Phase 3 Trials Show New PPAR Agonists Completely Normalize Liver Enzymes in Primary Biliary Cholangitis

Two phase 3 clinical trials presented this week at The Liver Meeting 2026 in Denver have demonstrated that a new class of drugs can completely normalize liver enzymes in the vast majority of patients with primary biliary cholangitis. The results validate a more aggressive treatment approach for the rare autoimmune disease.[4]

The trials, named ELSPIRE and IDEAL, tested the recently approved medications elafibranor and seladelpar in a patient population that had been historically excluded from clinical research. These patients had alkaline phosphatase levels that were elevated, but sat below the traditional threshold used to define severe disease.[1][2]

"The key issue in our understanding of PBC... is that it has become more and more clear that if you look at the best outcomes in patients that have PBC, it is in those that have achieved normal alkaline phosphatase," Dr. Kris V. Kowdley of the Liver Institute Northwest told MedPage Today.[4]

Both drugs belong to a class known as peroxisome proliferator-activated receptor agonists. By targeting these specific nuclear receptors, the medications reduce bile acid toxicity and liver inflammation, offering a highly effective second-line option for patients who do not respond to standard therapy.[4]

Closing the treatment gap

Primary biliary cholangitis is a chronic condition in which the body's immune system slowly destroys the small bile ducts within the liver. As bile backs up, it causes inflammation and scarring that can ultimately progress to cirrhosis and liver failure if left unchecked.[4]

The disease disproportionately affects women, who account for the vast majority of diagnoses, typically presenting between the ages of 40 and 60. Beyond the silent threat of liver fibrosis, the condition often causes debilitating fatigue and severe pruritus, an intense itching that can severely degrade a patient's quality of life.[4]

For decades, the first-line treatment has been ursodeoxycholic acid, a synthetic bile acid that helps move toxic bile out of the liver. However, up to 40 percent of patients experience an inadequate response to this foundational therapy, leaving them at risk for continued liver damage.[2][4]

In previous clinical trials for second-line therapies, researchers only enrolled patients whose alkaline phosphatase levels were at least 1.67 times the upper limit of normal. That arbitrary cutoff, derived from older response criteria, left patients with milder elevations largely unstudied.[1][4]

"People with PBC whose alkaline phosphatase remains elevated but below 1.67 times the upper limit of normal have been largely excluded from previous pivotal trials of second-line therapies," said Dr. Cynthia Levy of the University of Miami Miller School of Medicine.[1]

Yet recent epidemiological data has shown that even modest enzyme elevations above the normal range are associated with a shorter transplant-free survival. Hepatologists have increasingly recognized that leaving these patients with residual disease carries significant long-term risks.[3][4]

The ELSPIRE trial results

The ELSPIRE trial, sponsored by Ipsen and published simultaneously in the journal Hepatology, evaluated the dual alpha and delta receptor agonist elafibranor, marketed as Iqirvo. The study enrolled 92 adults across 10 countries who had an inadequate response or intolerance to standard therapy.[2][3]

Participants were randomized to receive either 80 milligrams of elafibranor daily or a placebo for 52 weeks. All enrolled patients had a baseline alkaline phosphatase between 1.0 and 1.67 times the upper limit of normal, placing them squarely in the previously neglected intermediate risk category.[2][3]

The results were striking. At week 52, 85.3 percent of patients receiving elafibranor achieved complete enzyme normalization, compared with just 23.3 percent of those in the placebo group. The drug also drove a 36.5 percent adjusted mean reduction in alkaline phosphatase from baseline.[2][3]

Beyond a single enzyme, elafibranor significantly improved other markers of liver health. Nearly 65 percent of treated patients achieved a complete biochemical response—defined as normal levels of alkaline phosphatase, total bilirubin, transaminases, and albumin—compared to 16.7 percent on placebo.[2][3]

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"The results of this study demonstrate that ALP normalization is an achievable goal for a substantial proportion of patients receiving elafibranor, even among those with moderately elevated ALP levels," Kowdley noted in a statement accompanying the data release.[4]

Seladelpar succeeds in IDEAL

Gilead Sciences presented parallel data from its phase 3 IDEAL study, which tested the selective delta receptor agonist seladelpar, sold under the brand name Livdelzi. Like ELSPIRE, the trial focused exclusively on the intermediate patient population with enzyme levels below the traditional threshold.[1][4]

The IDEAL trial randomized 96 adults to receive either seladelpar or a placebo over a 52-week period. The primary endpoint was a composite measure requiring both complete enzyme normalization and at least a 15 percent decrease from the patient's baseline level.[1]

Seladelpar met that primary endpoint in 75.4 percent of participants, compared to 16.1 percent of those receiving the placebo. The biochemical response was remarkably rapid, with 52.3 percent of treated patients reaching normalization after just one month of therapy.[1][4]

"IDEAL provides randomized, placebo-controlled evidence that seladelpar can improve biochemical response in this population," Levy said. "These findings can inform individualized treatment discussions, taking into account each individual's risk of disease progression, symptoms, and potential benefits and risks of additional therapy."[1]

Both elafibranor and seladelpar were generally well tolerated in their respective trials, with safety profiles consistent with earlier studies. Neither trial reported any new safety signals or treatment-linked serious adverse events that would preclude long-term use in this patient population.[1][2]

While older second-line treatments like obeticholic acid are known to exacerbate the severe itching associated with the disease, the new receptor agonists avoid this debilitating side effect. Previous trials have even demonstrated that seladelpar and elafibranor can actively reduce pruritus, offering a dual benefit for patient quality of life.[4]

Redefining clinical success

The dual presentations at the American Association for the Study of Liver Diseases mark a turning point in how hepatologists define clinical success. For years, reducing enzymes below the 1.67 threshold was considered an adequate response, largely because older drugs could not reliably push levels any lower.[4]

"As a proof of concept, you can achieve normalization in a very high proportion of patients if you start them earlier in the stage of the disease," Kowdley explained. The data suggests that accepting partial biochemical improvement is no longer necessary for most patients.[4]

Both drugs received accelerated approval from the U.S. Food and Drug Administration earlier in 2024 based on their performance in higher-risk patients. Elafibranor was approved in June following the ELATIVE trial, while seladelpar secured its authorization in August based on the RESPONSE study.[4]

Because those initial approvals were granted under the FDA's accelerated pathway, the manufacturers are required to conduct further studies to verify the drugs' clinical benefits. The robust data from ELSPIRE and IDEAL will likely serve as key evidence in securing full traditional approvals.[4]

Gilead Sciences confirmed it is already engaging with global regulatory authorities to discuss the IDEAL results. A label expansion could formally authorize seladelpar for patients with milder enzyme elevations, ensuring broader insurance coverage for the intermediate risk group.[1]

For the estimated 29 out of every 100,000 Americans living with primary biliary cholangitis, the shift toward complete biochemical normalization offers a tangible defense against disease progression. By halting liver damage earlier, these therapies could significantly reduce the future need for liver transplantation.[1]