Ionis Reports Encouraging Findings from Phase 2 Trial of ION224, Showing Clinical Effectiveness in NASH/MASH Treatment

Ionis has unveiled encouraging outcomes from its Phase 2 investigation of ION224, a DGAT2 antisense inhibitor aimed at addressing metabolic dysfunction-associated steatohepatitis (MASH), previously termed nonalcoholic steatohepatitis (NASH). The study, encompassing 160 patients over 51 weeks, successfully met its primary endpoint at doses of both 120 mg and 90 mg, demonstrating liver histologic improvement, alongside fulfilling the significant secondary endpoint of MASH resolution.

Key findings from the study include:

  • ION224 achieved a notable liver histologic improvement, with a reduction of at least 2 points in NAFLD Activity Score (NAS)* (p<0.001 (120 mg) and p=0.015 (90 mg)).
  • Subgroup analysis revealed substantial improvements in the primary endpoint among patients with both F2 and F3 (advanced) fibrosis.
  • Statistically significant MASH resolution without fibrosis worsening was achieved by ION224, as measured by biopsy (p=0.039).
  • 44% of patients treated with 120 mg experienced ≥50% relative reduction in liver steatosis measured by MRI-PDFF, compared to 3% for placebo.
  • 32% of patients treated with 120 mg achieved ≥1 stage improvement in fibrosis without worsening steatohepatitis, compared to 12.5% for placebo.
  • ION224 demonstrated safety and good tolerability throughout the study.

“This Phase 2 trial of ION224 marks a significant milestone, providing clinical evidence that reducing hepatic fat through DGAT2 inhibition correlates with improvements in MASH histological endpoints,” commented Rohit Loomba, MD, MHSc, Professor of Medicine and Chief, Division of Gastroenterology and Hepatology, University of California San Diego. “I believe ION224 presents a distinctive precision medicine opportunity, potentially complementing other therapies in development for MASH. I eagerly anticipate further evaluation of this promising investigational medicine.”

MASH, a severe form of metabolic dysfunction-associated steatotic liver disease (MASLD), can lead to liver fibrosis, cirrhosis, and liver-related mortality. ION224, a Ligand-Conjugated Antisense (LICA) medication, aims to mitigate diacylglycerol acyltransferase 2 (DGAT2) production to treat MASH patients.

“Reducing DGAT2 enzyme production decreases triglyceride overproduction, which contributes to excess liver fat, potentially causing liver damage and inflammation. We find the ION224 data encouraging, indicating that a monthly subcutaneous treatment targeting DGAT2 holds promise for MASH improvement and halting its progression to severe stages, including advanced liver fibrosis and cirrhosis,” stated Sanjay Bhanot, MD, PhD, Senior Vice President and Chief Medical Officer at Ionis. “DGAT2 inhibition offers a novel approach for MASH, a progressive disease in need of enhanced therapeutic options. We eagerly anticipate presenting the full study results at an upcoming medical conference and discussing the next steps for advancing this potentially transformative therapy for patients.”

The study demonstrated the safety and tolerability of ION224 in MASH participants, with no deterioration in hepatic or renal function, gastrointestinal side effects, or increased early termination rates compared to placebo. Additionally, no on-study deaths or treatment-related serious adverse events were reported.

The adaptive Phase 2 trial was a multi-center, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy, safety, and pharmacokinetics of multiple doses of ION224 when administered subcutaneously once-monthly in adults with MASH. It enrolled 160 patients who received either ION224 or placebo over 49 weeks. The study was powered for the primary endpoint, which was the percentage of patients achieving MASH histologic improvement, defined as a reduction of at least 2 points in NAS with at least 1-point improvement in hepatocellular ballooning or lobular inflammation, and without fibrosis worsening at the end of the treatment period.

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