Summary: In adults with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis (F1 to F3), the liver-directed antisense DGAT2 inhibitor ION224 met the primary histological endpoint at week 51. A two-point or greater NAS reduction with improved ballooning or inflammation and no fibrosis worsening was achieved by 46% on 90 mg (risk difference 27.4%, p=0.0094) and 59% on 120 mg (risk difference 40.1%, p=0.0002) versus 19% on placebo, with no treatment-related serious adverse events.
PICO Summary
| Element | Detail |
|---|---|
| Population | 160 randomised adults aged 18 to 75 with biopsy-confirmed MASH and fibrosis (stages F1 to F3) and baseline liver steatosis 10% or greater; 123 in the per-protocol set. Adaptive, two-part, multicentre, double-blind, placebo-controlled phase 2 trial at 43 sites in the USA and Puerto Rico (NCT04932512). |
| Intervention | Subcutaneous ION224 (antisense oligonucleotide inhibitor of DGAT2) once monthly at 60 mg (n=23), 90 mg (n=45), or 120 mg (n=46) for 51 weeks. |
| Comparison | Subcutaneous placebo once monthly (n=46) under identical, double-blind conditions. |
| Outcome | Primary endpoint (two-point or greater NAS reduction with one-point or greater improvement in ballooning or lobular inflammation, without fibrosis worsening at week 51, per-protocol): 90 mg 18/39 (46%), risk difference vs placebo 27.4% (95% CI 6.7 to 48.1), p=0.0094; 120 mg 20/34 (59%), risk difference 40.1% (95% CI 18.7 to 61.4), p=0.0002; placebo 6/32 (19%). Adverse events occurred in 94% on ION224 versus 89% on placebo, with no deaths and no treatment-related serious adverse events. No ARR or NNT was reported by the authors for the responder endpoint. |
ION224 (DGAT2 inhibitor) in MASH
Phase 2 RCT · MASH with fibrosis · 51 weeks
Both ION224 doses beat placebo on a biopsy responder endpoint with a clear dose gradient, but the result is phase 2 and per-protocol. The agent stays investigational.
Expert Commentary
This phase 2 trial offers the first clinical evidence that antisense-mediated DGAT2 inhibition can deliver histological improvement in MASH, and the verdict is encouraging but preliminary. Both active doses separated from placebo on a meaningful biopsy-based responder endpoint, with a clear dose gradient and confidence intervals that excluded no effect, and the histological gains were reported to be independent of bodyweight change, which is notable in a field crowded by weight-mediated mechanisms. The result must nonetheless be read with restraint. The primary analysis was confined to a per-protocol set of 123 of the 160 randomised participants, so the headline response rates are best-case estimates that an intention-to-treat analysis would likely temper, and a phase 2 histological signal is a long way from proven clinical benefit on cirrhosis, decompensation, or mortality. The trial was funded and conducted by the manufacturer, Ionis Pharmaceuticals, which warrants the usual caution about framing despite the double-blind, placebo-controlled design. Can I use this with my patients? Not yet. ION224 remains investigational and unavailable outside trials, so it does not change today’s management of any patient with MASH. The appropriate next step is a larger, longer phase 3 study with intention-to-treat analysis and durable clinical endpoints before this agent earns a place in practice.
References
Loomba R, Morgan E, Yousefi K, Li D, Geary R, Bhanot S, 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. doi:10.1016/S0140-6736(25)00979-1