In a significant breakthrough for metabolic dysfunction-associated steatohepatitis (MASH), Akero Therapeutics has announced promising topline results from its phase 2b SYMMETRY trial.1 The study revealed that 39% of patients receiving 50 mg of efruxifermin achieved a reversal of compensated cirrhosis (F4, Child-Pugh Class A) without worsening of MASH, compared to just 15% in the placebo group. Dr. Mazen Nourredin, the principal investigator for the SYMMETRY trial, underscored the significance of these findings, stating, "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. 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." 

The SYMMETRY trial (NCT05039450) was a multicenter, randomized, double-blind, placebo-controlled study. The study enrolled 182 adults with biopsy-confirmed cirrhosis due to MASH. Participants were administered weekly subcutaneous doses of either 28 mg or 50 mg efruxifermin or a placebo over 36 weeks, followed by a biopsy assessment at week 96. The trial's primary endpoint was at least a one-stage liver fibrosis improvement with no MASH worsening at week 36. 

• Completer cohort (patients with baseline and week 96 biopsies, n=134): 39% of patients in the 50 mg efruxifermin group showed cirrhosis reversal (p=0.009), compared with 15% in the placebo group.
• Intent-to-Treat (ITT) population (n=181): 29% of the 50 mg efruxifermin group experienced cirrhosis reversal versus 12% in the placebo group (p=0.031), representing a 17% effect size.
• Subgroup analysis (Patients not on GLP-1 therapy at baseline, n=97): 45% of patients in the 50 mg efruxifermin group experienced reversal of cirrhosis compared with 17% on placebo (p=0.009). 

Additionally, the study reported significant improvements in noninvasive biomarkers: 

• Enhanced liver fibrosis score reduction: 0.53-unit decrease for the 50 mg efruxifermin group (p<0.001).
• Liver stiffness reduction (FibroScan): 24% decrease for the efruxifermin group (p<0.05). 

There were no drug-related serious adverse events in the efruxifermin groups, though one death occurred in the placebo arm due to pneumonia. 

Liver disease remains a global health challenge;2 several phase 3 clinical trials for novel therapies are underway. Madrigal Pharmaceuticals' resmetirom (Rezdiffra) has recently shown promising results in the MAESTRO NASH trial,3 Additionally, Novo Nordisk's semaglutide is under evaluation in the phase 3 ESSENCE trial for metabolic dysfunction associated steatohepatitis,4 underscoring the growing momentum in NAFLD research. 

Akero is advancing its Phase 3 SYNCHRONY Outcomes study, which aims further to validate the long-term efficacy and safety of efruxifermin. If successful, this could pave the way for regulatory approval and expanded treatment options for MASH-related cirrhosis. Andrew Cheng, M.D., Ph.D., president and CEO of Akero Therapeutics, emphasized the potential of efruxifermin, noting, "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. We look forward to continuing evaluation of 50 mg EFX in our ongoing Phase 3 SYNCHRONY Outcomes study in patients with compensated cirrhosis due to MASH." 

References 

1. 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 Link: https://ir.akerotx.com/news-releases/news-release-details/akero-therapeutics-reports-preliminary-topline-results-showing (Press release 27 Jan 2025)
2. Dong X, Li JM, Lu XL, et al. Global burden of adult nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has been steadily increasing over the past decades and is expected to persist in the future. Transl Gastroenterol Hepatol. 2024:9:33. doi: 10.21037/tgh23118. eCollection 2024; PMID: 39091655.
3. Harrison SA, Bedossa P, Guy CD A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N Engl J Med 2024;390(6):497-509. doi: 10.1056/NEJMoa2309000; PMID: 38324483.
4. Newsome PN, Sanyal AJ, Engebretsen KA, et al. Semaglutide 2.4 mg in Participants With Metabolic DysfunctionAssociated Steatohepatitis: Baseline Characteristics and Design of the Phase 3 ESSENCE Trial. Aliment Pharmacol Ther. 2024;60(11-12):1525-1533. doi: 10.1111/apt.18331. PMID: 39412509.