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Improving NASH [Resmetirom] with a
little help from thyromimetics -Comment
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November 15, 2019
Vlad Ratziu
Institute for Cardiometabolism and Nutrition, Sorbonne Universites,
Paris, France; and Department of Hepatogastroenterology, Hospital
Pitie-Salpetriere 75013, Paris, France
Down the PDF here - Resmetirom (MGL-3196) for the treatment of non-alcoholic
steatohepatitis: a multicentre, randomised, double-blind,
placebo-controlled, phase 2 trial
Down the PDF here - Improving NASH with a little help from thyromimetics
Traditionally, non-alcoholic steatohepatitis (NASH) has been associated with insulin resistance-related clinical conditions, such as overweight and type 2 diabetes. However, a quantitative association between subclinical low thyroid function and hepatic steatosis has been shown in a population-based study1 and in a study of people with type 2 diabetes,2 which is independent of metabolic comorbidities.3 Incident steatosis occurs more often with higher baseline thyrotropin concentrations.4, 5 In rodents, mild hypothyroidism increases adipose tissue lipolysis, with subsequent hepatic fat accumulation. These changes lead to hepatic insulin resistance and increased glucose production, which exacerbates liver fat through hepatic lipogenesis.6 The histological severity of both steatohepatitis and fibrosis increases with increasing concentrations of thyrotropin, even in the sublinical or high normal range.7 The findings that, in proportion to the severity of liver damage, the hepatic activity of a thyroid hormone activating deiodinase is reduced and that of a deiodinase that degrades thyroid hormone is increased further suggest that damaged hepatic tissue is in a state of deficiency in active thyroid hormones.8 These findings are problematic, because thyroid hormones can reduce liver steatosis mainly through the induction of lipophagy and restoration of a healthy mitochondrial capacity.9 They might also interfere with fibrogenic pathways by inhibiting transforming growth factor β signalling,10 thereby preventing fibrosis progression. Additionally, they carry distinct lipid-lowering actions over a broad range of atherogenic lipoproteins, such as LDL cholesterol, large VLDL, apolipoprotein B, and lipoprotein(a).
Because liver and cardiovascular disease are the main causes of death in NASH patients, thyromimetics are appealing NASH therapies, provided that the activation of the α isoform of the thyroid receptor, which is responsible for the myriad clinical manifestations of hyperthyroidism, including tachycardia, defective bone metabolism, and muscle wasting, can be avoided. Previous attempts at designing selective thyromimetics were unsuccessful, resulting in unwanted side-effects, but resmetirom is a new, oral, liver-directed, highly selective thyroid receptor β agonist.11
In The Lancet, Harrison and colleagues12 randomly assigned 125 patients (63 [50%] female) to receive resmetirom (n=84) or placebo (n=41) for 36 weeks. They report an early reduction in liver fat content, with a mean difference from baseline over placebo of -22 ⋅5% (95% CI -32 ⋅9 to -12 ⋅2, p<0 ⋅0001) at 12 weeks, and a significant improvement in the pro-atherogenic lipid profile of NASH patients treated with resmetirom. Histological data showing resolution of NASH and fibrosis reduction (at least in patients with NASH resolution), two regulatory approvable endpoints, strongly favour a liver benefit; the lipid results suggest potential for cardiovascular benefit as well. The drug was weight neutral and without benefits on glycaemic control. It was well tolerated, a must for long-term therapy in mostly asymptomatic patients.
These are promising and welcome results for this new class of drugs. But some limitations of this phase 2 trial must be kept in mind. The sample size was modest and the histological outcomes, arguably the most important for patient benefit, were only analysed as secondary endpoints. At least half of the patients had early or no fibrosis, which, together with the short duration (<1 year) could explain the absence of antifibrotic effect in the resmetirom group. Some placebo patients with substantial weight loss were discarded from the analysis, which is understandable for exploratory purposes but reduces the overall robustness of the findings-resolution of steatohepatitis was no longer significant when they were kept in the analysis. The authors also adopted a definition of resolution of steatohepatitis that includes an additional requirement for a reduction in an aggregate score of steatosis, hepatic cell injury, and inflammation. This definition could favour potent antisteatogenic drugs without necessarily capturing a stronger anti-inflammatory effect. Because results using the usual definition (disappearance of ballooning with no or minimal inflammation, as per guidance from the US Food and Drug Administration) are not provided, comparisons with other trials are imperfect.
Despite these limitations, Harrison and colleagues provide valuable insight for early drug development in NASH. They show that a reduction in liver fat content is associated with NASH resolution, thus validating this MRI-based surrogate for proof-of-concept trials. The opposite was also true, although not generalisable because it might be dependent on the mechanism of action. 13 Particularly informative is that hepatic fat reduction was associated with improvement in inflammation and liver cell injury, favouring the current model of lipotoxicity-mediated injury in NASH. The study also confirms that NASH resolution leads to fibrosis reversal. If this reversal results in fewer individuals progressing to cirrhosis (as current phase 3 trials are set to demonstrate), a big step towards reducing the duration of registration trials will be possible. Finally, although counterintuitive, alanine aminotransferase reduction seemed to be slower than liver fat loss. This finding could mean that, for certain drugs, early assessment of alanine aminotransferase response (at 12 weeks in proof-of-concept trials) might miss biochemical activity.
Whether resmetirom works better in patients with more pronounced hepatic hypothyroidism is unknown, and most patients in this trial presumably had low rather than high normal baseline thyroid stimulating hormone concentrations. Additionally, the pharmacodynamics of resmetirom showed considerable individual variability, which affected the magnitude of hepatic effects. Nonetheless, resmetirom establishes a new class of NASH drugs now moving into a large phase 3 trial, with considerable excitement for investigators and patients.
I have received advisory board fees related to NASH treatments and NASH perception, awareness, and unmet needs from Genfit, Intercept, Galmed, AstraZeneca, Boehringer Ingelheim, Madrigal, Poxel, Allergan, Servier, Echosens, Coherus, Enanta, and Bristol-Myers Squibb. I am the principal investigator in NASH therapeutic trials: REGENERATE (Intercept), RESOLVE-IT (Genfit), ARREST (Galmed), and ARGON-1 (Enanta).
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