Aldafermin
Also known as: Aldafermin, FGF19 analog, FGF19 analogue, NGM282
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Summary
Aldafermin is an engineered analogue of the human hormone fibroblast growth factor‑19 (FGF19) that is administered by subcutaneous injection. It is being investigated as a disease‑modifying therapy for non‑alcoholic steatohepatitis (NASH) and metabolic‑dysfunction‑associated steatohepatitis (MASH), including patients with compensated cirrhosis, with the aim of reducing liver fibrosis, improving liver enzymes and lowering hepatic fat content.
Mechanism of Action
Aldafermin mimics FGF19 and activates the FGFR4/β‑Klotho receptor complex in hepatocytes. This signaling suppresses CYP7A1‑mediated bile‑acid synthesis, modulates lipid metabolism, and reduces de novo lipogenesis. By restoring bile‑acid homeostasis and improving metabolic pathways, the analogue lowers hepatic fat accumulation and fibrogenic signaling, while being engineered to avoid the tumor‑promoting activity seen with native FGF19.
What the Research Shows
A phase 2b, double‑blind, placebo‑controlled trial in 160 patients with compensated NASH cirrhosis showed that weekly subcutaneous aldafermin 3 mg for 48 weeks reduced the Enhanced Liver Fibrosis score (LSMean difference −0.5, p = 0.0003) and improved ALT, AST, liver stiffness and collagen biomarkers. A 2025 meta‑analysis of four RCTs (491 participants) reported higher rates of MASH resolution without fibrosis worsening (RR 3.04), improved composite fibrosis‑plus‑MASH outcomes (RR 5.86), and a dose‑dependent ≥30 % reduction in MRI‑PDFF (RR 3.14). Network meta‑analyses rank aldafermin among the top agents for lowering hepatic fat (SUCRA ≈ 84) and improving liver enzymes. Preclinical studies confirm non‑tumorigenic activity and favorable safety signals.
Reported Benefits
Clinical data indicate that aldafermin can modestly reverse fibrosis stage, lower liver enzyme levels, and reduce hepatic fat fraction, with a 20 % fibrosis‑improvement rate at the 3 mg dose versus 15 % with placebo. Meta‑analytic evidence shows a three‑fold increase in MASH resolution without fibrosis worsening and a similar safety profile to placebo. In comparative analyses, aldafermin ranks highly for liver‑function improvement and for achieving ≥30 % MRI‑PDFF decline, suggesting meaningful metabolic benefits in steatohepatitis patients.
Limitations of the Evidence
Evidence is limited to phase 2 trials and meta‑analyses of relatively small RCTs; long‑term outcomes such as cirrhosis decompensation, liver‑related mortality, or durability of fibrosis regression are not yet established. The most common adverse event is diarrhea, occurring in up to 40 % of higher‑dose recipients. While the analogue is designed to avoid the oncogenic potential of native FGF19, long‑term carcinogenicity data are lacking. Aldafermin remains investigational and is not approved for clinical use.
Safety Considerations
The predominant adverse effect reported is diarrhea (26 % at 1 mg, 40 % at 3 mg) compared with 18 % on placebo; discontinuations due to treatment‑related events were low (0–9 %). Overall adverse‑event rates did not differ significantly from placebo in pooled analyses. No increase in serious adverse events was observed, but monitoring for gastrointestinal symptoms and liver‑function changes is advised in trial settings.
How It Is Administered
Aldafermin is delivered by subcutaneous injection. Clinical studies have evaluated weekly dosing of 1 mg and 3 mg for up to 48 weeks. The formulation is a sterile peptide solution intended for injection; dosing schedules beyond the studied regimens have not been established.
Routes of Administration
Goals & Uses
- Non‑alcoholic steatohepatitis (NASH) treatmentLiver DiseaseModerate
- Primary biliary cholangitisAutoimmune Liver DiseaseLow
- Treatment of primary sclerosing cholangitis (PSC)Hepatology / Cholestatic DiseaseLow
- Reduction of bile acid synthesisMetabolicHigh
- Reduction of hepatic steatosis in NASHMetabolic / HepatologyModerate
- Improvement of liver fibrosis in NASHHepatologyModerate
- Non‑alcoholic steatohepatitis (NASH)IndicationModerate
Contraindications
- Known hypersensitivity to aldafermin or excipientsAllergyHigh
- Severe hepatic impairmentOrganHighLiver function concerns
- PregnancyPopulationModeratePotential fetal risk or insufficient safety data
- Known hypersensitivity to Aldafermin or any excipientAllergyModerate
- Hepatocellular carcinoma or high risk of hepatic malignancyOncologyHigh
Adverse Effects
- Injection site reactionsLocalCommon
- NauseaGastrointestinalCommonFeeling of sickness or urge to vomit
- Elevations in low-density lipoprotein (LDL) cholesterolMetabolic / LipidCommon
- Injection‑site reactionsLocalCommon
- Elevated LDL‑cholesterolLipidCommon
- DiarrhoeaGastrointestinalCommon
- DiarrheaGastrointestinalCommonLoose or frequent stools
- Hepatic enzyme elevationsHepaticUncommon
- Injection‑site reactionLocalCommon
- Elevated serum lipaseLaboratoryUncommon
- Abdominal painGastrointestinalUncommonPain or discomfort in the abdomen
Drug Interactions
- Bile acid sequestrants (e.g., cholestyramine)Moderate
- StatinsModerate
Population Constraints
- PregnancyReproductive SafetyRelative
- Pediatric patientsAgeAbsolute
- Paediatric patientsAgeRelative
- Decompensated cirrhosisHepatic ImpairmentRelative
Regulatory Status
- European UnionInvestigationalClinical trials authorized under EU Clinical Trial Regulation.
- United StatesInvestigationalPhase 2/3 trials ongoing for NASH.
- United KingdomInvestigationalBeing evaluated in UK clinical sites.
Not approved in any major jurisdiction; currently in Phase 2/3 clinical development.
Evidence & Sources
- Journal ArticleModerateRinella ME, et al.2024-01-01T00:00:00.000000Z
- Journal ArticleHighKhalil SM, et al.2025-01-01T00:00:00.000000Z
- Journal ArticleModerateRoberts SK, Majeed A2021-01-01T00:00:00.000000Z
- Journal ArticleHighShi R, et al.2025-01-01T00:00:00.000000Z
- Journal ArticleHighKoh B, et al.2026-01-01T00:00:00.000000Z
- Journal ArticleHighMarey MM, et al.2024-01-01T00:00:00.000000Z
Frequently Asked Questions
What condition is aldafermin being studied for?
Aldafermin is under investigation for non‑alcoholic steatohepatitis (NASH) and metabolic‑dysfunction‑associated steatohepatitis (MASH), including patients with compensated cirrhosis, with the goal of improving liver histology and reducing hepatic fat.
How does aldafermin differ from native FGF19?
Aldafermin is an engineered analogue that retains FGF19’s ability to activate FGFR4/β‑Klotho signaling but is modified to eliminate the tumor‑promoting activity seen with the native hormone, as demonstrated in preclinical safety studies.
What are the most common side effects?
Diarrhea is the most frequently reported adverse event, occurring in roughly one‑quarter to two‑thirds of participants depending on dose, and was the main reason for treatment discontinuation in a minority of cases.
Is aldafermin approved for use?
No. Aldafermin remains an investigational product; it has not received regulatory approval for any indication and is currently available only within clinical trials.
How is aldafermin administered?
The drug is given as a subcutaneous injection, typically once weekly, with doses of 1 mg or 3 mg evaluated in phase 2 studies over a 48‑week treatment period.
What is Aldafermin?
Aldafermin is an engineered analogue of the human hormone fibroblast growth factor‑19 (FGF19) that is administered by subcutaneous injection. It is being investigated as a disease‑modifying therapy for non‑alcoholic steatohepatitis (NASH) and metabolic‑dysfunction‑associated steatohepatitis (MASH), including patients with compensated cirrhosis, with the aim of reducing liver fibrosis, improving liver enzymes and lowering hepatic fat content.
What is Aldafermin used for?
Aldafermin is educationally associated with: Non‑alcoholic steatohepatitis (NASH) treatment, Primary biliary cholangitis, Treatment of primary sclerosing cholangitis (PSC), Reduction of bile acid synthesis, Reduction of hepatic steatosis in NASH, Improvement of liver fibrosis in NASH, Non‑alcoholic steatohepatitis (NASH). Educational only — not medical advice.
How is Aldafermin administered?
Recorded routes of administration: Subcutaneous.
What are the potential side effects of Aldafermin?
Reported adverse effects include: Injection site reactions, Nausea, Elevations in low-density lipoprotein (LDL) cholesterol, Injection‑site reactions, Elevated LDL‑cholesterol, Diarrhoea, Diarrhea, Hepatic enzyme elevations, Injection‑site reaction, Elevated serum lipase, Abdominal pain. This list is not exhaustive — consult a qualified clinician.
Who should avoid Aldafermin?
Recorded contraindications: Known hypersensitivity to aldafermin or excipients, Severe hepatic impairment, Pregnancy, Known hypersensitivity to Aldafermin or any excipient, Hepatocellular carcinoma or high risk of hepatic malignancy. Consult a qualified clinician before use.