Novel Therapy Reduced Liver Fat, Improved Fibrosis in MASH

Patients with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis who received a novel small molecule thyroid hormone receptor agonist achieved statistically significant reductions in liver fat, the phase IIb randomized VOYAGE trial showed.

At week 12, patients receiving VK2809 had significant reductions in liver fat, ranging from -49.5% with the 2.5-mg daily dose to -56.7% with the 10-mg dose taken every other day compared with -5.4% with placebo (P

“And these improvements were maintained at week 52,” Loomba observed during a late-breaking abstract session at the American Association for the Study of Liver Diseases annual meeting in San Diego, with significant reductions ranging from -34.3% with 1 mg of VK2809 daily to -56.3% with the 10-mg dose compared with -9.3% with placebo (P=0.006 and P

“Sustained liver fat reduction indicates potentially robust durability in treatment response,” he noted.

Response rates with VK2809 — defined as the proportion of patients experiencing reductions in liver fat ≥30% — were significantly different from placebo (27.1%) with the 2.5-mg dose (78.2%, PP=0.0002), and the 10-mg dose (87.8%, P

The percentage of patients who achieved resolution of MASH — previously known as nonalcoholic steatohepatitis — with no worsening of fibrosis ranged from 63% to 75% among those who received VK2809 compared with 29.3% with placebo, with significant differences observed with the three higher doses.

In addition, patients who received the 5-mg dose (51.9%) and the 10-mg dose (56.8%) had statistically significant improvements in fibrosis staging (≥1 stage) compared with placebo (34.1%), and 40.7% and 47.7% of these two dosing groups achieved a ≥1 stage improvement in fibrosis and resolution of MASH compared with 19.5% in the placebo group (P=0.021 and P=0.012, respectively).

Patients receiving VK2809 also had reductions in low-density lipoprotein cholesterol, triglycerides, and atherogenic proteins such as apolipoprotein B, lipoprotein(a), and apolipoprotein C-III, “showing the cardioprotective potential of this category of medications,” Loomba said.

MASH patients with clinically significant liver fibrosis (stages F2 and F3) are at high risk for progression to cirrhosis, which places them at greater risk for hepatocellular carcinoma, liver decompensation, need for transplant, and death.

Only one drug is currently indicated for MASH, a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD). The FDA granted accelerated approval to resmetirom (Rezdiffra) earlier this year based on results of the MAESTRO-NASH study. A number of other drugs are in development, however, including semaglutide (Ozempic, Wegovy).

The majority (97%) of reported treatment-emergent adverse events (TEAEs) were mild or moderate, and TEAEs leading to treatment discontinuation occurred in 6.1% of patients in the VK2809 groups compared with 9.2% of those receiving placebo. Rates of nausea, diarrhea, stool frequency, and vomiting were similar between groups.

VOYAGE was an international double-blind trial designed to assess the efficacy, safety, and tolerability of VK2809 in patients with biopsy-confirmed MASH and fibrosis.

The researchers enrolled 221 patients who had at least 8% liver fat content as measured by MRI-proton density fat fraction, as well as F2 and F3 fibrosis. The study allowed for up to 25% of enrolled patients to have F1 fibrosis provided they also had at least one additional risk factor, such as diabetes, obesity, or hypertension, among others.

Across the study arms, mean age was 52-53, 53-61% were women, 65-94% were white, and mean body mass index was 36-38.

Patients were randomized to receive placebo (n=62), or VK2809 at 1 mg daily (n=17), 2.5 mg daily (n=59), 5 mg every other day (n=36), or 10 mg every other day (n=57).

When asked to explain the rationale for assigning the higher doses of VK2809 every other day instead of daily, Loomba said the logic was that it would result in a lower total exposure while still achieving the robust reductions seen in the study.

“You are exposing patients to half the dose, but you are still achieving the same benefit,” he said.