Ionis announces positive results from Phase 2 study of ION224 to treat NASH/MASH

New Delhi: Ionis Pharmaceuticals announced positive results from a Phase 2 study of ION224, an investigational DGAT2 antisense inhibitor in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH), previously referred to as nonalcoholic steatohepatitis (NASH).

The study met its primary endpoint at both doses (120 mg and 90 mg), achieving liver histologic improvement, and also met the important secondary endpoint of MASH resolution.

ION224 is an investigational LIgand-Conjugated Antisense (LICA) medicine designed to reduce the production of diacylglycerol acyltransferase 2 (DGAT2) to treat patients with MASH. DGAT2 is an enzyme that catalyzes the final step in triglyceride synthesis in the liver. Reducing the production of DGAT2 should therefore decrease triglyceride synthesis in the liver. Additionally, there is evidence of an increase in both fatty acid oxidation and oxidative gene expression associated with antisense inhibition of DGAT2. ION224 offers a unique approach, which is potentially complementary to other therapies currently in clinical development.

Key highlights from the 160-patient study at 51 weeks included:

a. ION224 achieved statistically significant liver histologic improvement as measured by at least a 2-point reduction in NAFLD Activity Score (NAS)* (p<0.001 (120 mg) and p=0.015 (90 mg)).

b. Subgroup analysis indicated that significant improvements in the primary endpoint were observed in patients with both F2 and F3 (advanced) fibrosis.

c. ION224 achieved statistically significant MASH resolution without worsening of fibrosis, as measured by biopsy (p=0.039).

d. 44% of patients treated with 120 mg achieved ≥50% relative reduction in liver steatosis as measured by MRI-PDFF compared to 3% for placebo.

e. 32% of patients treated with 120 mg achieved a ≥1 stage improvement in fibrosis without worsening steatohepatitis as measured by biopsy compared to 12.5% for placebo.

f. ION224 was safe and well-tolerated in the study.

MASH is the more severe form of metabolic dysfunction-associated steatotic liver disease (MASLD) and can lead to liver fibrosis, cirrhosis and liver-related death. ION224 is an investigational LIgand-Conjugated Antisense (LICA) medicine designed to reduce the production of diacylglycerol acyltransferase 2 (DGAT2) to treat patients with MASH.

"Reducing the production of DGAT2 enzyme decreases the overproduction of triglycerides that contribute to excess liver fat, which can result in liver damage and inflammation. We are encouraged by these ION224 data, showing that a monthly subcutaneous medicine targeting DGAT2 has the potential to improve MASH and prevent its progression to more severe stages, including advanced liver fibrosis and cirrhosis," said Sanjay Bhanot, MD, PhD, senior vice president and chief medical officer at Ionis.

"The inhibition of DGAT2 represents a novel approach for MASH, a progressive disease in need of better treatment options. We look forward to sharing the full results from this study at an upcoming medical conference and discussing next steps to advance this potentially promising therapy for patients."

In this study, ION224 was safe and well-tolerated in MASH participants. Those in the ION224 study arms did not experience any worsening of hepatic or renal function or gastrointestinal side effects, and there was a lower rate of early termination compared to placebo. Additionally, there were no on-study deaths or treatment-related serious adverse events.

The adaptive Phase 2, two-part, multi-center, randomized, double-blind, placebo-controlled study was designed to assess the efficacy, safety and pharmacokinetics of multiple doses of ION224 when administered subcutaneously once-monthly in adults with MASH. The study enrolled 160 patients to receive ION224 or placebo over a period of 49 weeks. In Part 1, 93 patients were randomized 1:1:1 to the three dose cohorts (60, 90, and 120 mg) and within each dose cohort, randomized 3:1 to receive ION224 or placebo.

In Part 2, an additional 67 patients were randomized 1:1 to two selected dose cohorts (90 and 120 mg) and then in a 2:1 ratio to receive either ION224 or placebo within each cohort. The study was powered for the primary endpoint, which was the percentage of patients who achieved MASH histologic improvement, defined as achieving at least a 2-point reduction in NAS with at least 1-point improvement in hepatocellular ballooning or lobular inflammation, and without worsening of fibrosis at end of the treatment period.