HERALD: Thyroid receptor agonist well-tolerated, lowers liver fat in MASH at 12 weeks

Key takeaways:

• All ALG-055009 doses significantly reduced liver fat at 12 weeks vs. placebo.
• The thyroid hormone receptor-beta agonist was well tolerated, with no serious side effects.

SAN DIEGO — Once-daily ALG-055009 achieved “significant and robust reductions” in liver fat at 12 weeks and was well-tolerated among noncirrhotic patients with metabolic dysfunction-associated steatohepatitis, according to data.

“With several therapies coming along, when focusing on thyroid hormone receptor-beta agonists, it has become important to realize their importance in pathogenesis of steatohepatitis, as well as reversal of injury,” Rohit Loomba, MD, MHSc, director of the MASLD Research Center and chief of gastroenterology and hepatology at the University of California, San Diego, told attendees at The Liver Meeting.

“ALG-055009 is a highly potent and selective thyroid hormone receptor-beta agonist,” he continued. “It’s expressed in the liver and plays an important role in lipid metabolism. In previous studies, thyroid hormone receptor-beta agonists have been shown to reduce atherogenic lipids, decrease hepatic fat and improve liver histology in patients with MASH.”

In the phase 2a HERALD trial, Loomba and colleagues assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of ALG-055009 (Aligos Therapeutics) vs. placebo among adult patients with presumed MASH and stage 1 to 3 fibrosis.

The researchers randomly assigned patients to oral, once-daily ALG-055009 0.3 mg (n = 20), 0.5 mg (n = 22), 0.7 mg (n = 20) or 0.9 mg (n = 18) or placebo (n = 22) for 12 weeks. Patients weighing more than 85 kg were enrolled only in the ALG-055009 0.9 mg group.

At baseline and week 12, patients underwent MRI-proton density fat fraction (MRI-PDFF), with a final follow-up at 16 weeks.

The primary endpoint was relative change in liver fat at week 12, and secondary endpoints included safety, tolerability and changes in lipids, lipoproteins and sex hormone binding globulin (SHBG).

According to Loomba, all ALG-055009 groups achieved the primary endpoint, with “significant and robust reductions” in liver fat at week 12 compared with placebo (placebo-adjusted median relative change: 0.3 mg, 19.7%; 0.5 mg, 24.1%; 0.7 mg, 46.2%; 0.9 mg, 43.6%).

ALG-055009 also demonstrated a “significant, dose-dependent” increase in MRI-PDFF response, with 70% achieving at least a 30% relative reduction in liver fat at the 0.7 mg dose.

Among patients with stable glucagon-like peptide-1 agonist use, Loomba noted that “response to treatment was still maintained, irrespective of GLP-1 use in those treated with the drug.” Response to treatment was comparable between men and women.

Significant reductions were also reported in LDL cholesterol, lipoprotein(a) and apolipoprotein B, in addition to dose-dependent increases up to 90% from baseline in SHBG.

According to Loomba, there were no serious side effects with ALG-055009 and the majority of treatment-emergent adverse events were mild or moderate, with no clinical hypo- or hyperthyroidism noted. Occurrence of diarrhea was similar across treatment groups vs. placebo, and no “clinically concerning” laboratory, ECG or physical exam findings were reported.

“The drug was well-tolerated in this short 12-week trial,” Loomba told attendees. “These data support evaluation of longer duration of ALG-055009 for 48 or 52 weeks and its effect on liver histology in a future phase 2b trial.”