Novel DGAT2 Antisense Inhibitor Demonstrates Significant Histological Benefit In Biopsy-proven Mash Patients With Advanced Liver Fibrosis Stage F3: Subset Analysis Of A 51-week Multicenter Randomized

A recent analysis from the ION224-CS2 study has provided compelling evidence for the efficacy of ION224, a novel ligand-conjugated antisense inhibitor targeting diacylglycerol acyltransferase 2 (DGAT2), in treating advanced liver fibrosis. The subset analysis focused on patients with stage F3 fibrosis and demonstrated significant improvements in key markers of metabolic-associated steatohepatitis (MASH) resolution and liver fibrosis reduction.

Study Overview and Patient Demographics

The analysis included 39 biopsy-proven MASH patients with advanced fibrosis (stage F3), MASLD activity scores (NAS) ≥4, and MRI-PDFF (proton density fat fraction) ≥10%. Participants were randomized to receive monthly subcutaneous injections of ION224 (90 mg or 120 mg; n=26) or placebo (n=13) over 49 weeks, followed by a biopsy evaluation. The baseline characteristics showed:

• Average age: 57 years

• Body weight: 109.7 kg

• Female: 51%

• Type 2 diabetes: 59%

• MRI-PDFF: 21%

Key Findings

Reduction in NAS and MASH Resolution

The primary endpoint—≥2-point reduction in NAS with ≥1-point improvement in hepatocellular ballooning or lobular inflammation without worsening fibrosis—was achieved in 61.5% of ION224-treated patients versus 15.4% in the placebo group (p=0.006). Additionally, 46.2% of ION224 patients demonstrated combined improvements in hepatocellular ballooning and lobular inflammation compared to 15.4% in the placebo group.

MASH resolution without fibrosis worsening was observed in 30.8% of ION224-treated patients, compared to 15.4% in the placebo arm.

Fibrosis and Liver Fat Reduction

A notable 46.2% of ION224-treated patients achieved ≥1 stage improvement in fibrosis without worsening steatohepatitis, compared to 30.8% in the placebo group. Liver fat reduction, as measured by MRI-PDFF, was significantly higher in the ION224 group, with:

• ≥30% reduction in 88.5% of patients vs. 38.5% in placebo (p=0.002).

• ≥50% reduction in 53.8% of patients vs. 7.7% in placebo (p=0.005).

Safety and Tolerability

ION224 was well-tolerated with no treatment-related serious adverse events, gastrointestinal side effects, or significant weight changes. The 120 mg dose also showed a placebo-adjusted improvement in HbA1c by 0.5%.

Implications

These findings underscore ION224’s potential as a treatment for advanced liver fibrosis in MASH patients, independent of weight changes. By demonstrating significant improvements in fibrosis, liver fat reduction, and histological markers of inflammation, ION224 represents a promising therapeutic option for a patient population with limited effective treatments. Further studies are warranted to confirm these benefits and optimize dosing strategies.

This analysis supports ION224’s potential to redefine the treatment landscape for MASH patients with advanced fibrosis.

By - Eeshan Aggarwal

Reference: Hepatology. Volume 80, Issue S1. Abstract Supplement for The Liver Meeting by the American Association for the Study of Liver Diseases (AASLD), November 15-19, 2024, San Diego, CA.