Efruxifermin is an investigational drug for a serious form of non-alcoholic fatty liver disease. This medication is a long-acting analog of fibroblast growth factor 21 (FGF21).
Understanding Nonalcoholic Steatohepatitis
Nonalcoholic steatohepatitis, now often termed metabolic dysfunction-associated steatohepatitis (MASH), represents a serious liver disease where fat accumulation within the liver leads to inflammation and cellular damage. This condition is considered the more severe form of nonalcoholic fatty liver disease (NAFLD). Unlike simple fatty liver, MASH involves ongoing inflammation that can progressively harm liver cells.
The sustained inflammation and damage in MASH can lead to the development of scar tissue, a process known as fibrosis. As fibrosis progresses, it can result in advanced scarring called cirrhosis, which significantly impairs liver function and can lead to liver failure. Individuals with MASH also face an increased risk of developing liver cancer. This condition is often associated with underlying metabolic disorders such as obesity, type 2 diabetes, high cholesterol, and insulin resistance.
Mechanism of Action
Efruxifermin functions by mimicking the biological activity of fibroblast growth factor 21 (FGF21), a natural hormone that plays a role in regulating systemic energy balance, glucose metabolism, and lipid oxidation. This investigational drug is engineered to be more stable and have a longer duration of action in the body compared to naturally occurring FGF21. It achieves its effects by acting as an agonist, binding to specific fibroblast growth factor receptors, primarily FGFR1c, FGFR2c, and FGFR3c, with the co-receptor β-klotho (KLB) facilitating this signaling.
Efruxifermin addresses various aspects of MASH pathology. It reduces fat accumulation in liver cells by enhancing lipid oxidation and decreasing lipogenesis. The drug also decreases liver inflammation by influencing inflammatory pathways. It directly impacts the fibrotic process by inhibiting the activation of hepatic stellate cells.
Clinical Trial Findings
Clinical investigations have explored the effectiveness of efruxifermin in treating MASH, including the Phase 2b HARMONY and SYMMETRY studies. The HARMONY trial focused on patients with pre-cirrhotic MASH with stage 2 or 3 fibrosis. In this study, patients receiving efruxifermin achieved at least a one-stage improvement in liver fibrosis without their MASH worsening. At 24 weeks, approximately 39% to 41% of patients treated with 28 mg or 50 mg of efruxifermin met this outcome, compared to about 19% to 20% in the placebo group. After 96 weeks, between 46% and 75% of patients in the efruxifermin groups showed fibrosis improvement without MASH worsening, in contrast to 24% in the placebo group. MASH resolution was also observed in approximately 55% to 59% of patients treated with efruxifermin, compared to 18% of those on placebo.
The SYMMETRY trial investigated efruxifermin in patients with compensated cirrhosis due to MASH, a more advanced stage of the disease. At 96 weeks, 39% of patients who received the 50 mg dose experienced a reversal of cirrhosis with no worsening of MASH. This outcome was higher than the 15% observed in the placebo group. Efruxifermin is the first treatment to demonstrate fibrosis reversal in patients with MASH-related cirrhosis. Building on these results, efruxifermin is progressing into Phase 3 clinical trials under the SYNCHRONY program, which includes studies targeting both pre-cirrhotic MASH and compensated cirrhosis.
Administration and Safety Profile
Efruxifermin is administered as a subcutaneous injection, given once weekly. The drug has shown an acceptable safety and tolerability profile in clinical studies. Most reported adverse events were mild to moderate in severity and transient.
The most frequently observed side effects involved gastrointestinal issues. These included diarrhea, reported by approximately 40% to 54% of patients, nausea, affecting about 28% to 46% of patients, and increased appetite, noted in about 16% to 40% of patients. Some patients also experienced reactions at the injection site, such as redness. While reductions in bone mineral density were observed in some patients, the occurrence of fractures was similar between the efruxifermin and placebo groups. Discontinuation rates due to adverse events remained low across the trials.