Akero Therapeutics' SYMMETRY Trial Offers Hope for Cirrhosis Patients—What Investors Need to Know

The publication of Akero Therapeutics’ Phase 2b SYMMETRY trial in the New England Journal of Medicine marks a pivotal moment in the treatment of metabolic dysfunction-associated steatohepatitis (MASH)-related cirrhosis. While the trial’s primary endpoint at 36 weeks fell short of statistical significance, the data at 96 weeks paints a compelling picture of Efruxifermin (EFX) as a potential breakthrough therapy. For investors, this trial represents both a risk and an opportunity in a field where unmet medical needs are vast and competition remains limited.

A Delayed But Definitive Signal

The SYMMETRY trial enrolled 182 patients with compensated cirrhosis (F4 fibrosis) due to MASH, a population with no approved treatments. At the 36-week primary endpoint, the 50mg and 28mg EFX doses showed modest numerical improvements over placebo (19% vs. 18% vs. 13%), but the differences were not statistically significant. This initial underwhelming result, however, gave way to stronger data over time.

By week 96, the picture changed dramatically. The 50mg EFX group achieved a statistically significant 29% fibrosis improvement rate (vs. 11% placebo, p=0.031) in the intent-to-treat (ITT) analysis. A deeper dive into patients with complete biopsy data (N=134) revealed an even stronger response: 39% in the 50mg group versus 15% in placebo (p=0.009). The delayed efficacy suggests EFX’s mechanism—targeting the FGF21 pathway to drive fibrosis regression—requires sustained dosing to achieve its full effect.

Why This Matters for Investors

The clinical significance of these results cannot be overstated. Cirrhosis due to MASH progresses to liver failure, cancer, or death in roughly 20% of patients. Current therapies focus on managing symptoms, not reversing fibrosis. EFX’s ability to demonstrate improvement in a high-risk population, even in a small trial, positions Akero as a leader in a space with $5.4 billion in annual global market potential for NASH therapies, according to EvaluatePharma.

The trial’s design also hints at strategic advantages for Akero:
1. Non-invasive biomarkers (e.g., FibroScan, ELF scores) showed parallel improvements, which could streamline future trials and reduce reliance on invasive biopsies.
2. Safety data was reassuring, with only mild gastrointestinal side effects reported.
3. Phase 3 plans (SYNCHRONY Outcomes) are already underway, targeting fibrosis improvement and clinical outcomes (e.g., reduced liver decompensation) over 104 weeks.

Market Dynamics and Risks

Akero faces hurdles, however. Competitors like Madrigal Pharmaceuticals (MDGL) and Arrowhead Pharmaceuticals (ARWR) are also in late-stage development for MASH therapies. Regulatory scrutiny of non-invasive endpoints could delay approvals, and pricing pressure in the U.S. market remains a risk.

Yet EFX’s time-dependent efficacy offers a unique selling point. Unlike some competitors, which may show rapid but transient effects, EFX’s sustained response could carve out a niche in long-term management of advanced fibrosis.

Conclusion: A High-Reward, High-Risk Bet on a Breakthrough

The SYMMETRY trial’s 96-week data solidifies EFX’s potential as the first therapy to reverse cirrhosis in MASH patients, a landmark achievement. While the Phase 2b results are imperfect, they create a clear path to Phase 3 success, particularly if the 50mg dose’s robust response in biopsy-confirmed patients holds in a larger trial.

Investors should weigh the risks—small trial size, competitive landscape, and regulatory challenges—against the $3.2 billion peak sales potential analysts estimate for EFX in cirrhosis alone. With no approved alternatives, even modest market penetration could deliver outsized returns.

As Akero progresses toward Phase 3, the stock’s performance will hinge on whether regulators and payers view EFX’s delayed efficacy as a strength, not a flaw. For now, the NEJM publication and 96-week data make this a compelling story in a space where patients—and investors—are waiting for a cure.

In a field as desperate as advanced liver disease, even incremental progress can be transformative. Akero’s EFX may just be that progress.