Off-label fenofibrate improves liver health in PBC patients: Study
Researchers see 'accessible and affordable' option for patients
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Long-term, off-label treatment with fenofibrate significantly reduces liver damage markers and improves prognostic scores in primary biliary cholangitis (PBC) patients who do not respond to ursodeoxycholic acid (UDCA), according to a real-world study in the U.S.
UDCA (sold in the U.S. as Urso and Actigall, with generics available) is the first-line therapy for PBC.
Fenofibrate is approved in the U.S. under the brand names Antara and Lipofen (with generics available) to treat abnormally high levels of fatty molecules in the blood. It belongs to a therapy class called peroxisome proliferator-activated receptor (PPAR) agonists, which has shown promise as a second-line PBC therapy.
“Given [the observed effectiveness], and its favourable safety profile, fenofibrate should be further considered as an accessible and affordable second-line therapy in PBC,” the researchers wrote.
The study, “Long- Term Use of Fenofibrate as Second- Line Therapy in Primary Biliary Cholangitis: A Retrospective Study,” was published in the journal Alimentary Pharmacology & Therapeutics.
‘Growing evidence’
A chronic form of cholangitis, PBC is marked by inflammation in the bile ducts, the tubes that carry the digestive fluid bile, within the liver. As a result, bile flow is stalled (a condition known as cholestasis), and bile builds to toxic levels in the liver, causing damage and scarring.
While UDCA has greatly improved patients’ outcomes and reduced the number of patients needing liver transplants, about 40% fail to respond properly to the therapy.
“Over recent years, growing evidence has supported a shift to the use of peroxisome proliferator-activated receptor (PPAR) agonists as second-line therapy for PBC,” the researchers wrote.
In addition to regulating genes involved in fatty molecule metabolism, PPAR proteins regulate bile metabolism, inflammation, and scarring. PPAR agonists, or activators, are therefore expected to help reduce PBC-related cholestasis and dampen pro-inflammatory signaling in the liver and bile ducts.
Livdelzi (seladelpar) and Iqirvo (elafibranor) are two PPAR agonists for adults with PBC who don’t respond to UDCA. Fenofibrate is an older, widely available PPAR agonist that is being investigated in PBC clinical trials. The American Association for the Study of Liver Diseases (AASLD) has recommended it “as an option for second-line therapy in PBC,” the researchers wrote.
The team retrospectively analyzed data from 59 PBC patients with an incomplete response to first-line UDCA and who received off-label fenofibrate for at least six months as second-line therapy between 2012 and 2024. All were followed at a single U.S. center.
Most patients were women (86.4%) and white (78%), with a median age at diagnosis of 50.5. The majority of participants (88%) received the standard daily fenofibrate dose of 145-160 mg, while the rest received lower doses (45-80 mg).
All but four patients had at least one year of follow-up. The average duration of fenofibrate treatment was 44.8 months (about 3.7 years).
At treatment initiation, mean levels of alkaline phosphatase (ALP), a liver damage marker, were 2.3 times the upper limit of normal (ULN). Overall, patients showed a significant reduction in ALP levels across all years analyzed.
After one year on fenofibrate, 57.9% of participants had achieved ALP normalization. This proportion rose to 64.9% after two years, 73.1% after three years, and 84.6% after four years. The median time to ALP normalization was 9.49 months.
Other markers of liver injury, including alanine aminotransferase (ALT) and bilirubin, also showed favorable trends. Blood ALT levels dropped significantly after one year and continued to decrease through year four.
Blood bilirubin levels did not change significantly overall. Twenty-two percent of participants had bilirubin above the ULN at treatment start. That proportion fell to 16% after year one, 11.5% after year two, and 6.5% after year three.
Patients took a median of six to 10 months after starting fenofibrate to meet criteria commonly used to reflect adequate treatment response.
The team also looked at prognostic scores that help predict the risk of worse outcomes in PBC. Median GLOBE-PBC scores dropped significantly during the first three years on fenofibrate. UK-PBC risk scores, in contrast, did not change significantly over the three years analyzed.
FIB-4, a blood-based marker often used to estimate liver scarring, remained stable over four years of follow-up.
Fifteen patients stopped taking fenofibrate after an average of 30.1 months. Seven were discontinued due to side effects, most often worsening liver tests, which were seen in 5%. Muscle aches or diarrhea led to stopping treatment for 3.4% of patients, and two stopped because of worsening pre-existing kidney disease.
The researchers said the findings support the “current AASLD guidelines in recommending consideration of off-label fenofibrate as an accessible, clinically effective, and cost- effective therapeutic option for second-line therapy in PBC.”
