Efruxifermin reverses MASH-related cirrhosis in Phase 2 trial
'Unprecedented' results seen in adults with severe fatty liver disease
Treatment with Akero Therapeutics’ investigational efruxifermin led to reversals of compensated cirrhosis, or irreversible scarring in a still-functioning liver, among adults with metabolic dysfunction-associated steatohepatitis (MASH), a severe form of fatty liver disease.
Those are the top-line results from the Phase 2b SYMMETRY clinical trial (NCT05039450) — data that Akero classified as both “unprecedented” and statistically significant in a company press release.
These preliminary findings are in line with data from the Phase 2b HARMONY trial (NCT04767529), which showed that use of the therapy reduced liver scarring, known as fibrosis, among adults with MASH-related fibrosis that hadn’t yet progressed to cirrhosis.
“These exciting results, which build on last year’s … results for the Phase 2b HARMONY study … show [efruxifermin’s] potential to improve outcomes not only for patients with pre-cirrhotic fibrosis, but also for those with compensated cirrhosis — a population in urgent need of effective therapeutic options,” Andrew Cheng, MD, PhD, president and CEO of Akero, said in the release, which reported the company’s financial results for 2024 and provided business updates.
Akero is now further investigating efruxifermin across the MASLD/MASH spectrum via three clinical trials in its Phase 3 SYNCHRONY program. The results of that program are expected to support regulatory applications seeking efruxifermin’s approval for MASH patients with or without compensated cirrhosis, according to the company.
3 Phase 3 studies now testing efruxifermin in over 3,000 patients
Together, the three ongoing studies of efruxifermin are enrolling more than 3,000 people with MASH across the globe.
The SYNCHRONY Outcomes study (NCT06528314) is testing the therapy candidate against a placebo in more than 1,000 MASH patients with compensated cirrhosis at 155 sites worldwide.
SYNCHRONY Histology (NCT06215716) is seeking 1,650 adults with biopsy-confirmed MASH-related fibrosis, but no cirrhosis, at nearly 300 sites worldwide. The study remains on track to report certain one-year results during the first half of 2027, according to the company.
The SYNCHRONY Real-World trial (NCT06161571) involves adults who were diagnosed noninvasively with MASLD/MASH and who have some degree of liver fibrosis. This trial has completed enrollment of 601 participants in its main placebo-controlled part, with preliminary top-line results due next year.
MASH, formerly known as nonalcoholic steatohepatitis or NASH, is a severe form of metabolic dysfunction-associated steatotic liver disease, known as MASLD, in which fat accumulates in the liver in the context of metabolic conditions such as obesity or type 2 diabetes.
In people with MASH, excess fat in the liver leads to inflammation and fibrosis, which can eventually lead to cirrhosis, where liver fibrosis becomes irreversible.
In people with compensated cirrhosis, the scarring doesn’t stop the liver from working, but the condition can easily progress to decompensated cirrhosis, in which the liver can no longer function and a liver transplant is the only viable disease treatment.
We remain committed to advancing [efruxifermin] as a potential therapeutic breakthrough for individuals living with advanced MASH and look forward to building upon this momentum as we progress our Phase 3 SYNCHRONY program.
Efruxifermin, given via subcutaneous, or under-the-skin, injections, is designed to mimic the activity of FGF21, a naturally occurring hormone that regulates metabolism and fat storage. In so doing, it’s expected to be able to address all core drivers of MASH progression, per the company.
“We remain committed to advancing [efruxifermin] as a potential therapeutic breakthrough for individuals living with advanced MASH and look forward to building upon this momentum as we progress our Phase 3 SYNCHRONY program,” Cheng said.
Phase 2 SYMMETRY results show treatment results improved over time
In the SYMMETRY trial, 181 MASH patients with biopsy-confirmed compensated cirrhosis were enrolled. All were randomly assigned to receive weekly injections of either efruxifermin (28 mg or 50 mg) or a placebo for 96 weeks, or nearly two years.
In patients, fibrosis is staged on a scale from F0, for no fibrosis, to F4, for cirrhosis. Each of the trial participants was at F4 at the study’s start.
Its main goal was to assess the proportion of patients who achieved a reduction in fibrosis by at least one stage without MASH worsening — reflective of cirrhosis reversal — after 36 weeks, or about eight months.
The results showed that the proportion of patients achieving this goal did not significantly differ between the groups at 36 weeks, failing to meet that main goal. However, the difference between the efruxifermin and placebo groups continued to grow over time — roughly doubling between weeks 36 and 96.
In the primary analysis group — the 134 participants with available biopsy data at the study’s start and week 96 — the 96-week data showed that 39% of those given 50 mg efruxifermin met the main goal. Among participants given the 28 mg dose, 29% met that goal. This compared with 15% of those given the placebo. The difference between the high-dose efruxifermin and placebo groups reached statistical significance, per the company.
Analyses across the entire study population and in the subgroup of patients not taking GLP-1 agonists — a class of medications used to treat obesity and type 2 diabetes — showed similar patterns.
In the primary analysis group, significantly more patients given 28 mg (59%) or 50 mg efruxifermin (55%) experienced MASH resolution than those in the placebo group (18%).
Noninvasive measures of liver fibrosis, liver injury, and metabolic biomarkers similarly favored efruxifermin’s high dose over the placebo.
Efruxifermin was generally well tolerated, with the most common side effects being diarrhea, nausea, increased appetite, and injection site redness.
Overall, the data were consistent with 96-week findings from the similarly designed HARMONY trial involving adults with MASH-related precirrhotic liver fibrosis.
In HARMONY, significantly more patients treated with 50 mg efruxifermin achieved fibrosis reductions than those on a placebo (40% vs. 0%). Also, 30% of those on the high dose had a near-complete reversal of MASH-related disease, which did not occur for any patient on the placebo.
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