AT A GLANCE

A new study published in the Lancet concludes that a liver-directed antisense inhibitor of diacylglycerol O-acyltransferase 2 (DGAT2), ION224, may be a safe and effective therapeutic strategy for metabolic dysfunction–associated steatohepatitis (MASH).¹

“ION224, a liver-directed antisense inhibitor of DGAT2, suppresses de novo lipogenesis, an important metabolic pathway associated with lipotoxicity and the underlying inflammation, hepatocellular injury, and fibrosis in MASH,” explain study authors Loomba et al. “This study aimed to prospectively assess the safety and efficacy of ION224 in patients with MASH and fibrosis.”

As part of an adaptive, two-part, multicenter, randomized, double-blind, placebo-controlled, phase 2 trial conducted at 43 clinical sites in the USA and Puerto Rico, the authors enrolled in patients with biopsy-confirmed MASH and fibrosis (stages F1–F3) and baseline liver steatosis ≥10%. During part 1 of the study, participants were randomly assigned (1:1:1) to subcutaneous injections of ION224 60, 90, or 120 mg or placebo, once per month, while part 2 participants were randomly assigned (2:1) to ION224 90 or 120 mg or placebo after a pre-specified interim analysis of safety and efficacy (liver steatosis).

The primary study analysis was performed in a predefined per-protocol set of patients who received at least 10 of 13 doses of the study drug without missing three consecutive doses and who underwent a final liver biopsy at the end of treatment. The primary endpoint of interest was a ≥2-point reduction in the Non-Alcoholic Fatty Liver Disease Activity Score Activity Score (NAS) with a ≥1-point improvement in hepatocellular ballooning or lobular inflammation, without worsening of fibrosis, at Week 51.

According to the authors, between June 8, 2021, and Dec 27, 2022, 160 participants were randomly assigned to receive ION224 60 mg (n = 23), 90 mg (n = 45), or 120 mg (n = 46) or placebo (n = 46), with 123 subsequently included in the per-protocol set. Ultimately, the primary endpoint was met in 18 (46%) of 39 participants in the 90-mg and 20 (59%) of 34 participants in the 120-mg group compared to six (19%) of 32 participants in the placebo group. Adverse events were documented in 107 (94%) of participants treated with ION224 compared to 41 (89%) of 46 participants treated with placebo.

“This study provides the first clinical evidence that antisense-mediated inhibition of DGAT2 with ION224 could be a safe and efficacious strategy for the treatment of MASH. The observed histological improvements were independent of changes in bodyweight, suggesting potential to combine with other therapies such as GLP-1–based treatments,” conclude the authors.

Reference

1.     Loomba R, Morgan E, Yousefi K, et al. Antisense oligonucleotide DGAT-2 inhibitor, ION224, for metabolic dysfunction-associated steatohepatitis (ION224-CS2): results of a 51-week, multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2025;406(10505):821–831.