Results From the 52-Week Phase 2b VOYAGE Trial of VK2809 in Patients With Biopsy-Confirmed Non-Alcoholic Steatohepatitis and Fibrosis: A Randomized, Placebo-Controlled Trial

Lian and colleagues presented data from the 52-week phase 2b VOYAGE trial, which evaluated the investigational agent VK2809, a potent and selective THR-β agonist.^1,2 VK2809 has been demonstrated to have liver-targeting characteristics, including CYP3A4-mediated cleavage; because CYP3A4 is primarily expressed in the liver, this results in a largely targeted delivery of the drug to the liver tissue.

The VOYAGE study was designed as a 12-month, double-blind, placebo-controlled, phase 2b trial. In this study, patients with biopsy-confirmed MASH were randomized to treatment with either placebo or VK2809 at 1 of 4 doses (1.0 mg once daily, 2.5 mg once daily, 5 mg every other day, or 10 mg every other day). At baseline, patient characteristics were well balanced, with females more prevalent than males across all arms, and age, weight, and BMI consistent across all arms.

The primary endpoint of the VOYAGE study was the change in MRI-PDFF at 3 months. A significant reduction in liver fat was observed at this time point at all doses of VK2809, except 1.0 mg once daily, compared with placebo. Patients experienced up to a 57% median reduction in MRI-PDFF from baseline. Importantly, these reductions in liver fat were sustained or improved through week 52, which showed up to a 56% median reduction in MRI-PDFF from baseline. Up to 85% of patients treated with VK2809 achieved a 30% or more decrease in liver fat at 12 weeks; this was increased to 88% at the week 52 time point. A reduction in liver fat was found to correlate with improved odds of long-term histology benefit.

Resolution of MASH without worsening of fibrosis was observed in up to 75% of patients (Figure 5). At the highest 2 doses of VK2809 (5 mg or 10 mg every other day), a significant proportion of patients achieved a 1-stage or higher improvement in fibrosis, without worsening of MASH. Among this group, similar fibrosis improvement rates were observed among patients with F2 or F3 stages.

Figure 5.

Proportion of patients (all with baseline magnetic imaging and week 52 biopsy) treated with VK2809 in the phase 2b VOYAGE trial demonstrating resolution of metabolic dysfunction-associated steatohepatitis with no worsening of fibrosis. QD, every day; QOD, every other day. Adapted from Lian B, et al. AASLD abstract 5016. Presented at: The Liver Meeting; November 15-19, 2024; San Diego, CA.¹

These promising results with VK2809 provide further validation for targeting thyroid hormone receptor beta as an effective treatment for patients with MASH and significant fibrosis. The high rates of MASH resolution, fibrosis improvement, and reduction in liver fat fraction lend support to developing VK2809 in phase 3 trials. The beneficial effects on lipid levels seen in this trial may also lead to improved cardiovascular outcomes with longterm use; however, these beneficial effects need to be proven in prospective trials.

— Naim Alkhouri, MD

The majority (94%) of treatment-emergent AEs reported were mild or moderate, and the rates of discontinuations due to an AE were balanced across the VK2809 doses and in comparison to placebo. The rates of gastrointestinal-related AEs in VK2809-treated patients were similar to placebo-treated patients.