Pegbelfermin Shows Promise in Addressing Liver Fibrosis in MASH

Once shelved after showing suboptimal efficacy results in 2 midstage studies,1 pegbelfermin is emerging as a promising treatment for treating liver fibrosis in patients with metabolic dysfunction-associated steatohepatitis (MASH).2

Reviewing data from multiple randomized clinical trials (RCTs), researchers found consistent improvements in MASH-related liver fibrosis with 10 mg of the drug compared with placebo without additional safety concerns. They published their findings in JHG Open.

Outside of liver fibrosis improvements, pegbelfermin also significantly improved MASH vs placebo. | Image credit: filins - stock.adobe.com

“Pegbelfermin, a polyethylene glycol-modified (PEGylated) recombinant human FGF21 analog with an extended half-life, has been evaluated in clinical trials for treating MASH, with several studies reporting promising results,” wrote the researchers. “However, this study represents the first quantitative analysis of pegbelfermin's efficacy in treating liver fibrosis.

To date, just 1 treatment has received a nod from the FDA to treat MASH-related fatty liver. In April 2024, the agency granted accelerated approval to resmetirom (Rezdiffra; Madrigal Pharmaceuticals), an oral thyroid hormone receptor-β agonist.3

Data from 452 patients across 3 different RCTs showed improvements in both adiponectin and PRO-C3, primary end points in the trials. Though the findings were positive, the researchers noted the limited number of available studies for their analysis and the short treatment duration included in the studies. All 3 studies were a duration of 48 weeks.

Compared with placebo, 10 mg of pegbelfermin resulted in significant improvements in adiponectin concentration (mean difference [MD], 18.23; 95% CI, 6.35-30.11; P = .003) and significant reductions in PRO-C3 concentration (MD, –25.50; 95% CI, –43.95 to –7.05; P = .007).

Outside of liver fibrosis improvements, the 10 mg dose also significantly improved MASH (risk ratio [RR], 2.84; 95% CI, 1.18-6.78; P = .02) compared with placebo.

A dose of 20 mg also resulted in significant improvements in adiponectin concentration (MD, 18.09; 95% CI, 5.88, 30.31; P = .004) and reductions in PRO-C3 (MD, -19.54; 95% CI, -33.33 to -5.76; P = .005) compared with placebo, though it did not yield significant improvements in MASH.

A third primary end point, liver stiffness, saw no significant improvements with 10 mg pegbelfermin (RR, 1.31; 95% CI, 0.84-2.04; P = .23) or 20 mg pegbelfermin (RR, 1.41; 95% CI, 0.98-2.02; P = .07) compared with placebo.

“However, liver stiffness is regulated by various factors, including exercise habits, as highlighted by Nakano et al,” explained the researchers. “Their study demonstrated that individuals aged ≥65 years with MASLD and ALT > 30 U/L had a significantly higher prevalence of hepatic fibrosis, but exercise habits were associated with a lower prevalence of significant fibrosis. This suggests that lifestyle interventions such as regular physical activity may have a modifying effect on liver stiffness even when pharmacological treatments do not yield significant improvements.”

NASH CRN Fibrosis Score, a secondary end point, was not significantly affected by pegbelfermin versus placebo.

Secondary end points also offered insights into safety signals associated with pegbelfermin. Compared with placebo, 10 mg pegbelfermin did not significantly increase the risk of treatment-emergent adverse events (RR, 1.05; 95% CI, 0.95, 1.16; P = .33). The most common side effects were gastrointestinal, though incidences were not statistically significant. Risk of nausea was 1.15 (95% CI, 0.38-3.46; P = .8) and risk of diarrhea was 1.09 (95% CI, 0.39-3.08; P = .87).

References

1. Armstrong A. Bristol Myers becomes latest victim of unforgiving NASH as midstage asset shelved. Fierce Biotech. November 18, 2021. Accessed April 10, 2025. https://www.fiercebiotech.com/biotech/bristol-myers-becomes-latest-victim-unforgiving-nash-as-mid-stage-asset-shelved
2. Shahzil M, Hasan F, Kazmi SK, et al. Evaluating the effectiveness of pegbelfermin in MASH-associated hepatic fibrosis a meta-analysis and systematic review of randomized controlled trials. JHG Open. 2025;9(3):e70131. doi:10.1002/jgh3.70131
3. FDA approves first MASH drug. Nat Biotechnol. Published online April 17, 2024. doi:10.1038/s41587-024-02220-4