The Long Game: How Akero’s Efruxifermin Could Rewrite the Rules for Cirrhosis Treatment

The biotech world is no stranger to the “long game,” but few trials have exemplified its necessity as clearly as Akero Therapeutics’ Phase 2b SYMMETRY study for efruxifermin (EFX). Presented at the EASL Congress 2025, the data reveal a stark lesson: for patients with compensated cirrhosis due to metabolic dysfunction-associated steatohepatitis (MASH), reversing fibrosis isn’t a sprint—it’s a marathon. While the trial initially missed its primary endpoint at Week 36, the results at Week 96 tell a compelling story—one that could position EFX as a first-in-class therapy in a market with no approved treatments and a 50% five-year mortality rate without intervention.

The Trial’s Nuanced Success: Why Time Matters

The SYMMETRY trial enrolled 182 patients with biopsy-confirmed F4 cirrhosis caused by MASH. Participants were randomized to receive weekly subcutaneous doses of EFX (28mg or 50mg) or placebo for 96 weeks. The primary endpoint—proportion of patients achieving ≥1 stage fibrosis improvement without worsening MASH at Week 36—was not statistically significant. However, this initial disappointment gave way to a breakthrough at Week 96:

• Completer analysis (N=134):
• 39% of EFX 50mg patients improved fibrosis vs 15% in placebo (p=0.009).

• Placebo-adjusted improvement nearly doubled between Week 36 (10%) and Week 96 (24%).

• Intent-to-treat (ITT) analysis (N=181):

• 29% of EFX 50mg patients improved vs 11% in placebo (p=0.031).

The delayed efficacy suggests that EFX’s FGF21 mimetic mechanism—targeting both lipid metabolism and fibrosis—requires time to accumulate therapeutic effects in advanced cirrhosis. This is critical, as earlier-stage trials in non-cirrhotic NASH (e.g., Phase 2a) saw faster responses. For investors, the takeaway is clear: Akero’s dosing regimen and trial design must account for this prolonged timeline in Phase 3.

Safety and Subgroup Consistency: A Steady Foundation

EFX’s safety profile remains consistent with prior trials, with mild gastrointestinal events (diarrhea, nausea) as the most frequent adverse effects. Importantly, no treatment-related serious adverse events were reported. Even more promising: efficacy held across subgroups, including patients with type 2 diabetes and those on GLP-1 agonists or statins—key demographics in the MASH population.

Non-invasive markers like the ELF test and FibroScan also showed sustained improvement in EFX-treated patients, reinforcing the histological data. For a field historically reliant on invasive biopsies, this offers a pathway to scalable clinical development.

The Market Opportunity: A 50% Mortality Risk, No Approved Options

Compensated cirrhosis due to MASH is a silent killer. With no therapies approved for fibrosis reversal, patients face a 50% risk of death or liver failure within five years without a transplant. The global MASH market is projected to exceed $6 billion by 2030, but current treatments (e.g., semaglutide for metabolic control) address symptoms, not fibrosis. EFX’s ability to target both pathways—metabolic correction and fibrosis reversal—positions it as a potential cornerstone therapy.

Akero’s Phase 3 program (SYNCHRONY) will test EFX across all stages of MASH, including cirrhosis. If Week 96 efficacy holds in larger trials, the drug could carve out a $2B+ annual revenue stream, especially if it secures accelerated approval based on non-invasive biomarkers.

Risks and Considerations for Investors

While the data are encouraging, challenges remain:
1. Primary endpoint timing: Regulators may question the clinical relevance of delayed endpoints. Akero must demonstrate that 96-week data align with real-world treatment windows.
2. Competitor activity: Other FGF21-based therapies (e.g., Novo Nordisk’s setrusumab) are in Phase 3 for NASH, though none focus on advanced cirrhosis.
3. Commercialization hurdles: Penetration will depend on demonstrating cost-effectiveness in high-risk populations.

Conclusion: A Breakthrough in a Deserted Landscape

The SYMMETRY trial’s Week 96 data mark a turning point. With a 39% fibrosis improvement rate in cirrhotic patients—a population with no alternatives—EFX could redefine standard care. The doubled efficacy over time underscores the biological plausibility of prolonged treatment, aligning with the disease’s slow progression.

For investors, the calculus is this: Akero holds a first-mover advantage in a critically underserved market. Even a conservative 20% market share in cirrhotic MASH would translate to $1.2B in annual sales, while broader NASH applications could amplify that figure. While execution risks exist, the data’s statistical significance (p=0.009 in completers) and consistent safety profile suggest a high probability of Phase 3 success.

In a sector where NASH drugs have often disappointed, EFX’s results offer a rare combination of mechanistic logic and clinical impact. For Akero, the long game is paying off—and investors would be wise to bet on it.