Efruxifermin reduces fibrosis in MASH cirrhosis

The long-acting, bivalent fibroblast growth factor 21 analogue efruxifermin reduced fibrosis at 96 weeks in patients with compensated cirrhosis due to metabolic dysfunction-associated steatohepatitis (MASH) in the phase 2b SYMMETRY trial.

At 96 weeks of treatment, 29 percent of patients had at least one stage of improvement in fibrosis without worsening of MASH compared with 11 percent for placebo.

There were also improvements in MASH-related histologic findings, noninvasive markers of liver injury and fibrosis, as well as in markers of glucose and lipid metabolism at 96 weeks.

“For the first time, we have shown significant, unprecedented improvement in fibrosis with the regimen,” said Dr Mazen Noureddin from the Houston Methodist Hospital, Texas, US. “The histologic improvement in fibrosis corroborated with noninvasive tests, presenting an overall picture of liver injury and function that suggests liver health is maintained or slightly improved with efruxifermin.”

Currently, there are no approved therapies that reverse fibrosis in MASH-related cirrhosis. Efruxifermin has demonstrated antifibrotic effects in previous studies, but these were observed in patients with less advanced disease (F2-F3 fibrosis).

SYMMETRY enrolled 181 patients aged18–75 years with biopsy-confirmed compensated cirrhosis due to MASH (Child-Pugh A), 80 percent of whom had diabetes and obesity.  Patients were at high risk of hepatic decompensation.  [EASL 2025, abstract GS-012]

Patients received subcutaneous efruxifermin (28 mg or 50 mg) weekly or placebo in a 1:1:1 ratio. Liver biopsies were obtained at weeks 36 and 96 and 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.

SYMMETRY of findings

The primary endpoint involved a reduction of at least one stage of fibrosis without worsening of MASH at week 36, while the same measure served as 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 of 61 patients (13 percent) in the placebo group, 10 of 57 patients (18 percent) in the 28 mg efruxifermin group (p=0.62), and 12 of 63 patients (19 percent) in the 50 mg efruxifermin group (p=0.52).

“We saw a 24 percent improvement in the 50 mg group vs 14 percent in those on placebo [and 22 percent on the 28-mg dose] at the 36-week analysis. When the patients continued treatment up to 96 weeks, we saw up to 39 percent improvement [50-mg dose] in fibrosis by one stage without worsening of MASH vs 15 percent for placebo [and 29% with 28 mg]. This represents a difference of 24 percent [between placebo and 50 mg] that was statistically significant [p<0.01],” Noureddin reported.

In the intent-to-treat analysis, at week 96, a reduction in fibrosis without worsening of MASH occurred in 7 of 61 patients (11 percent) in the placebo group, 12 of 57 patients (21 percent) in the 28 mg efruxifermin group, and 18 of 63 patients (29 percent) in the efruxifermin 50 mg group. “It was up to 29 percent with 50 mg compared with 11 percent with placebo, and that’s an 18 percent statistically significant difference [p<0.05].”

Fifty percent of responders at week 36 had a sustained response through week 96.  Eight percent of patients who had no response at week 36 responded at week 96. “This emphasizes the role of ongoing treatment in cirrhotic patients,” said Noureddin.

Dr Zobair Younossi from the Inova Fairfax Medical Campus, Fairfax County, Virginia, US, commented that the best aspect of SYMMETRY is that “it gives us a potential treatment for patients with cirrhosis who are at highest risk for bad outcomes in metabolic dysfunction-associated steatotic liver disease.”