Pegbelfermin
Also known as: BMS-986036, BMS‑986036, pegbelfermin, PEGylated FGF21
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Summary
Pegbelfermin is an investigational, PEGylated analogue of fibroblast growth factor‑21 (FGF21) designed for subcutaneous administration in patients with non‑alcoholic steatohepatitis (NASH) and metabolic dysfunction‑associated steatohepatitis (MASH). It aims to modulate energy metabolism and liver inflammation to improve fibrosis and reduce liver fat. Phase‑2b trials (FALCON 1 and 2) and several meta‑analyses have evaluated its efficacy and safety.
Mechanism of Action
Pegbelfermin is a polyethylene‑glycol‑conjugated form of human FGF21, a hormone that signals through the β‑klotho/FGFR1c receptor complex on hepatocytes and hepatic stellate cells. This activates MAPK and AMPK pathways, enhancing fatty‑acid oxidation, suppressing de‑novo lipogenesis, improving insulin sensitivity, and exerting anti‑inflammatory effects that may limit fibrogenesis.
What the Research Shows
Two randomized, double‑blind, placebo‑controlled phase 2b studies (FALCON 1 in stage 3 fibrosis, FALCON 2 in compensated cirrhosis) gave weekly sub‑cutaneous pegbelfermin (10‑40 mg) for 48 weeks. Neither met its primary histologic endpoint, but trends showed greater ALT/AST reductions, decreased hepatic fat fraction, improved liver stiffness, and less lobular inflammation, especially at 20‑40 mg. A dose‑response meta‑analysis of four RCTs (n = 546) found significant, non‑linear transaminase reductions up to ~30 mg/week with a rebound after ~28 weeks. A broader systematic review of FGF‑21 analogues (including pegbelfermin) reported a pooled risk ratio of 1.83 for ≥1‑stage fibrosis improvement versus placebo, though adverse‑event rates were higher. A network meta‑analysis ranked pegbelfermin among the more effective agents for achieving ≥30 % MRI‑PDFF decline.
Reported Benefits
Evidence suggests pegbelfermin can lower serum ALT and AST, modestly reduce hepatic fat content, and improve lobular inflammation. Meta‑analytic data across FGF‑21 analogues indicate a higher likelihood of achieving ≥1‑stage fibrosis improvement without disease worsening compared with placebo, particularly at doses up to 30 mg weekly and during the first 24‑28 weeks of therapy.
Limitations of the Evidence
The pivotal phase 2b trials failed to achieve statistically significant primary histologic endpoints, and observed improvements did not reach significance. Benefit appears dose‑limited, with a ceiling effect and potential rebound after ~28 weeks. Sample sizes were modest, long‑term outcomes are unknown, and no regulatory approval has been granted. Findings rely on short‑term studies and indirect meta‑analyses, limiting certainty about clinical relevance.
Safety Considerations
Pegbelfermin was generally well tolerated; overall adverse‑event rates were comparable to placebo. Serious adverse events occurred more frequently in active arms but were deemed unrelated to treatment, and only one patient discontinued due to worsening ascites. No treatment‑related serious events were reported, and no participants withdrew because of adverse events in the dose‑response meta‑analysis. Monitoring liver function and fluid status is advisable during therapy.
How It Is Administered
Pegbelfermin is formulated for subcutaneous injection and has been studied as a once‑weekly dose ranging from 10 to 40 mg. In clinical trials the drug was administered by healthcare professionals or self‑injection under supervision. The PEGylated molecule prolongs circulating half‑life, allowing weekly dosing.
Routes of Administration
Goals & Uses
- Treatment of primary biliary cholangitis (PBC)Liver DiseaseLow
- Reduction of hepatic fibrosis in NASHLiver DiseaseModerate
- Reduce hepatic steatosisLiver DiseaseModerate
- Improvement of dyslipidemiaMetabolicModerate
- Improve insulin sensitivityMetabolic DisorderModerate
- Improvement of insulin sensitivityMetabolicLow
- Reduction of hepatic steatosis in NASHMetabolic / HepatologyModerate
Contraindications
- Severe renal impairment (eGFR <30 mL/min/1.73 m²)RenalModerate
- PregnancyPopulationHighPotential fetal risk or insufficient safety data
- Known hypersensitivity to pegbelfermin or PEG-containing productsAllergyHigh
Adverse Effects
- Injection site reactionsLocalCommon
- AlopeciaDermatologicUncommonHair loss
- HeadacheNeurologicUncommonPain in the head or upper neck
- NauseaGastrointestinalUncommonFeeling of sickness or urge to vomit
- Injection‑site erythemaLocalCommon
- Anti-drug antibodies (ADA)ImmunologicalUncommon
- DiarrheaGastrointestinalUncommonLoose or frequent stools
Drug Interactions
- Cytochrome P450 substratesLow
- Insulin / insulin secretagoguesModerate
- Lipid-lowering agents (statins, fibrates)Low
Population Constraints
- Severe renal impairmentOrgan ImpairmentRelative
- Pediatric patientsAgeRelative
- Lactating womenReproductiveRelative
- Severe hepatic impairment (Child-Pugh C)Organ ImpairmentRelative
- Pediatric patients (<12 years)PediatricRelative
- Elderly (>75 years)GeriatricRelative
Regulatory Status
- European UnionUnknownNo EMA marketing authorization; clinical studies in Europe.
- United StatesInvestigationalIND active; Phase 2b/3 trials ongoing.
- United KingdomInvestigationalNo MHRA approval; investigational use only in clinical trials.
Not approved; completed Phase 2 trials with encouraging biomarker data; ongoing Phase 2b/3 studies in NASH.
Evidence & Sources
- Journal ArticleModerateAbdelmalek MF, et al.2024-01-01T00:00:00.000000Z
- Journal ArticleModerateLoomba R, et al.2024-01-01T00:00:00.000000Z
- Journal ArticleHighLu Y, et al.2024-01-01T00:00:00.000000Z
- Journal ArticleModerateZhang CY, Liu S, Yang M2023-01-01T00:00:00.000000Z
- Journal ArticleHighJeong C, et al.2024-01-01T00:00:00.000000Z
- Journal ArticleHighKoh B, et al.2026-01-01T00:00:00.000000Z
Frequently Asked Questions
What disease is pegbelfermin being tested for?
Pegbelfermin is being investigated for non‑alcoholic steatohepatitis (NASH) and metabolic dysfunction‑associated steatohepatitis (MASH), conditions characterized by liver inflammation, fat accumulation, and fibrosis.
How is pegbelfermin given to patients?
The drug is supplied as a solution for subcutaneous injection and has been studied as a once‑weekly dose (10‑40 mg) administered by a healthcare professional or self‑injection under guidance.
What have clinical trials shown about its effectiveness?
Phase‑2b trials did not meet their primary histologic endpoints, but showed trends toward lower liver enzymes, reduced hepatic fat, and modest improvements in inflammation. Meta‑analyses suggest a higher chance of fibrosis improvement compared with placebo, especially at doses up to 30 mg weekly.
Are there any safety concerns?
Overall adverse‑event rates were similar to placebo. Serious adverse events were more frequent in active arms but were not considered treatment‑related; one case of worsening ascites led to discontinuation. No participants stopped treatment due to adverse events in pooled analyses.
How does pegbelfermin work in the liver?
It mimics the hormone FGF21, binding the β‑klotho/FGFR1c receptor complex to activate signaling pathways that increase fatty‑acid oxidation, decrease lipogenesis, improve insulin sensitivity, and reduce inflammatory signaling, which together may limit fibrotic progression.
What is Pegbelfermin?
Pegbelfermin is an investigational, PEGylated analogue of fibroblast growth factor‑21 (FGF21) designed for subcutaneous administration in patients with non‑alcoholic steatohepatitis (NASH) and metabolic dysfunction‑associated steatohepatitis (MASH). It aims to modulate energy metabolism and liver inflammation to improve fibrosis and reduce liver fat. Phase‑2b trials (FALCON 1 and 2) and several meta‑analyses have evaluated its efficacy and safety.
What is Pegbelfermin used for?
Pegbelfermin is educationally associated with: Treatment of primary biliary cholangitis (PBC), Reduction of hepatic fibrosis in NASH, Reduce hepatic steatosis, Improvement of dyslipidemia, Improve insulin sensitivity, Improvement of insulin sensitivity, Reduction of hepatic steatosis in NASH. Educational only — not medical advice.
How is Pegbelfermin administered?
Recorded routes of administration: Subcutaneous.
What are the potential side effects of Pegbelfermin?
Reported adverse effects include: Injection site reactions, Alopecia, Headache, Nausea, Injection‑site erythema, Anti-drug antibodies (ADA), Diarrhea. This list is not exhaustive — consult a qualified clinician.
Who should avoid Pegbelfermin?
Recorded contraindications: Severe renal impairment (eGFR <30 mL/min/1.73 m²), Pregnancy, Known hypersensitivity to pegbelfermin or PEG-containing products. Consult a qualified clinician before use.