PPAR agonists effective in UDCA-resistant primary biliary cholangitis
Medicines shown to improve liver function biochemical markers, ease itching
A class of medicines called PPAR agonists that modulate genes involved in inflammation and scarring improve biochemical markers of liver function and ease itching in people with primary biliary cholangitis (PBC) who don’t respond to ursodeoxycholic acid (UDCA).
“These findings provide evidence that PPAR agonists lessen the risk of disease progression and reduce symptoms in patients with PBC,” wrote researchers who conducted a meta-analysis of clinical trials. The analysis, “Peroxisome Proliferator-Activated Receptor (PPAR) Agonists for Patients With Primary Biliary Cholangitis With Inadequate Response to Ursodeoxycholic Acid (UDCA): A Systematic Review and Meta-Analysis of Randomized Controlled Trials,” was published in JGH Open.
A chronic form of cholangitis, PBC is marked by inflamed bile ducts, the tubes that carry the digestive fluid bile from the liver to the intestines. Bile duct inflammation causes bile to accumulate in the liver and leak into the bloodstream, leading to itching (pruritus) and liver damage.
The first-line treatment for PBC is UDCA, sold as Urso and Actigall, as well as in generic forms. It’s a nontoxic bile acid that can promote bile flow, thereby reducing liver damage. About 40% of PBC patients treated with UDCA don’t adequately respond, however, which could lead to liver transplant or death.
What are PPAR agonists?
Peroxisome proliferator-activated receptor (PPAR) agonists work by activating PPARs, proteins that regulate genes involved in inflammation and scarring related to PBC, thereby reducing bile overload and suppressing pro-inflammatory signaling in the liver and bile ducts.
Livdelzi (seladelpar), sold as Lyvdelzi in Europe, is an activator of PPAR-delta and is approved in the U.S. and Europe for adults with PBC who don’t respond to UDCA. Iqirvo (elafibranor) is an activator of PPAR-delta and PPAR-alpha, and is approved as a second-line treatment in the U.S. and elsewhere for adults with PBC. Saroglitazar, which activates PPAR-alpha and PPAR-gamma, is undergoing clinical trial testing as a PBC therapy. In a separate analysis, saroglitazar combined with UDCA improved biomarkers for liver injury. Fenofibrate is a PPAR-alpha activator also being investigated with UDCA.
Lastly, bezafibrate, a PPAR-alpha activator, is being tested in multiple clinical trials, including in combination with Ocaliva (obeticholic acid), an approved treatment for PBC. New data from a Phase 2 trial (NCT04594694) that’s testing the Ocaliva-bezafibrate combination showed a significant reduction in liver damage biomarkers.
Evaluating PPAR agonists’ safety, effectiveness
Here, researchers examined the evidence that supports the safety and efficacy of PPAR agonists as part of a meta-analysis of published studies. They selected 12 randomized controlled trials (RCTs) involving 973 patients, all of whom were unresponsive to UDCA alone.
“To the best of our knowledge, this meta-analysis, incorporating data from 12 RCTs with 973 patients, is the largest and most updated meta-analysis on this topic to date,” they wrote.
According to the analysis, patients receiving PPAR agonists achieved significantly higher rates of the composite biochemical response, a predefined combination of biochemical markers, over those receiving a placebo. In a subgroup analysis, combination therapy with UDCA and various PPAR agonists, except fenofibrate, resulted in a significantly greater composite biochemical response than UDCA alone.
PPAR agonists with UDCA significantly reduced the mean levels of alkaline phosphatase (ALP), a biomarker for liver damage, than UDCA alone. The results were consistent across different types of PPAR agonists. Consistent with these findings, PPAR agonists combined with UDCA significantly increased the proportion of patients with normalized ALP levels over UDCA alone.
Selective PPAR agonists also significantly reduced itch scores compared with a placebo and, when combined with UDCA, significantly decreased itching over UDCA alone.
No differences in adverse effects were observed between PPAR agonists plus UDCA and UDCA alone, and between PPAR agonists and a placebo regarding serious adverse events.
“This meta-analysis supports the use of PPAR agonists as effective treatments for improving biochemical markers, including ALP normalization and pruritus reduction, in patients with PBC who do not respond to UDCA,” wrote the researchers, who said more studies are needed to “assess long-term safety and patient-centered outcomes.”
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