced NASH fibrosis also have increased morbidity and mortality from progression of their liver disease, including progression to cirrhosis, liver failure, and hepatocellular carcinoma.
No approved therapy for NASH exists, and its prevalence has increased with the increasing global prevalence of obesity.
As with other metabolic diseases, lifestyle modifications are effective but difficult to achieve and maintain.
Resmetirom is in phase 3 with toppling results reported in this press release. There is an Expanded Access program.
2019 Lancet
Summary
Background
Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation, hepatocellular injury, and progressive liver fibrosis. Resmetirom (MGL-3196) is a liver-directed, orally active, selective thyroid hormone receptor-β agonist designed to improve NASH by increasing hepatic fat metabolism and reducing lipotoxicity. We aimed to assess the safety and efficacy of resmetirom in patients with NASH.
Methods
MGL-3196-05 was a 36-week randomised, double-blind, placebo-controlled study at 25 centres in the USA. Adults with biopsy confirmed NASH (fibrosis stages 1-3) and hepatic fat fraction of at least 10% at baseline when assessed by MRI-proton density fat fraction (MRI-PDFF) were eligible. Patients were randomly assigned 2:1 by a computer-based system to receive resmetirom 80 mg or matching placebo, orally once a day. Serial hepatic fat measurements were obtained at weeks 12 and 36, and a second liver biopsy was obtained at week 36. The primary endpoint was relative change in MRI-PDFF assessed hepatic fat compared with placebo at week 12 in patients who had both a baseline and week 12 MRI-PDFF. This trial is registered with ClinicalTrials.gov, number NCT02912260.
Findings
348 patients were screened and 84 were randomly assigned to resmetirom and 41 to placebo at 18 sites in the USA. Resmetirom-treated patients (n=78) showed a relative reduction of hepatic fat compared with placebo (n=38) at week 12 (-32·9% resmetirom vs -10·4% placebo; least squares mean difference -22·5%, 95% CI -32·9 to -12·2; p<0·0001) and week 36 (-37·3% resmetirom [n=74] vs -8·5 placebo [n=34]; -28·8%, -42·0 to -15·7; p<0·0001). Adverse events were mostly mild or moderate and were balanced between groups, except for a higher incidence of transient mild diarrhoea and nausea with resmetirom.
Interpretation
Resmetirom treatment resulted in significant reduction in hepatic fat after 12 weeks and 36 weeks of treatment in patients with NASH. Further studies of resmetirom will allow assessment of safety and effectiveness of resmetirom in a larger number of patients with NASH with the possibility of documenting associations between histological effects and changes in non-invasive markers and imaging.
Funding
Madrigal Pharmaceuticals.
Introduction
Non-alcoholic steatohepatitis (NASH) is the active, progressive form of non-alcoholic fatty liver disease (NAFLD), defined as the presence of 5% or more hepatic steatosis with inflammation and hepatocyte injury (eg, ballooning), with or without fibrosis.
NAFLD and NASH are both associated with a group of comorbid conditions that include metabolic syndrome, obesity, type 2 diabetes, hypertension, dyslipidaemia, and hypothyroidism. As with other metabolic conditions, NASH is associated with increased cardiovascular risk, including cardiovascular death.
Patients with more advanced NASH fibrosis also have increased morbidity and mortality from progression of their liver disease, including progression to cirrhosis, liver failure, and hepatocellular carcinoma.
No approved therapy for NASH exists, and its prevalence has increased with the increasing global prevalence of obesity.
As with other metabolic diseases, lifestyle modifications are effective but difficult to achieve and maintain.
In small clinical trials, pioglitazone (thought to address insulin resistance) and vitamin E (thought to address oxidative stress) improved liver histology. Obeticholic acid, a bile acid analogue that activates farnesoid X receptors, and elafibranor, a peroxisome proliferator-activated receptor (PPAR) α and δ agonist, improved liver histology in phase 2 studies.
Ongoing phase 3 studies (NCT02548351, NCT02704403) are assessing their long-term efficacy and safety.
Thyroid hormone receptor β (THR-β) is highly expressed in hepatocytes and is responsible for regulating the metabolic pathways in the liver that are frequently impaired in NAFLD and NASH.
Animal studies have shown that THR-β has an important role in the reduction of triglycerides and cholesterol, improving insulin sensitivity, promoting liver regeneration, and reducing apoptosis. Evidence suggests that NASH might be, in part, a condition of diminished liver thyroid hormone levels or hepatic hypothyroidism, and the incidence of clinical and subclinical hypothyroidism is higher in patients with NAFLD or NASH relative to age-matched controls.
Liver biopsy is an invasive technique with associated morbidity. A goal of the field is to find non-invasive tests that predict outcome of non-alcoholic steatohepatitis treatments to avoid use of serial liver biopsies. In addition to improving the understanding of the pharmacology and safety of resmetirom in patients with non-alcoholic steatohepatitis, this study provides results of serial non-invasive imaging of liver fat content, serial biomarkers of liver injury and fibrosis, and serial liver biopsies at baseline and after 36 weeks of treatment, providing the potential to show associations between changes in non-invasive measures and liver histology.
Implications of all the available evidence
There is an unmet need for treatments of non-alcoholic steatohepatitis, and no European Medicines Agency or Food and Drug Administration-approved treatments exist. The results of our phase 2 study show the efficacy of resmetirom in rapidly decreasing liver fat content and markers of inflammation and fibrosis and non-alcoholic steatohepatitis with fibrosis on liver biopsy at week 36, highlighting its therapeutic potential in non-alcoholic steatohepatitis. A larger clinical trial of longer duration is ongoing to fully assess the safety and efficacy of resmetirom in patients with non-alcoholic steatohepatitis with advanced fibrosis.
Non-alcoholic fatty liver disease includes a spectrum of chronic hepatic diseases, with non-alcoholic steatohepatitis being the most aggressive phenotype, leading to an increased risk of developing cirrhosis. To identify clinical trials of the treatment of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, we searched PubMed for English language articles published from Jan 1, 2007, to July 1, 2019, with the search terms "NAFLD", "NASH", "fatty liver", "thyroid hormone", and "thyroid hormone receptor beta". We found no controlled clinical trials investigating a thyroid hormone analogue in the treatment of non-alcoholic steatohepatitis, and therefore the current study represents a first-in-class trial in this patient population. Resmetirom is a liver-directed molecule that is highly targeted towards thyroid hormone receptor-β designed to avoid the toxicities associated with an excess of systemic thyroid hormone, shown to be largely mediated through thyroid hormone receptor-α. On the basis of established preclinical and clinical biological activity and safety, resmetirom is being assessed for the treatment of non-alcoholic steatohepatitis with fibrosis in a phase 3 clinical trial.
Resmetirom (MGL-3196) is a liver-directed, orally active agonist of THR that is around 28 times more selective than triiodothyronine for THR-β versus THR-α.
It is highly protein bound (>99%), has poor tissue penetration outside the liver, and shows specific uptake into the liver. In NASH, selectivity for THR-β might provide metabolic benefits of thyroid hormone that are mediated by the liver, while avoiding unwanted systemic actions of excess thyroid hormone in heart and bone that are largely mediated through THR-α.
In preclinical NASH animal models, thyroid analogues, including resmetirom, have been shown to reduce hepatic triglycerides, steatosis, lipid peroxidation, inflammatory and fibrosis markers, and alanine aminotransferase.
In an earlier study, resmetirom doses of 50-200 mg per day in healthy participants with mildly elevated LDL cholesterol were shown to be well tolerated and resulted in significant reductions in atherogenic lipids, including LDL cholesterol (up to 30%), apolipoprotein B (28%), and triglycerides (up to 60%) at doses of 80 mg and higher.
This study was designed to determine the effect of resmetirom on hepatic fat compared with placebo at week 12 and week 36 in patients with NASH and stage 1-3 fibrosis. Steatosis was assessed by MRI-proton density fat fraction (MRI-PDFF), a sensitive measure of hepatic fat. Secondary objectives were to assess safety and tolerability and to assess the effects of resmetirom on liver histology, serum lipids, alanine aminotransferase, and biomarkers of inflammation and fibrosis.
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