New class of thyromimetics reduce liver fat to improve NASH

Selective thyromimetic drugs that reduce liver fat are showing promise as the first potential pharmacological agents to treat patients with nonalcoholic steatohepatitis (NASH), research in the Lancet shows.

Patients with NASH had significant declines in hepatic fat compared with a placebo group after 12 weeks of taking a selective, liver-directed thyroid beta receptor agonist, according to a phase II study.

The 72 patients randomised to receive the treatment – called resmetirom – 80 mg once daily were also significantly more likely to have improved NASH on liver biopsy at 12 and 36 weeks compared to the 38 patients on placebo.

The drug is one of a new class of  thyroid receptor β agonists that avoid the activation of the α isoform of the thyroid receptor responsible for the clinical manifestations of hyperthyroidism such as tachycardia, defective bone metabolism, and muscle wasting.

The study assessed the safety and efficacy of resmetirom in reducing the relative change in MRI-PDFF assessed hepatic fat compared with placebo at week 12.

Patients were eligible for inclusion if they had biopsy confirmed NASH (fibrosis stages 1–3) and hepatic fat fraction of at least 10% at baseline when assessed by MRI-PDFF.

They were randomised to receive 80 mg orally of the drug daily or placebo. Meanwhile MRI-PDFF was performed after 12 and 36 weeks of treatment and a second liver biopsy was obtained at week 36.

Overall, patients had high levels of diabetes, hypertension and abnormal blood lipids as well as other symptoms linked to metabolic syndrome such as high body mass index and waist circumference.

Resmetirom therapy was associated with significant reductions in relative and absolute hepatic fat fraction from baseline compared with placebo.

At week 12, the change in median relative fat from baseline was –36·3% and similar hepatic fat reductions compared with baseline and with placebo were observed at 36 weeks.

Treatment with resmetirom also resulted in statistically and clinically significant reductions in multiple atherogenic lipids and lipoproteins, including LDL cholesterol, apolipoprotein B, triglycerides, apolipoprotein CIII, and lipoprotein(a), according to the US trial investigators.

Moreover, they note that MRI-PDFF responders (defined by ≥30% relative fat reduction at week 12 compared with baseline) showed an enhanced NASH resolution response (defined as at least a 2-point reduction in NAS plus ballooning score of 0 with lobular inflammation score of 0 or 1).

Meanwhile NASH resolution responders also showed a marked reduction in fibrosis (61% with ≥1-point reduction in fibrosis stage).

Examining safety, investigators said resmetirom was well tolerated though it was associated with an increase in mild and a few moderate gastrointestinal adverse events, particularly loose stools.

Discussing the study with the limbic, Professor Jacob George, Head of the Department of Gastroenterology and Hepatology at Westmead Hospital in Sydney, said that drugs that reduce liver fat by activating the thyroid hormone beta receptor are generating a lot of interest because they both reduce liver fat and they also improve serum lipids.

“With this agent the receptor is localised to the liver – we’re activating the receptor on the liver cells that the thyroid hormone would normally bind to.”

And this liver-targeted sensitivity, he says, not only potentially reduces the risk of systemic effects but also causes a cascade of metabolic consequences.

“This class of drug does a whole lot of things, which includes reducing liver fat and reducing blood lipids in a favourable way as well as promoting liver regeneration. The hope is that if you can reduce liver fat then hopefully it will follow that you can reduce liver inflammation and scarring. So, on the face of it, these results are good and certainly warrant going into a phase III study.”

That study is already underway, says Professor George who himself is involved in the Australian arm of the trial, which he says has just begun recruiting.

“The biggest safety signal that we’re looking for now is that these drugs have no consequences on cardiovascular and diabetes outcomes because patients with NASH have a systemic disease of metabolic syndrome with hyperlipidemia, and in fact the leading cause of death for a lot of patients is cardiovascular disease. So we’ll be looking at ECGs, cardiovascular markers such as cholesterol and triglycerides as well as diabetes markers.”

Longer term studies will need to look at absolute hard clinical endpoints like liver cancer and liver failure Professor George added noting that any provisional regulatory approval based on outcomes from the phase III study would be revoked if the FDA could not be convinced that the drug doesn’t prevent people dying from liver-related outcomes.

“This is a very active field for therapeutic research we desperately need new drugs for this disease because it’s a very common problem but there is still a lot of proof that needs to be done before we can actually implement these drugs in clinical practice.”

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