ION224 Phase 2 Success: ION224 Effective in NASH/MASH Treatment

Ionis Pharmaceuticals has reported promising findings from a Phase 2 clinical trial of ION224, a novel DGAT2 antisense inhibitor, for the treatment of metabolic dysfunction-associated steatohepatitis, known as MASH, which was formerly referred to as NASH. The trial successfully met its primary goal, showing significant liver histological improvement in patients treated with ION224 at both dosages of 120 mg and 90 mg. Additionally, the study achieved the secondary endpoint of MASH resolution without fibrosis deterioration.

The 160-patient trial, which spanned 51 weeks, revealed several noteworthy outcomes. Notably, there was a statistically significant decrease in the NAFLD Activity Score (NAS) by at least two points for both dosages, with a p-value of less than 0.001 for the 120 mg dosage and 0.015 for the 90 mg dosage. The improvements were pronounced in patients with advanced fibrosis stages F2 and F3. Furthermore, 44% of the patients on the 120 mg dosage experienced a 50% or greater reduction in liver fat as measured by MRI-PDFF, compared to only 3% in the placebo group. In terms of fibrosis, 32% of the 120 mg dosage group showed a one-stage or greater improvement without steatohepatitis worsening, in contrast to 12.5% in the placebo group.

ION224 demonstrated a favorable safety profile, being well-tolerated with monthly subcutaneous administration. There were no reports of hepatic or renal function deterioration or gastrointestinal side effects among the study participants. The rate of early study withdrawal was lower in the ION224 group compared to the placebo group, and no study-related deaths or serious adverse events were recorded.

Dr. Rohit Loomba, a leading expert in the field, highlighted the significance of the trial, stating that it is the first to show a correlation between reduced liver fat following DGAT2 inhibition and improvements in MASH histological endpoints. He anticipates that ION224 could offer a unique and precise medical approach for MASH, potentially complementing other treatments in development.

MASH is a severe form of fatty liver disease linked to obesity, pre-diabetes, and diabetes. It can progress to liver fibrosis, cirrhosis, and even lead to liver-related mortality. ION224, as a LICA medicine, is designed to lower the production of DGAT2, an enzyme involved in the final step of liver triglyceride synthesis. By reducing DGAT2, ION224 is expected to decrease liver triglyceride synthesis and, consequently, liver fat accumulation, which is a key factor in liver damage and inflammation.

Dr. Sanjay Bhanot, a senior executive at Ionis, expressed optimism about the drug's potential to improve MASH conditions and halt disease progression to severe stages like advanced liver fibrosis and cirrhosis. The study's design was robust, involving a randomized, double-blind, placebo-controlled approach with multiple dosages administered once a month. The trial was divided into two parts, enrolling a total of 160 patients over 49 weeks.

ION224 represents a potentially groundbreaking treatment for MASH, a disease in urgent need of effective therapies. The study's positive results are a step forward in the quest for better treatment options for this progressive liver disease. The full study findings are expected to be presented at an upcoming medical conference, where the next steps for this promising therapy will be discussed.