Phase II MASH Trial Success for Ionis Antisense Drug

A Phase II clinical trial for a drug candidate developed by Ionis Pharmaceuticals has successfully achieved its primary goal, targeting metabolic dysfunction-associated steatohepatitis (MASH), a liver condition previously referred to as nonalcoholic steatohepatitis. The trial involved 160 participants diagnosed with MASH, who were randomly assigned to receive either a placebo or one of three monthly subcutaneous doses of ION224. This ligand-conjugated antisense medicine was specifically designed to reduce the production of DGAT2, an enzyme associated with fatty liver disease.

After a period of 51 weeks, the trial demonstrated that a significantly higher proportion of patients in the top two dose groups showed histological improvement in their MASH condition without an increase in fibrosis, compared to those who received the placebo. The trial's primary endpoint was met, with p values for the effective 90-mg and 120-mg doses being 0.015 and less than 0.001, respectively. Further analysis revealed that patients with F2 and F3 fibrosis, which are moderate stages of fibrosis on a four-point scale, experienced improvements with ION224 treatment.

Secondary endpoint data indicated that ION224 outperformed the placebo in terms of MASH resolution without fibrosis worsening, as determined by biopsy. At the highest dose, 44% of patients showed a 50% or greater reduction in liver fat, as measured by imaging, compared to only 3% of those on the placebo. Additionally, a favorable trend was observed for liver scarring, with 32% of patients in the high-dose group experiencing at least a one-stage improvement in fibrosis without worsening of MASH, as opposed to 12.5% in the placebo group.

The FDA requires Phase III clinical trials to demonstrate a one-stage improvement in fibrosis without worsening of MASH or the resolution of MASH without fibrosis worsening. Recent studies have shown more promising results, with Madrigal Pharmaceuticals meeting both endpoints in Phase III trials for its THR-β agonist, resmetirom. The FDA is expected to make a decision on the approval of resmetirom soon.

Ionis may face competition in the market if it successfully brings ION224 to market, as several companies are developing MASH treatments targeting various mechanisms. This includes Boehringer Ingelheim's glucagon/GLP-1 receptor dual agonist, survodutide, and Akero Therapeutics' FGF21 analog, efruxifermin. Additionally, other companies like Pfizer, Sinew Pharma, and Viking Therapeutics are focusing on DGAT1 inhibitors, with Pfizer having a candidate in mid-stage development.

The success of this Phase II clinical trial for ION224 is a significant milestone for Ionis Pharmaceuticals and holds promise for the treatment of MASH, a condition that affects many individuals worldwide. The results of the trial underscore the potential of antisense medicine in addressing complex metabolic disorders and highlight the ongoing efforts within the pharmaceutical industry to develop innovative treatments for liver diseases.