Liver and Bile
Lancet. 2025;406(10505):821-831
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
Background: ION224, a liver-directed antisense inhibitor of diacylglycerol O-acyltransferase 2 (DGAT2), suppresses de novo lipogenesis, an important metabolic pathway associated with lipotoxicity and the underlying inflammation, hepatocellular injury, and fibrosis in metabolic dysfunction-associated steatohepatitis (MASH). This study aimed to prospectively assess the safety and efficacy of ION224 in patients with MASH and fibrosis.
Methods: ION224-CS2 was an adaptive, two-part, multicentre, randomised, double-blind, placebo-controlled, phase 2 trial conducted at 43 clinical sites in the USA and Puerto Rico in patients aged 18–75 years with biopsy-confirmed MASH and fibrosis (stages F1, F2, and F3) and baseline liver steatosis ≥ 10%. In part 1, participants were randomly assigned (1:1:1) to subcutaneous injections of ION224 60 mg, 90 mg, or 120 mg, or placebo, once per month. In part 2, participants were randomly assigned (2:1) to ION224 90 mg and 120 mg or placebo after a pre-specified interim analysis of safety and efficacy (liver steatosis). The primary endpoint was ≥ 2-point reduction in Non-Alcoholic Fatty Liver Disease Activity Score (NAS) with ≥ 1-point improvement in hepatocellular ballooning or lobular inflammation, and without worsening of fibrosis at week 51. The primary analysis was in a predefined per-protocol set that included patients who received at least 10 of 13 doses of the study drug without missing 3 consecutive doses and completed the final liver biopsy at the end of treatment.
Findings: Between June 8, 2021, and December 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), of whom 123 were included in the per-protocol set. The primary endpoint was met in 18 (46%) of 39 participants in the 90-mg group (predicted risk 46.2% [95% CI: 30.5–61.8]; risk difference 27.4% [95% CI: 6.7–48.1], p = 0.0094) and 20 (59%) of 34 in the 120-mg group (58.8% [42.3–75.4]; 40.1% [18.7–61.4], p = 0.0002) compared with 6 (19%) of 32 in the placebo group (predicted risk 18.7% [95% CI: 5.2–32.3]). ION224 was safe and well tolerated. Adverse events were reported in 107 (94%) of participants treated with ION224 and 41 (89%) of 46 participants treated with placebo. There were no deaths and no treatment-related serious adverse events.
Interpretation: 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 body weight, suggesting potential to combine with other therapies such as GLP-1 based treatments.