Editorial Note: Metabolic dysfunction-associated steatohepatitis (MASH) has emerged as a leading cause of chronic liver disease worldwide. With the increasing prevalence of obesity and type 2 diabetes, the incidence of MASH continues to rise, making it a significant public health concern. Currently, treatment options remain limited, highlighting the urgent need for novel therapeutic approaches. A recent multicenter randomized controlled trial (ICONA), published in the Journal of Hepatology, has drawn attention for its evaluation of Icosabutate, an FFAR1/FFAR4 agonist, as a potential treatment for MASH. The study focused on its efficacy and safety, particularly its impact on liver fibrosis.The ICONA trial was a multicenter, randomized, double-blind, placebo-controlled Phase IIb study that enrolled 280 patients with MASH between the ages of 18 and 75. Participants were randomly assigned to receive either 300 mg of Icosabutate, 600 mg of Icosabutate, or a placebo for 52 weeks, with 93, 95, and 92 patients in each group, respectively. A total of 228 patients completed the study, and follow-up liver biopsies were conducted at week 52 to assess treatment outcomes. The primary endpoint was the proportion of patients in the 600 mg Icosabutate group achieving MASH resolution, defined as a ballooning score of 0 and a lobular inflammation score of 0–1, with no worsening of fibrosis. Secondary endpoints included fibrosis improvement, defined as at least a one-stage reduction in fibrosis severity, fibrosis improvement without worsening of MASH, and changes in hepatic biochemical markers, inflammatory biomarkers, fibrosis activity markers, and insulin resistance.
The results showed that 23.9% of patients in the 600 mg Icosabutate group achieved MASH resolution, compared to 14.5% in the placebo group, although this difference did not reach statistical significance (P=0.13). However, in terms of fibrosis improvement, both the 300 mg and 600 mg Icosabutate groups demonstrated a significantly higher proportion of patients with at least a one-stage improvement in fibrosis compared to the placebo group (29.3% and 23.9% vs. 11.3%). This effect was particularly notable in patients with fibrosis stages F2 and F3.
To further evaluate the drug’s effect, the study utilized artificial intelligence-assisted digital pathology tools (AIM-MASH and qFibrosis), which supported the findings that Icosabutate contributed to fibrosis improvement. In addition, Icosabutate significantly improved hepatic biochemical markers, inflammatory biomarkers, and fibrosis activity markers, with the most pronounced benefits observed in the 600 mg treatment group.
Icosabutate was well tolerated overall, with most adverse events being mild to moderate and not related to the study drug. The most frequently reported side effects were nausea and diarrhea. Importantly, no cases of drug-induced liver injury or treatment-related serious adverse events were observed.
The researchers concluded that the ICONA study provides preliminary evidence supporting the efficacy and safety of Icosabutate in MASH treatment. Although the primary endpoint did not reach statistical significance, the positive secondary endpoint results, combined with the observed improvements in hepatic biomarkers, inflammation, and fibrosis activity markers, suggest that Icosabutate has therapeutic potential. Its role in improving fibrosis, in particular, offers a promising new option for MASH patients.
Looking ahead, larger and longer-term clinical trials are needed to further validate Icosabutate’s efficacy and safety. Additionally, exploring combination therapies involving Icosabutate could be a valuable avenue for future research.
