Thyroid hormone receptor-beta agonist achieves ‘robust reduction’ in liver fat in MASH

Key takeaways:

• VK2809 significantly reduced liver fat vs. placebo at week 12, with results maintained at week 52.
• The thyroid hormone receptor agonist also achieved MASH resolution and fibrosis improvement at week 52.

SAN DIEGO — VK2809 demonstrated “robust reductions” in liver fat as early as 12 weeks in metabolic dysfunction-associated steatohepatitis, as well as MASH resolution and improvement in fibrosis by week 52, according to late-breaking data.

VK2809 (Viking Therapeutics) is a thyroid hormone receptor-beta agonist and a “novel prodrug,” Rohit Loomba, MD, MHSc, director of the MASLD Research Center and professor of medicine and chief of gastroenterology and hepatology at the University of California, San Diego, told attendees at The Liver Meeting. “In a phase 2 trial that was previously presented at AASLD, we showed that all the doses of VK2809, from 5 mg to 10 mg, were better than placebo in achieving robust reduction in [MRI-proton density fat fraction (MRI-PDFF)], up to 78% at week 12.”

In the phase 2b VOYAGE trial, Loomba and colleagues randomly assigned patients with biopsy-confirmed MASH to VK2809 1 mg (n = 17) or 2.5 mg (n = 59) every day, 5 mg (n = 36) or 10 mg (n = 57) every other day or placebo (n = 62). The researchers performed liver biopsies at baseline and end of treatment and MRI-PDFF at baseline and week 12.

The primary endpoint was a change in MRI-PDFF at 3 months, and the secondary endpoint was change in histology at 12 months.

Loomba noted similar age, weight and BMI across all dosing groups at baseline, and approximately one-third of patients had stage 3 fibrosis.

‘Potentially robust durability’ in treatment response

According to Loomba, there were “robust and statistically significant” reductions in liver fat at week 12 with VK2809 doses 2.5 mg to 10 mg vs. placebo (2.5 mg, 49.5%; 5 mg, 42.5%; 10 mg, 56.7%; placebo, 5.4%).

“These improvements were maintained at week 52 in MRI-PDFF,” he added, noting significant reductions at all doses vs. placebo at this timepoint (1 mg, 34.3%; 2.5 mg, 54.2%; 5 mg, 46.7%; 10 mg, 56.3%; placebo, 9.3%) — up to 56% median reduction.

“Sustained liver fat reduction indicates potentially robust durability in treatment response,” Loomba said.

In addition, patients receiving VK2809 achieved at least a 30% reduction in MRI-PDFF at week 12, which ranged from 52.9% to 84.9% and “correlated with long-term improvement in liver histology at the end of treatment.”

This response was maintained through week 52, with a combined response rate of 79% across all VK2804 groups.

Significant MASH resolution, fibrosis improvement

According to Loomba, up to 75% of VK2809-treated patients achieved MASH resolution with no worsening of fibrosis vs. 29.3% of placebo-treated patients (P < .0001).

“We are excited to see these results,” he said, noting this outcome is an FDA regulatory endpoint for subpart H approval in a phase 3 program.

In addition, VK2809 5 mg and 10 mg led to significant improvement in fibrosis by at least one stage with no worsening of MASH vs. placebo (51.9%, 56.8% vs. 34.1%), with similar improvement rates among patients with baseline stage 2 or 3 fibrosis.

“The numbers are small,” Loomba noted, “but it gives you good confidence that the drug should work across the spectrum of fibrosis stages.”

In an analysis of noninvasive biomarkers at week 52, there also were improvements in NIS4 and plasma lipids such as LDL cholesterol, triglycerides, apolipoprotein B and lipoprotein(a).

“These are consistent across the spectrum of thyroid hormone receptor-beta agonists, showing the cardioprotective potential of this category of medication,” Loomba said.

Most treatment-emergency adverse events were mild or moderate (97%), with similar gastrointestinal events between VK2809 and placebo.

“The VOYAGE trial shows that the primary endpoint demonstrating robust reduction in liver fat was achieved at week 12,” Loomba said. “We also noted histologic endpoints demonstrate both MASH resolution and fibrosis improvement and a combination of both at week 52, and significant reductions in plasma lipids.”

He added, “There was excellent tolerability ... [and] promising safety.”