Efruxifermin Reverses MASH Compensated Cirrhosis in Phase 2b SYMMETRY Study

Akero Therapeutics has announced preliminary topline week 96 results from the phase 2b SYMMETRY study of efruxifermin in patients with biopsy-confirmed compensated cirrhosis (F4), Child-Pugh Class A, due to metabolic dysfunction-associated steatohepatitis (MASH).1

According to a January 27, 2025, press release, 39% of patients with baseline and week 96 biopsies who were treated with efruxifermin 50 mg experienced reversal of cirrhosis with no worsening of MASH, compared to 15% for placebo (P = .009). In the intent-to-treat (ITT) population with all missing week 96 biopsies treated as failures, 29% of patients in the 50 mg efruxifermin group experienced reversal of cirrhosis with no worsening of MASH, compared to approximately 12% in the placebo group (P = .031).1

“Until today, we’ve not had the prospect of an effective treatment for compensated cirrhosis due to MASH, which is associated with high rates of short-term morbidity and mortality,” Mazen Nourredin, MD, a professor of medicine and transplant hepatologist at Houston Methodist Hospital, and principal investigator for the SYMMETRY study, said in a press release.1 “Now we have reason to be optimistic about the future potential of EFX as a much-needed treatment for cirrhosis, if approved. I’m so happy for my patients and patients all around the world."

Although resmetirom (Rezdiffra) is currently the only US Food and Drug Administration-approved MASH therapeutic, it is only indicated for patients with MASH and moderate to advanced fibrosis, representing a lingering unmet need for those with MASH and cirrhosis.2

Engineered to mimic the biological activity profile of native FGF21, efruxifermin is currently being evaluated in 3 ongoing phase 3 studies. In multiple phase 2 studies, it has been observed to reverse fibrosis, resolve MASH, reduce noninvasive markers of fibrosis and liver injury, and improve insulin sensitivity and lipoprotein profile.1

A multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 2b trial, SYMMETRY enrolled 182 adult patients with biopsy-confirmed compensated cirrhosis (F4, Child-Pugh A) due to MASH. Participants were randomly assigned to receive once-weekly subcutaneous dosing of 28 mg or 50 mg of efruxifermin, or placebo for 36 weeks.1

The study’s primary efficacy endpoint was the proportion of patients who achieved ≥ 1 stage fibrosis improvement without worsening of MASH at week 36. Week 96 secondary measures included ≥1 stage fibrosis improvement and no worsening of MASH, MASH resolution, change from baseline in liver enzymes, noninvasive markers of liver fibrosis, glycemic control, and lipoproteins, as well as safety and tolerability measures.1

Topline week 96 results showed that among patients with baseline and week 96 biopsies (n = 134), 39% of those treated with efruxifermin 50 mg (n = 46) experienced reversal of cirrhosis with no worsening of MASH, compared to 15% for placebo (n = 47; P = .009). In the ITT population (n = 181), 29% of patients in the 50 mg efruxifermin group (n = 63) experienced reversal of cirrhosis with no worsening of MASH, compared to approximately 12% in the placebo group (n = 61; P = .031).1

In a subgroup of patients with baseline and week 96 biopsies who were not taking GLP-1 at baseline (n = 97), 45% of those in the 50 mg efruxifermin group experienced reversal of cirrhosis with no worsening of MASH (n = 29) compared to 17% for placebo (n = 36; P = .009), suggesting the observed reversal of cirrhosis was not attributable to GLP-1 therapy.1

While there were no deaths in the efruxifermin group, a single death occurred in the placebo arm due to pneumonia. Of note, no serious adverse events were determined to be related to the study drug. Across both efruxifermin groups, the most frequent adverse events were grade 1 or 2, gastrointestinal in origin (diarrhea, nausea, and increased appetite), and transient in nature.1

“We believe today’s first-ever public report of reversal of cirrhosis due to MASH, whether by completer or ITT analysis, sets EFX apart from other approved or investigational treatments in the MASH landscape as a compound with transformational potential,” said Andrew Cheng, MD, PhD, president and chief executive officer of Akero.1 “We look forward to continuing evaluation of 50mg EFX in our ongoing Phase 3 SYNCHRONY Outcomes study in patients with compensated cirrhosis due to MASH.”

References

1. Akero Therapeutics. Akero Therapeutics Reports Preliminary Topline Results Showing Statistically Significant Reversal of Compensated Cirrhosis (F4) Due to MASH—by Both Completer and ITT Analyses—at Week 96 in Phase 2b SYMMETRY Study. January 27, 2025. Accessed January 27, 2025. https://www.globenewswire.com/news-release/2025/01/27/3015438/0/en/Akero-Therapeutics-Reports-Preliminary-Topline-Results-Showing-Statistically-Significant-Reversal-of-Compensated-Cirrhosis-F4-Due-to-MASH-by-Both-Completer-and-ITT-Analyses-at-Week.html
2. Brooks A. Resmetirom (Rezdiffra) Receives Historic FDA Approval for Noncirrhotic NASH. HCPLive. March 14, 2024. Accessed January 27, 2025. https://www.hcplive.com/view/resmetirom-rezdiffra-receives-historic-fda-approval-for-noncirrhotic-nash