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The approval of ursodeoxycholic acid (UDCA) for primary biliary cholangitis (PBC) in 1997 marked a pivotal turning point in management of the condition, of liver transplant and death. However, UDCA's arrival was for all patients with PBC.

Up to 40% of patients with PBC won't sufficiently respond to UDCA, David N. Assis, MD, of Yale Liver Clinics and Yale New Haven Hospital in New Haven, Connecticut, told MedPage Today. "They still have a better outcome than if they had never been on it, but they're not necessarily benefitting sufficiently, and those are the ones that still tend to progress," he said.

In addition, a small proportion of patients, perhaps about 5%, cannot tolerate UDCA, said Brett E. Fortune, MD, medical director of the liver transplant program at Montefiore Medical Center in New York City. "It's usually a very well-tolerated drug, but there are some people who have an allergy to it and some who have gastrointestinal symptoms -- nausea, vomiting, abdominal disruption, and diarrhea," he told MedPage Today.

The continued need for additional therapies led researchers and physicians to discover that off-label could benefit some PBC patients. One key study found that nearly a third of patients with an inadequate response to UDCA responded to the addition of bezafibrate, which is unavailable in the U.S., but fenofibrate is another option, supporting its use as adjunctive therapy.

Then came the of the farnesoid X receptor (FXR) agonist obeticholic acid (Ocaliva) as a second-line treatment for adults with PBC, either in combination with UDCA for those with an inadequate response or as a single agent in patients unable to tolerate UDCA.

However, the downsides with obeticholic acid were not trivial. It appears to increase pruritus in a dose-dependent manner, said Ehud Zigmond, MD, director of the Center of Liver Diseases at Sheba Medical Center in Israel, and "studies showed there is some harm to patients who have advanced liver disease like decompensated cirrhosis," which led to a boxed warning, followed by additional restrictions in 2021.

failed to impress the FDA, and the agency declined to fully approve obeticholic acid for PBC in November, though the drug remains on the market.

Zigmond told MedPage Today that he has some patients who did not respond adequately to combined UDCA and bezafibrate and only began to improve after starting obeticholic acid.

The drug has also led to improvements in liver fibrosis, he said, and another benefit is that its mechanism differs from UDCA and the off-label fibrates, which are in the same class of peroxisome proliferator-activated receptor (PPAR) agonists that also includes the two newest drugs to receive accelerated approval for PBC, seladelpar (Livdelzi) and elafibranor (Iqirvo).

Furthermore, a of have suggested triple therapy -- UDCA with obeticholic acid and a fibrate -- can improve outcomes in those with insufficient response to UDCA, but the evidence remains thin and the future of obeticholic acid uncertain.

Therefore, the accelerated approvals of PPAR agonists elafibranor and seladelpar have been welcome additions to the PBC armamentarium. Seladelpar in particular was the first treatment to show clinically meaningful and significant improvements in pruritus.

Now it remains to be seen how they perform in the real world. Rare but serious, and even fatal, side effects with obeticholic acid only showed up with broader real-world use, and there are known rare side effects with bezafibrate, Zigmond said, including myopathy, especially when taken with statins, and increases in creatinine, suggesting renal function deterioration.

It's too early to tell, however, whether the newly approved PPAR agonists will share any of these risks. "It's hard to compare because these side effects are quite rare," Zigmond said. "I think that we will fully know how safe and efficacious the new PPARs are after they have been in the market and we see bigger numbers of patients taking them."

The results of ongoing studies of the new drugs are starting to roll in, including findings in more advanced-stage disease that obeticholic acid cannot safely treat. presented at this year's American College of Gastroenterology annual meeting showed that patients with both early and advanced-stage PBC had improvements in biochemical response with elafibranor compared with placebo. Two serious adverse events potentially related to elafibranor included hepatic failure and Crohn's disease.

At the same meeting, from the open-label, long-term ASSURE safety study showed that more than half of patients with PBC and cirrhosis taking seladelpar achieved meaningful improvements in cholestasis and markers of liver injury, with no serious adverse effects.

"I think as we get more information, we will find that adjunctive therapy in those with partial response [to UDCA] will probably benefit from being on those drugs," Fortune said, "but that is not proven in literature yet."

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