AMSTERDAM — A once daily, 50 mg dose of efruxifermin reduced fibrosis at 96 weeks in patients with compensated cirrhosis due to metabolic dysfunction-associated steatohepatitis (MASH) compared with placebo, but it did not significantly reduce fibrosis at 36 weeks (primary endpoint), according to results from the phase 2b SYMMETRY trial.

Efruxifermin is a long-acting, bivalent fibroblast growth factor 21 analogue. At 96 weeks of treatment, a statistically significant 29% of patients had at least one stage of fibrosis improvement without MASH worsening (secondary outcome) compared with 11% on placebo.

Results also suggested improvements in MASH-related histologic findings, non-invasive markers of liver injury and fibrosis, as well as markers of glucose and lipid metabolism at 96 weeks. Now the 50 mg dose of efruxifermin is being investigated in phase 3 development.

Academic-clinician Mazen Noureddin, MD, MHSc, of the Sherrie and Alan Conover Center for Liver Disease and Transplantation at Houston Methodist Hospital, Texas, presented the findings here at the at the European Association for the Study of the Liver (EASL) Congress 2025. The work was published simultaneously in The New England Journal of Medicine .

Noureddin said that, for the first time, they showed “significant, unprecedented improvement in fibrosis” on the regimen. He added that the “histologic improvement in fibrosis corroborated with non-invasive tests, presenting an overall picture of liver injury and function that suggests liver health is maintained or slightly improved by efruxifermin compared to placebo.”

Despite being a major cause of liver failure and transplantation, there are currently no approved therapies that reverse fibrosis in MASH-related cirrhosis. Efruxifermin has shown antifibrotic effects in earlier studies of patients with less advanced disease (F2-F3 fibrosis). Now, this phase 2b, randomized, placebo-controlled, double-blind trial, shows efficacy and safety with efruxifermin in patients with MASH who had biopsy-confirmed compensated cirrhosis at stage 4 fibrosis.

The Trial

SYMMETRY was conducted across 45 sites in the US, Mexico, and Puerto Rico. It enrolled 181 adults with biopsy-confirmed compensated cirrhosis due to MASH (Child-Pugh A), 80% of whom had diabetes and obesity . Patients were at high risk for hepatic decompensation.

Participants were 18-75 years of age, had liver histologic features consistent with MASH, and had compensated cirrhosis (stage 4 fibrosis with a Child-Pugh score of 5 or 6). They also had type 2 diabetes or two components of metabolic syndrome comprising obesity, dyslipidemia, elevated blood pressure, and elevated fasting glucose level. Approximately 80% of the patients had biopsy-confirmed MASH.

Patients received weekly subcutaneous efruxifermin (28 mg or 50 mg) or placebo in a 1:1:1 ratio. Liver biopsies were obtained at weeks 36 and 96 and were included in the intention-to-treat and safety analyses. Overall, liver biopsy data were available for 154 patients at week 36 and for 134 patients at week 96.

The primary endpoint comprised a reduction of at least one stage of fibrosis without worsening of MASH at week 36, while the same measure comprised the secondary outcome at week 96.

At 36 weeks, in the intent-to-treat analysis, a reduction in fibrosis without worsening of MASH was seen in 8/61 patients (13%) in the placebo group, 10/57 patients (18%) in the 28 mg efruxifermin group (95% CI, -11 to 17; P = .62), and 12/63 patients (19%) in the 50 mg efruxifermin group (95% CI, -10 to 18; P = .52).

Referring to the 36-week completer analysis, Noureddin reported, “We see here, 24% in the 50 mg group compared with 14% in those on placebo [and 22% on the 28-mg dose]. When they continue treatment up to 96 weeks, we saw up to 39% improvement [50-mg dose] in fibrosis by one stage without worsening of MASH compared to 15% placebo [and 29% with 28 mg]. This is a difference of 24% [between placebo and 50 mg] that was statistically significant [ P < .01],” he reported.

In the intent-to-treat analysis, at week 96, a reduction in fibrosis without worsening of MASH occurred in 7/61 patients (11%) in the placebo group, in 12/57 patients (21%) in the 28 mg efruxifermin group (95% CI, -4 to 24), and in 18/63 patients (29%) in the 50 mg efruxifermin group (95% CI, 2-30). “It was up to 29% in the 50 mg compared with 11%, and that’s an 18% statistically significant difference [ P < .05].”

The proportion of week 36 responders who sustained response to week 96 were 50% (n = 4), 67% (n = 6), and 75% (n = 9), in the placebo, 28 mg, and 50 mg groups, respectively. Expanded response (non-response at week 36 but response at week 96) was 8% (n = 3), 19% (n = 6), and 26% (n = 9) respectively.

“This emphasizes the role of ongoing treatment in cirrhotic patients,” said Noureddin. He also added that they saw “consistent responses across multiple baseline subgroups for the primary histological endpoint and at week 96 with the 50 mg.”

Nearly all participants (99% on efruxifermin and 97% on placebo) reported adverse events. Any serious adverse events were reported in 26%, 24%, and 18% in the 28 mg, 50 mg, and placebo groups, respectively. Gastrointestinal side effects were most common: diarrhea (42%, 54%, and 30% on 28 mg, 50 mg, and placebo, respectively), nausea (30%, 46%, 30%, respectively), and increased appetite (16%, 40%, 7%, respectively) and mostly of mild-to-moderate nature. Administration-site reactions (erythema) were also more common with efruxifermin (13%, 16%, and 6%, respectively). After week 36 and prior to week 96, discontinuations due to adverse events were 0%, 2%, and 3% in the placebo, 28 mg, and 50 mg, respectively. “After week 36, there were very few discontinuations due to side effects,” reported Noureddin.

Poor bone health is a common complication of cirrhosis, and across all treatment groups, 43% of participants had osteopenia at baseline, but only 4% were treated with bisphosphonates. Placebo-adjusted, significant relative reductions in bone mineral density (-5%) for spine and hip were observed for both treatment groups at week 96 or about 2%-3% per year. The number of participants experiencing fractures was equal across all treatment groups, added Noureddin.

Commenting on the study, delegate and chairman of the Global NASH Council, Zobair M Younossi, MD, professor and chairman of the department of medicine at Inova Fairfax Medical Campus, Fairfax County, Virgina, told Medscape Medical News , “The key to this whole area is that there are treatments that have been developed for non-cirrhotic MASH, F2 and F3, but there is currently nothing that is positive for people with cirrhosis and MASH. This study shows there is improvement in all categories even in those with diabetes and even when they are controlled for some alcohol consumption.” He added, “I think that the best aspect of this is that it gives us a potential treatment for those patients who are at highest risk for bad outcomes in MASLD, which are those with cirrhosis.”

The study was supported by Akero Therapeutics. Noureddin declared grants, consultant roles, and stock options from many pharmaceutical companies, including Akero. Younossi reported no relevant financial relationships.

The findings were presented during a dedicated session on AI and hepatology, May 8, 2025, at the EASL Congress 2025.