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Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial
Abstract
Background Pegbelfermin (BMS-986036), a PEGylated human fibroblast growth factor 21 (FGF21) analogue, has previously been shown to improve markers of metabolism and liver fibrosis in obese patients with type 2 diabetes. In this phase 2a study, we aimed to evaluate the safety and efficacy of pegbelfermin in patients with non-alcoholic steatohepatitis.Methods In this multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 2a study, we recruited adults (aged 21-75 years) with a body-mass index of at least 25 kg/m 2, biopsy-confirmed non-alcoholic steatohepatitis (fibrosis stage 1-3), and a hepatic fat fraction of at least 10% when assessed by magnetic resonance imaging-proton density fat fraction. These patients were enrolled at 17 medical centres in the USA. Eligible patients were stratified by type 2 diabetes status and they were randomly assigned (1:1:1) by a computer-based system to receive subcutaneous injections of placebo once a day, 10 mg pegbelfermin once a day, or 20 mg pegbelfermin once a week, all for 16 weeks. Participants, the study team administering treatment, and investigators analysing outcomes (who were independent of the study team and had no further involvement) were masked to treatment groups. The primary outcomes were safety and the absolute change in hepatic fat fraction after 16 weeks of treatment. All patients who were randomly assigned to groups and received the study drug or placebo were included in the primary analyses. This trial was registered with ClinicalTrials.gov, number NCT02413372.Findings Between May 12, 2015, and Aug 4, 2016, 184 overweight or obese patients with non-alcoholic steatohepatitis were screened for study inclusion. Of these, 95 (52%) patients were excluded because they no longer met study criteria and 80 (43%) patients entered the placebo lead-in phase. After further exclusions, 75 (94%) patients were randomly assigned to groups, received at least one dose of treatment (25 patients to receive 10 mg pegbelfermin once a day; 24 patients to receive 20 mg pegbelfermin once a week, and 26 patients to receive placebo), and were included in the primary analysis. A prespecified interim analysis at week 8 showed a greater than expected change in the primary outcome and supported early closing of patient enrolment, since this analysis indicated that the full planned sample size was not needed. We observed a significant decrease in absolute hepatic fat fraction in the group receiving 10 mg pegbelfermin daily (-6·8% vs -1·3%; p=0·0004) and in the group receiving 20 mg pegbelfermin weekly (-5·2% vs -1·3%; p=0·008) compared with the placebo group. Most adverse events were mild; the most common events were diarrhoea in eight (16%) of 49 patients treated with pegbelfermin and two (8%) of 26 patients treated with placebo and nausea in seven (14%) patients treated with pegbelfermin and two (8%) patients treated with placebo. There were no deaths, discontinuations due to adverse events, or treatment-related serious adverse events.Interpretation Treatment with subcutaneously administered pegbelfermin for 16 weeks was generally well tolerated and significantly reduced hepatic fat fraction in patients with non-alcoholic steatohepatitis. Further study of pegbelfermin is warranted in patients with non-alcoholic steatohepatitis. Additional studies that use liver biopsies would allow for the assessment of pegbelfermin's effects on liver histology. Moreover, further studies should allow assessments of the safety and effectiveness of pegbelfermin in a larger number of patients.Funding Bristol-Myers Squibb.
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“Pegbelfermin showed a reduction in hepatic fat (measured via MRI‐PDFF) and liver transaminases over a 16‐week treatment period as well as an improved lipid profile; [53] however, no histological readouts were available which hampers applicability of the results and warrants further studies on this compound.”
From Current treatment of non‐alcoholic fatty liver disease (2022) · cites this paper as [53]
In the citing paper
“Pegbelfermin showed a reduction in hepatic fat (measured via MRI‐PDFF) and liver transaminases over a 16‐week treatment period as well as an improved lipid profile; [53] however, no histological readouts were available which hampers applicability of the results and warrants further studies on this compound.”
From Current treatment of non‐alcoholic fatty liver disease (2022) · cites this paper as [53]
In the citing paper
“all analogues consistently have a pronounced ability to decrease plasma triglyceride levels, in many cases by as much as ~70% (refs. 81,87–91).”
From Metabolic messengers: FGF21 (2021) · cites this paper as [89]
In the citing paper
“two other FGF21 analogues, AKR-001 (also known as efruxifermin)88 and pegbelfermin89,90, have not been found to significantly decrease body weight in people with obesity or type 2 diabetes.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [89]
In the citing paper
“the magnitude of the glucose-lowering effects of FGF21 analogues is clearly lower in humans than rodents81,87–91, perhaps because of differences in brown adipose tissue metabolism between species65.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [89]
In the citing paper
“Administration of the FGF21 analogues AKR-001 (ref. 88) and pegbelfermin89 in humans with NASH results in marked absolute decreases in liver fat (up to 70%) and significant amelioration of liver fibrosis88,89.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [89]
In the citing paper
“clinical studies in patients with obesity and type 2 diabetes have found that FGF21-analogue administration markedly induces plasma adiponectin levels81,87–89”
From Metabolic messengers: FGF21 (2021) · cites this paper as [89]
In the citing paper
“PF-05231023 has been found to increase markers of bone turnover in humans81, whereas AKR-001 (ref. 88) and pegbelfermin89 have not.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [89]
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Metadata
- Authors
- Sanyal, A., Charles, E. D., Neuschwander-Tetri, B. A., Loomba, R., Harrison, S. A., Abdelmalek, M. F., Lawitz, E. J., Halegoua-DeMarzio, D., Kundu, S., Noviello, S., Luo, Y., & Christian, R.
- Affiliations
- Virginia Commonwealth University (US)
- Bristol-Myers Squibb (United States) (US)
- University of California San Diego (US)
- Pinnacle Clinical Research (US)
- Duke University (US)
- The University of Texas at San Antonio Health Science Center (US)
- Thomas Jefferson University (US)
- Corresponding author
- Charles, Edgar D
- ORCID
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2018-12
- Volume
- 392
- Issue
- 10165
- Pages
- 2705-2717
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- OpenAlex
- W2905440332
- Cited by
- 550
- References
- 43
- Citations by year
- 2026: 40 · 2025: 52 · 2024: 87 · 2023: 82 · 2022: 76 · 2021: 83 · 2020: 91 · 2019: 36 · 2018: 1
- FWCI
- 41.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- PEGylation, nonalcoholic steatohepatitis, hepatic fat fraction, liver fibrosis, obesity, type 2 diabetes, drug safety, drug efficacy, subcutaneous injection, liver disease treatment
- MeSH terms
- Adult, Diabetes Mellitus, Type 2, Double-Blind Method, Drug Administration Schedule, Female, Fibroblast Growth Factors, Humans, Injections, Subcutaneous, Male, Middle Aged, Obesity, Polyethylene Glycols, Non-alcoholic Fatty Liver Disease
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