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 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 ten of 13 doses of the study drug without missing three consecutive doses and completed the final liver biopsy at the end of treatment. ION224-CS2 was registered at ClinicalTrials.gov (NCT04932512) and is closed.

Findings: 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), 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 six (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 bodyweight, suggesting potential to combine with other therapies such as GLP-1 based treatments.

Funding: Ionis Pharmaceuticals.