SAN DIEGO—The results of several studies presented at The Liver Meeting 2024 suggest there is a robust treatment pipeline for metabolic dysfunction–associated steatohepatitis and metabolic dysfunction–associated steatotic liver disease.
“These are exciting times in the field of MASLD/MASH, with a very promising pipeline of pharmacotherapies in development,” said Bubu Banini, MD, PhD, an assistant professor of medicine and Translational Research Director of the Metabolic Health and Weight Loss Program, Digestive Diseases, at Yale Medicine, in New Haven, Conn. Dr. Banini, who was not involved with any of the studies presented below, told Gastroenterology & Endoscopy News that the meeting provided “a glimpse of even more exciting things to come.”
Among the therapies in development, efruxifermin was shown to improve liver fibrosis without worsening MASH; denifanstat showed significant improvement in both MASH resolution and fibrosis; and FXR314 was shown to significantly reduce liver fat content without the adverse event profile seen for previous FXR agonists.
“We have seen a trend in improved clinical trials results as multiple mechanisms of action have passed into advanced development,” said Eric Lawitz, MD, the medical director of the Texas Liver Institute and a clinical professor of medicine at The University of Texas Health in San Antonio. Dr. Lawitz was an author on both the denifanstat and FXR314 studies.
Denifanstat
Denifanstat is an oral fatty acid synthase inhibitor that can be taken once a day. The drug blocks de novo lipogenesis, a key pathway for driving progressive lipotoxicity, inflammation and fibrosis in MASH. It also affects immune cells and has a direct impact on the hepatic stellate cell, Dr. Lawitz said (abstract 0170).
In this multicenter, double-blind, placebo-controlled phase 2b trial conducted at 100 clinical sites in the United States, Canada and Poland, investigators randomized 168 patients to receive 50 mg of denifanstat (n=112) or placebo (n=56) for 52 weeks.
In the intention-to-treat group (ITT), 42 patients taking denifanstat (38%) had a 2-point or greater improvement in nonalcoholic fatty liver disease activity score (NAS) without fibrosis worsening compared with nine patients (16%) in the placebo group (common risk difference, 21.0%; 95% CI, 8.1%-33.9%; P=0.0035). Furthermore, 29 of the patients taking denifanstat (26%) showed MASH resolution with a 2-point or greater improvement in NAS without worsening fibrosis compared with six participants in the placebo group (11%) (common risk difference, 13.0%; 95% CI, 0.7%-25.3%; P=0.0173).
The drug also improved fibrosis. In the ITT group, 33 patients receiving denifanstat (30%) saw improved fibrosis by one or more stages according to the NASH Clinical Research Network score, without worsening steatohepatitis, compared with eight patients given the placebo (14%) (common risk difference, 11.8%, –1.3 to 24.8; P=0.40). In the modified ITT group, fibrosis improved by a stage or more without worsening steatohepatitis in 33 of 81 denifanstat patients (41%) compared with eight of 45 patients (18%) given placebo.
None of the serious adverse events (AEs) (12% of patients in the denifanstat group and 5% in the placebo group) were thought to be drug-related. The most frequent AEs included COVID-19 (denifanstat group, 17%; placebo group, 11%), dry eye symptoms (9% vs. 14%) and alopecia (19% vs. 4%).
“The distinctive mechanism of action combined with an oral treatment displaying strong antifibrotic outcomes is exciting for the MASH field,” Dr. Lawitz noted. “I am eager to see the phase 3 trial and its results.”
The full study was published in The Lancet Gastroenterology and Hepatology after the meeting (2024;9[12]:1090-1100).
Efruxifermin
Efruxifermin is a bivalent fibroblast growth factor 21 (Fc-FGF21) analog. The drug, given subcutaneously, replicates FGF21 agonism of fibroblast growth factor receptor 1c, 2 or 3c (abstract 0158).
In a phase 2b, multicenter, randomized, double-blind and placebo-controlled study conducted over 96 weeks, patients were randomly assigned to receive 28 or 50 mg of efruxifermin or placebo for 96 weeks. Liver biopsies were assessed at the start of the study (baseline) and at weeks 24 and 96.
Results at week 24, which were published in 2023, met the study’s primary end point of fibrosis improvement greater than or equal to one stage and no worsening of MASH (Lancet Gastroenterol Hepatol 2023;8[12]:1080-1093).
At 96 weeks, patients treated with the drug continued to experience improvements. The response rate for fibrosis improvement greater than or equal to one stage without worsening MASH rose from 40% of patients at week 24 to 75% at week 96. The percentage of patients who had a two-stage improvement in fibrosis more than doubled in that period from 15% to 36%.
The investigators concluded that the drug’s effects “were sustained, expanded, and deepened” through the final week of the study.
Efruxifermin is undergoing phase 3 trials (ClinicalTrials.gov Identifier: NCT06215716).
FXR314
FXR314 is a novel nonsteroidal, non–bile acid FXR agonist taken orally once a day (abstract 0037). In this multicenter, placebo-controlled phase 2 trial, 214 patients were randomized to receive 3 or 6 mg of FXR314, or placebo for 16 weeks.
At the end of treatment, patients receiving 3 and 6 mg of FXR314 had statistically significant reductions in liver fat content from baseline, with a 22.8% mean percentage reduction (P=0.0010) for 3 mg and 17.5% mean percentage reduction for 6 mg (P=0.0267). The percentage of patients with a greater than 30% MRI-derived proton density fat fraction reduction was 29.2% for 3 mg (P=0.0023) and 32.3% for 6 mg of FXR314 (P=0.002), compared with 9.5% for placebo.
The drug was safe and well tolerated. AEs were mild to moderate, and the AE profile was similar for FXR314 and the placebo (3 mg of FXR314, 68.1%; 6 mg, 73.2%; placebo, 67.6%). There was also no evidence of FXR-class AEs, such as pruritus (3 mg of FXR314, 2.8%; 6 mg, 4.2%; placebo, 2.8%) or increase in low-density lipoprotein cholesterol (3 mg of FXR314, 1.5%; 6 mg, 4.5%; placebo, 3.6%).
“This phase 2 trial provided proof of concept that intestinal activation can [induce] positive effects on liver fat reduction without the typical class-related adverse events,” Dr. Lawitz said. “It needs to be determined in the future how this translates into histologic end points of MASH resolution and fibrosis improvement.”
Unanswered Questions
Research into all three drugs showed significant progress in MASH and MASLD treatment, but many questions remain unanswered, according to Dr. Lawitz.
“Although combination therapy is an attractive concept, it is still necessary to clarify the best methods of combination treatment,” Dr. Lawitz explained. “We look forward to the consistent flow of phase 3 results that will be emerging over the next few years.”
As more pharmacologic treatment options are developed, Dr. Banini advised that some current practices will remain relevant. “Lifestyle modification aimed at weight loss and increased physical activity will remain key recommendations.”
—Jillian Mock
Dr. Banini reported financial relationships with Boehringer Ingelheim (BI), Merck and Novo Nordisk. Dr. Lawitz reported financial relationships with 89Bio, Akero, Amgen, AstraZeneca, BI, BMS, DSM, Enanta, Enyo, Exalenz, Galectin, Galmed, GENFIT, Gilead, GSK, Hightide, Intercept, Inventiva, Janssen, Lilly, Madrigal, Merck, NGM, Northsea, Novartis, Novo Nordisk, Organovo, Poxel, Sagimet, Takeda, Terns, Viking and Zydus.
This article is from the May 2025 print issue.