What Is Efruxifermin and How Does It Treat Liver Disease?

Efruxifermin is an experimental drug designed to mimic and enhance the activity of a natural hormone called FGF21, targeting the root metabolic problems that drive fatty liver disease and its progression to scarring and cirrhosis. It works by clearing excess fat from the liver, calming inflammation, and reducing fibrosis, all at once. In clinical trials, roughly twice as many patients treated with efruxifermin showed meaningful improvement in liver scarring compared to those on placebo, and those benefits grew stronger with longer treatment. The drug is not yet approved but is currently in large-scale phase 3 testing.

The Liver Disease Efruxifermin Is Built to Treat

The condition efruxifermin targets has gone through a recent name change that can cause confusion. What used to be called nonalcoholic steatohepatitis (NASH) is now officially called metabolic dysfunction-associated steatohepatitis, or MASH. The name swap reflects a better understanding that the disease is driven by metabolic problems like insulin resistance, obesity, and abnormal lipid handling, not simply by the absence of alcohol use.

MASH is not just a fatty liver. In MASH, the liver is actively inflamed and its cells are being injured. Excess fat overwhelms liver cells, triggering oxidative stress and mitochondrial damage, which causes them to release distress signals that recruit immune cells and activate scar-forming cells called hepatic stellate cells.¹ The cross talk between injured liver cells, immune cells, and stellate cells creates a self-reinforcing cycle of inflammation and fibrosis.² Left unchecked, mild scarring (stage 1 or 2 fibrosis) can advance to severe scarring (stage 3) and eventually cirrhosis (stage 4), which carries the risk of liver failure and liver cancer.

Until very recently, there were no drugs specifically approved for MASH. Patients were told to lose weight, manage diabetes, and hope the scarring did not worsen. That makes efruxifermin’s clinical results particularly notable.

How Efruxifermin Works

FGF21 is a hormone your body already makes. It helps regulate how fat is stored, burned, and shuttled between tissues. Among other things, FGF21 tells the liver to oxidize fatty acids rather than stockpile them, improves insulin sensitivity in fat tissue, and dials down inflammation. In people with healthy metabolisms, FGF21 keeps hepatic fat accumulation in check.

Efruxifermin is an engineered version of FGF21, fused to the Fc portion of a human antibody. That Fc fusion gives it two advantages over the natural hormone: a much longer half-life, meaning it stays active in the body long enough to be dosed once a week, and stronger binding to the FGF21 receptor complex.³ It activates multiple receptor subtypes in both the liver and fat tissue, which lets it hit the disease from several angles simultaneously: reducing liver fat, lowering liver enzyme levels that signal cell damage, improving blood lipid profiles, and pushing back against fibrosis.⁴

The FGF21 Paradox

Here is where the biology gets counterintuitive. People who already have fatty liver disease tend to have elevated blood levels of FGF21, not low ones.⁵ If the body is already producing more of this hormone, why would giving even more of it help?

The leading explanation is that MASH patients develop a form of FGF21 resistance, analogous to the insulin resistance that often accompanies the disease. The body cranks up FGF21 production as a protective response to liver stress, but the downstream signaling becomes blunted, so the hormone’s effects are muted. Efruxifermin appears to overcome that resistance partly through its enhanced receptor affinity and partly through the supraphysiological doses used in treatment. The high circulating levels achieved with weekly injections seem to push past the signaling block that renders native FGF21 insufficient.

What the HARMONY Trial Showed

The strongest evidence for efruxifermin comes from the HARMONY trial, a phase 2b study that enrolled patients with biopsy-confirmed MASH and moderate to severe fibrosis (stages 2 and 3). Participants received a weekly subcutaneous injection of efruxifermin at either 28 mg or 50 mg, or a placebo.

At 24 weeks, about 39% of patients on 28 mg and 41% on 50 mg achieved at least a one-stage improvement in fibrosis without any worsening of their MASH, compared to 20% on placebo.⁶ For MASH resolution specifically, the treated groups showed response rates between 47% and 76%, compared to 15% with placebo.⁴

The trial then continued out to 96 weeks, which is where things got more interesting. Among all enrolled patients, about half of those on 50 mg efruxifermin showed fibrosis improvement without MASH worsening, versus roughly one in five on placebo. But among the subset who actually completed the full treatment and had biopsies at 96 weeks, the numbers were striking: three-quarters of patients in the 50 mg group improved their fibrosis by at least one stage, compared to about a quarter on placebo.⁷ That is a large gap. It is worth noting that the patients who stayed in the trial long enough to get biopsied at 96 weeks may have been those who tolerated the drug best, so the completer analysis likely paints a rosier picture than the full population. Still, the overall trend was clear: longer treatment produced better outcomes.

Separately, there is also evidence of benefit in cirrhosis. One analysis of efruxifermin in patients with compensated cirrhosis (stage 4 fibrosis) reported that about 39% of participants showed reversal of their cirrhosis.⁸ Reversing established cirrhosis is an unusually aggressive claim for a liver drug, and it will need to be confirmed in larger trials, but the signal is one that researchers are taking seriously.

How Quickly It Clears Liver Fat

Beyond the fibrosis and histology endpoints, efruxifermin has a remarkably fast effect on liver fat itself. In a phase 2a trial, all three dose groups tested (28 mg, 50 mg, and 70 mg) produced statistically significant drops in hepatic fat fraction after 16 weeks. The placebo group barely moved, while the treatment groups reduced liver fat by roughly 12 to 14 absolute percentage points.⁹ For context, many MASH patients start with liver fat fractions above 15–20%, so reductions of that magnitude can bring a person close to or below the threshold considered normal.

How It Compares to Resmetirom

The obvious question is how efruxifermin stacks up against resmetirom, the first drug approved specifically for MASH (sold under the brand name Rezdiffra). Resmetirom works through a completely different mechanism. It is a thyroid hormone receptor agonist that accelerates the liver’s internal fat metabolism. Both drugs reduce liver fat, but the magnitude differs.

A network meta-analysis comparing the two found that efruxifermin produced a substantially larger relative reduction in liver fat on MRI, about 63% versus 37% for resmetirom. Efruxifermin also drove a meaningful drop in AST, a liver enzyme that reflects cell damage, while resmetirom’s effect on AST was not statistically significant in the same analysis.¹⁰ These are indirect comparisons across different trials, not a head-to-head study, so they come with caveats. But the difference in liver fat reduction is large enough to be meaningful even accounting for trial design variation.

The two drugs also differ in practical ways. Resmetirom is a daily oral pill. Efruxifermin is a weekly subcutaneous injection. For some patients, the convenience of a pill wins. For others, a once-weekly shot is manageable, especially if the efficacy gap holds up in phase 3 data. The field is watching closely to see whether the two drugs end up competing or being used in combination.

Pairing Efruxifermin With GLP-1 Drugs

Many people with MASH also have type 2 diabetes, and a large portion of those patients are already taking a GLP-1 receptor agonist like semaglutide or liraglutide. This raises a practical question: does efruxifermin still work in people who are already on one of these drugs?

A phase 2 study tested exactly that. Patients with MASH and type 2 diabetes who were already on a stable GLP-1 receptor agonist were randomized to add either efruxifermin or placebo. The combination group saw a 65% reduction in liver fat at 12 weeks, compared to a 10% reduction in those continuing on the GLP-1 drug alone.¹¹ The most common side effects in the combination group were mild to moderate gastrointestinal symptoms, similar to what is seen with efruxifermin alone.¹²

This matters because GLP-1 drugs themselves have liver benefits, both through weight loss and through direct metabolic effects. If efruxifermin adds substantial liver fat clearance on top of what a GLP-1 drug already delivers, the combination could become a standard approach for patients with both conditions.

Side Effects and Tolerability

In clinical trials so far, efruxifermin has been reasonably well tolerated. The most common side effects are gastrointestinal: diarrhea and nausea. In the HARMONY trial, diarrhea occurred in about 40% of patients on either efruxifermin dose, compared to 19% on placebo. Nausea hit roughly 28–42% of treated patients versus 23% on placebo. The reassuring detail is that nearly all of these events were mild or moderate in severity.¹³

There were no major safety signals that led to early termination of the trials. That said, phase 2 trials enroll hundreds of patients, not thousands, and they last months to a couple of years. Rare or slow-developing problems can slip through at this stage. Phase 3 trials, with their larger populations and longer follow-up, are designed to catch exactly those kinds of issues.

Bone and Cardiovascular Signals Worth Tracking

One area researchers are keeping an eye on involves the broader FGF21 pathway’s effects beyond the liver. A study of a different long-acting FGF21 molecule (not efruxifermin itself, but one in the same drug class) found that it lowered triglycerides substantially but also produced modest changes in markers of bone turnover, along with increases in blood pressure and pulse rate.¹⁴ That was the first report showing blood pressure and heart rate effects from a pharmacological FGF21 molecule in humans.

Whether efruxifermin specifically produces the same cardiovascular signals is not yet established with long-term data. The HARMONY trial did not flag blood pressure or heart rate as major concerns, but the patient population was relatively small and the monitoring period is still short by cardiovascular safety standards. Given that MASH patients often already have high blood pressure and metabolic syndrome, this is an area where the phase 3 trials will need to provide clear reassurance. Bone health is another domain where long-term monitoring will be important, especially in postmenopausal women who may already be losing bone density.

Where Efruxifermin Stands in Development

Efruxifermin is currently in phase 3 testing under a program called SYNCHRONY, which includes three large, randomized, placebo-controlled trials. One trial focuses on patients with pre-cirrhotic MASH (fibrosis stages 2 and 3) using liver biopsy as the primary endpoint. A second evaluates safety and tolerability in a broader, real-world population of patients with MASH or fatty liver disease across fibrosis stages 1 through 4, using non-invasive measures rather than biopsies. The third is designed specifically for patients who already have compensated cirrhosis (stage 4 fibrosis) and will track whether efruxifermin prevents clinical outcomes like liver decompensation, liver transplant, or death.

That third trial is particularly ambitious. MASH drug development has traditionally focused on earlier-stage disease where fibrosis improvement is easier to demonstrate on biopsy. Enrolling patients with established cirrhosis and tracking hard clinical outcomes is a longer and more expensive path, but it is also the one that answers the question patients care about most: does this drug keep me alive and out of the hospital?

No timeline has been publicly confirmed for when efruxifermin might reach regulatory submission, but the SYNCHRONY trials are actively enrolling. If the phase 3 data hold up as well as the phase 2 results suggest, efruxifermin would become only the second drug approved for MASH, and the first injectable option in the class. For patients with more advanced disease, particularly those with stage 3 fibrosis or compensated cirrhosis, it could fill a gap that resmetirom’s current approval does not cover.

Alcohol-Related Liver Disease and Other Potential Uses

Most of the clinical focus on efruxifermin has been on MASH, but the underlying FGF21 biology hints at a broader therapeutic reach. Elevated FGF21 levels have also been documented in alcohol-related fatty liver disease, where the hormone appears to serve a protective role. Preclinical work suggests that FGF21 can help reverse the progression of alcohol-induced liver injury.⁵ Whether efruxifermin or similar FGF21 analogs will be tested in that population remains to be seen, but the rationale is there.

FGF21 analogs also produce systemic metabolic improvements: lower triglycerides, higher adiponectin, better insulin sensitivity, and some degree of weight loss. These are not just liver endpoints; they are cardiovascular risk factors. If efruxifermin turns out to reduce the rate of heart attacks or strokes in MASH patients, the way GLP-1 drugs did in diabetes, that would transform its commercial and clinical profile. No trial is currently powered to test that hypothesis, but the cardiometabolic data from earlier studies has been strong enough that researchers are paying attention to what the larger phase 3 datasets might reveal.