Icosabutate fails MASH Phase 2 trial but shows some benefits in liver
Oral therapy found to ease liver scarring vs. placebo in ICONA study
Northsea Therapeutics’ oral therapy candidate icosabutate was not superior to a placebo at resolving metabolic dysfunction-associated steatohepatitis (MASH) — a severe form of fatty liver disease — without worsening liver scarring, or fibrosis, in MASH patients, according to newly published clinical trial findings.
While these results meant that the trial failed to meet its main goal, icosabutate, when given daily for one year, was found to significantly ease liver fibrosis relative to the placebo, per the researchers, who noted that the data were assessed with both conventional and artificial intelligence-, or AI-, based methods.
In addition, other biomarker analyses suggested a positive effect of icosabutate on liver health, inflammation, and blood sugar control.
These findings are among the final data from the Phase 2b ICONA clinical trial (NCT04052516), completed in late 2022, and end-of-trial analyses. The data were detailed in “A phase IIb randomised-controlled trial of the FFAR1/FFAR4 agonist icosabutate in MASH,” a study published in the Journal of Hepatology.
“We’re very pleased with the overall ICONA dataset,” Rob de Ree, Northsea’s CEO, said in a company press release. In the time since ICONA’s launch in 2019, de Ree added, “the MASH landscape has changed dramatically,” and it’s become increasingly recognized that easing fibrosis is “the most clinically relevant and therapeutically challenging endpoint,” or outcome measure, in clinical trials.
Lab-made icosabutate tested in MASH patients in clinical trial
Both the trial and analyses were sponsored by Northsea, and three study authors are affiliated with the company. Overall, the observed benefits seen in the clinical trial were consistent with those reported in mouse models treated with icosabutate.
de Ree said the company now aims to test the therapy in people with even more severe cases of this fatty liver disease.
“We look forward to further developing icosabutate in more advanced MASH patients as a [single therapy] or as a combination therapy,” de Ree said. “We believe there’s an important place for a safe, well tolerated, oral antifibrotic with add-on benefits on glycemic [blood sugar] control, inflammation and [certain damaging fats] in the MASH therapeutic landscape.”
MASH, formerly known as nonalcoholic steatohepatitis or NASH, is characterized by excess fat accumulation in the liver — the hallmark of fatty liver disease — that drives inflammation and fibrosis. It occurs in the context of cardiometabolic risk factors such as obesity, high blood sugar, and type 2 diabetes. Over time, the liver can become seriously and irreversibly damaged.
The researchers noted that long-chain omega-3 fatty acids, via activation of the free fatty acid receptor 1 (FFAR1) and 4 (FFAR4), have liver-specific anti-inflammatory effects and help control blood sugar, which could be promising for treating MASH.
However, these fatty molecules — commonly found in fish like salmon or mackerel — are also broken down by the body to generate energy, which can limit their therapeutic effects.
Icosabutate is a lab-made molecule designed to mimic the effects of these long-chain fatty acids on FFAR1/FFAR4, but with structural modifications to enhance liver targeting and resist metabolism for energy production, thereby enhancing its therapeutic potential.
We look forward to further developing icosabutate in more advanced MASH patients as a [single therapy] or as a combination therapy. … We believe there’s an important place for a safe, well tolerated, oral antifibrotic with add-on benefits on glycemic [blood sugar] control, inflammation and [certain damaging fats] in the MASH therapeutic landscape.
ICONA included 187 biopsy-confirmed MASH patients, ages 18 to 75, with mild to severe liver fibrosis. The participants were randomly assigned to receive an oral capsule of either one of two icosabutate doses (300 or 600 mg) or the placebo, once per day for a year.
Analyses used AI-based tools to more objectively assess therapy
The study’s main goal was to assess the proportion of patients who achieved MASH resolution without liver fibrosis worsening. While this outcome was achieved by a higher percentage of patients given icosabutate’s low (19%) or high dose (23.9%) relative to those on placebo (14.5%), the differences failed to reach statistical significance. That meant the study’s goal was not met.
Still, conventional analyses of liver biopsy tissue showed that significantly more patients given 300 mg icosabutate achieved at least a one-stage reduction in liver fibrosis after a year compared with those on the placebo (29.3% vs. 11.3%).
The superiority of icosabutate’s low dose over the placebo was also observed in the subset of patients with moderate or severe fibrosis, with rates of 13% in the placebo group, 30.8% in the 300 mg group, and 28.3% in those given 600 mg.
Among participants with type 2 diabetes — who comprised about 40%-50% of each treatment group — more than 1 in 5 patients treated with icosabutate experienced fibrosis reduction of at least one stage, compared with none of those on the placebo. Specifically, individuals receiving the 300 mg dose saw a reduction in scarring of 28.6%, while those given the 600 mg dose experienced a reduction of 21.2%.
In their analyses, the researchers used two different AI-based tools to review the data. Importantly, according to the team, the findings using these digital tools — believed to offer more objectivity than manual analyses by experts — tended to reflect similar benefits of icosabutate on fibrosis, although favoring the higher dose, and with more pronounced benefits in patients with advanced fibrosis.
“[AI] tools, as employed in this study, … are more reproducible and less subject to reader subjectivity,” the team wrote, suggesting their use in future clinical studies.
A significant benefit of 600 mg icosabutate over the placebo was also observed in multiple biomarkers of liver health, fibrosis, inflammation, and blood sugar control.
The treatment was generally safe and well tolerated, the data showed.
“Nausea and diarrhoea were the most common adverse events, with nausea more frequently reported in patients assigned to icosabutate,” the researchers wrote.
Northsea also noted that icosabutate did not significantly decrease either patients’ liver fat content or body weight. As such, the company noted that icosabutate may be positioned for use in combination with treatments designed to promote such changes. These include GLP-1 receptor antagonists, a class of medications for obesity and diabetes that includes well-known brand names such as Ozempic and Wegovy.
“These results warrant further investigation in larger and longer clinical trials of icosabutate [alone] or in combination with other agents as a possible treatment for MASH,” the researchers wrote.
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