AN INVESTIGATIONAL treatment significantly reduced liver fat after 12 weeks in adults with metabolic dysfunction-associated steatohepatitis (MASH), according to results from a phase 2a clinical trial.
The greatest reductions were observed with higher doses of ALG-055009, a selective thyroid hormone receptor beta (THR-β) agonist, with treatment also showing a favourable short-term safety profile.
MASH is a progressive form of metabolic dysfunction-associated steatotic liver disease characterised by excess liver fat, inflammation, and liver cell injury. Over time, the condition can lead to fibrosis, cirrhosis, and other serious liver complications.
THR-β agonists are designed to target metabolic processes in the liver, with potential effects including reductions in liver fat and harmful blood lipids.
Researchers conducted the HERALD trial to assess the efficacy and safety of ALG-055009 in adults with non-cirrhotic MASH.
The randomised, double-blind, placebo-controlled trial included 102 adults aged 18–75 years with a BMI of at least 25 kg/m² and presumed MASH with F1–F3 liver fibrosis.
Participants were randomly assigned to receive ALG-055009 at daily doses of 0.3 mg, 0.5 mg, 0.7 mg, or 0.9 mg, or placebo, for 12 weeks. The highest-dose group was restricted to participants weighing more than 85 kg.
The primary outcome was the percentage change in liver fat from baseline, measured using MRI.
At 12 weeks, liver fat decreased by an average of 6.9% in the 0.3 mg group, 11.2% with 0.5 mg, 25.9% with 0.7 mg, and 24.3% with 0.9 mg. By comparison, liver fat increased by 7.3% in the placebo group.
After accounting for the placebo response, reductions were statistically significant for the 0.5 mg, 0.7 mg, and 0.9 mg dose groups. The largest placebo-adjusted average reduction was 33.2% in participants receiving 0.7 mg.
The findings provide early evidence that ALG-055009 can reduce liver fat in people with MASH, with the stronger effects generally observed at higher doses.
Researchers also assessed the drug’s safety and tolerability. Adverse events were reported in 45–65% of participants across the ALG-055009 groups, compared with 73% of those receiving placebo.
Most adverse events were mild or moderate, with diarrhoea, fatigue, and constipation amongst the most frequently reported. No serious adverse events occurred amongst participants receiving ALG-055009, and there were no deaths.
Importantly for a drug targeting thyroid hormone receptors, researchers observed no clinically meaningful changes in thyroid function.
Although the reduction in liver fat is encouraging, the 12-week trial was not designed to determine whether ALG-055009 improves liver inflammation or reverses fibrosis.
Liver fat was measured using MRI rather than liver biopsies, meaning the study cannot establish whether treatment produced improvements in the microscopic features of MASH.
The trial was also relatively small, with approximately 20 participants in each treatment group, and the highest dose was tested only in participants weighing more than 85 kg.
Nevertheless, the randomised, placebo-controlled design strengthens the evidence that the observed liver fat reductions were related to treatment.
The researchers conclude that the significant reductions in liver fat and absence of major safety concerns support further clinical development of ALG-055009. Longer studies incorporating liver histology will now be needed to establish whether these changes translate into improvements in MASH and liver fibrosis.
Reference
Loomba R et al. ALG-055009 in non-cirrhotic adults with metabolic dysfunction-associated steatohepatitis (HERALD): a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet Gastroenterol Hepatol. Published online August 26, 2026.
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