As the management landscape of primary biliary cholangitis (PBC) changes, new second-line options offer effective alternatives for patients who respond inadequately to standard first-line treatment with ursodeoxycholic acid (UDCA).

In a recent update in Digestive Diseases and Sciences, hepatologist Sammy Saab, MD, MPH, a professor in the Departments of Medicine and Surgery at the David Geffen School of Medicine at the University of California Los Angeles, and colleagues shared insights on the evolution of PBC therapy. This uncommon autoimmune cholestatic liver disease, whose etiology is still not clearly understood, causes small bile duct injury leading to cirrhosis and liver failure.

“An update was necessary because of paradigm shifts in the management and treatment of PBC,” Saab told Medscape Medical News. “There’s also an increased interest in personalized and tailored therapy, better patient risk assessment, and new therapies for patients who do not response adequately to UDCA.” Saab noted that while 60%-80% of patients do respond to UDCA and very few experience adverse effects, nonresponders risk liver complications and may need transplantation.

The update is also timely because of the recent voluntary withdrawal of the therapeutic option of the bile acid analogue obeticholic acid (Ocaliva) from the market at the FDA’s request owing to safety concerns, added hepatologist David N. Assis, MD, an associate professor of medicine - digestive diseases at Yale University School of Medicine in New Haven, Connecticut. “Many providers will benefit from readjusting their second-line treatment strategies after this withdrawal to focus on the recently approved peroxisome proliferator activated receptor agonists (PPARs) and the off-label option of fibrates such as fenofibrate,” Assis, who was not involved in writing the update, told Medscape Medical News.

“Obeticholic acid had a challenging side effect profile that limited its impact in patients with PBC,” noted Andrew Muir, MD, professor of medicine and chief of the Department of Gastroenterology at Duke University, Durham, North Carolina, in an interview. The COBALT study, reported early in 2025, also found no improvement in clinical outcomes among patients with PBC after treatment with obeticholic acid, he added. With the arrival of new agents for treatment, the withdrawal of obeticholic acid was not surprising, said Muir, who has served as an investigator for studies of the bile-blocking PPARs elafibranor (Iqirvo) and seladelpar (Livdelzi).

Epidemiology

Global estimates of PBC prevalence vary considerably, but recent adjusted PBC prevalence has risen in the US from approximately 22 per 100,000 population in 2006 to about 41 per 100,000 in 2021. Why it affects women more commonly than men is not fully understood, Assis said. “But there is likely an interaction between the effect of sex-specific hormones and the female predisposition to autoimmunity in general, given that most autoimmune diseases are also more common in women.”

According to Saab, “It’s unclear why we’re seeing overall PBC risk increasing. It’s possible that cardiometabolic factors can be contributing to worsening liver disease severity. Fortunately, the availability of therapies for patients who do not respond to UDCA should mitigate the risk of disease progression and thus the need for liver transplantation.”

The seeming increase is also likely a result of heightened awareness and more frequent testing to improve diagnosis, treatment, and survival rates, said Mark G. Swain, MD, MSc, a professor of medicine and head of the Departments of Gastroenterology and Hepatology at the University of Calgary in Calgary, Alberta, Canada, and not a coauthor of the update. “There will likely be an uptick in the number of patients who need and will be started on second-line therapy,” he told Medscape Medical News.

Assis noted that PBC is increasingly found alongside metabolic dysfunction-associated steatotic liver disease (MASLD). “And having two liver disorders concurrently can increase the risk of ongoing inflammation and fibrosis. Therefore, the rise in metabolic syndrome and MASLD can increase the risk of disease progression over time.”

First-Line UDCA

Although previously used off-label for PBC, the gallstone drug UDCA was officially approved for PBC in 1997. But while UDCA can increase survival and reduce transplantation, this standard treatment may not address extrahepatic symptoms such as pruritus and fatigue.

Swain pointed to an increased understanding of the risk for inadequate response to first-line UDCA, not only at baseline and after a year’s therapy but also at earlier treatment time points — at 6 months, for example. The growing awareness of MASLD and its cousin metabolic dysfunction-associated steatohepatitis, will lead to more liver testing, including enzyme assays and workup pathways such as antimitochondrial antibody measurement, and these tests will likely have the effect of increasing PBC diagnosis rates, he said.

In terms of comorbid synergy, a recent study suggested the combination of MASLD and PBC leads to worse clinical outcomes. “This observation makes sense and implies that healthy living and eating habits and consideration of other approaches targeted at improving liver steatosis should be encouraged in PBC patients,” Swain said.

And while relapse after response to first-line PBC therapy is uncommon, he added, “If this happens, a patient’s treatment adherence needs to be specifically addressed. In addition, other complicating liver diseases including autoimmune hepatitis overlap should also be considered.”

Earlier Treatment Monitoring

“Recent expert opinion recommends assessing response to UDCA in 6 rather than 12 months in patients with advanced liver disease,” Saab said. He also stressed the importance of considering PBC in the differential diagnosis of patients presenting with cholestatic liver disease.

“Risk assessment is critical in determining when we define UDCA response,” Saab said. Factors associated with UDCA failure include advanced liver disease, male sex, age younger than 45, elevated liver enzymes, ductopenia, and more biopsy-established interface hepatitis, or piecemeal necrosis.

New Second-Line Therapies

While treatment always begins with UDCA, second-line medications are recommended as add-on therapy, absent a substantial drop in alkaline phosphatase (ALP).

Saab pointed out that with the withdrawal of obeticholic acid, used as second-line therapy for almost 10 years, new players have come on the market: the PPARs elafibranor and seladelpar. Shown to reduce alkaline phosphatase levels and improve pruritus and fatigue, they can, however, have a range of adverse muscle, abdominal, gastric, and other side effects, as well as undesirable interactions with other drugs.

Seladelpar was approved by the FDA in 2024 for adults with PBC who had intolerance or an insufficient response to UCDA, said Christopher Bowlus, MD, of the University of California, Davis, and colleagues in a poster presented at The Liver Meeting 2025.

The primary outcome was characterization of the outcomes of patients with PBC who switched from obeticholic acid to seladelpar. The researchers reviewed data from 396 patients who began seladelpar, including 130 who switched within 3 months of obeticholic acid discontinuation and 266 who began seladelpar as monotherapy or added it to UCDA.

Among patients who switched from obeticholic acid, mean ALP decreased from 235 U/L at baseline to 171 U/L after a mean of 119 days of treatment. Among patients who as an add-on or monotherapy, 2L group, ALP decreased from 290 U/L at baseline 194 U/L after a mean of 98 days of treatment.

Additionally, an ALP < 1.67 x ULN, considered a benchmark of treatment response in PBC, increased from 55% at baseline to 83% after seladelpar treatment among patients who switched to seladelpar within 3 months and from 53% at baseline to 74% after treatment among those who started as add-on or monotherapy.

Notably, 93% of patients maintained treatment throughout the study period and safety signals were similar between the groups and between baseline and posttreatment periods.

“The most surprising finding was the greater improvement in serum alkaline phosphatase when patients switched from obeticholic acid to seladelpar, which suggests that seladelpar may be more effective in improving serum alkaline phosphate than obeticholic acid,” said Bowlus. Based on these findings, patients with PBC and physicians can feel comfortable that for those previously treated with obeticholic acid, seladelpar should be as effective, if not more, he said.

The study findings were limited by the use of a large healthcare database, which provided a considerable sample size but lacked detailed patient information, Bowlus told Medscape Medical News. “Replication of these data in a cohort of patients with more detailed data would ensure confidence in the findings,” he said.

Elafibranor Shows Effectiveness

In a study published in The New England Journal of Medicine, Kris Kowdley, MD, of Washington State University, Spokane, Washington, and colleagues randomized 161 adults with PBC who had an inadequate response or unacceptable side effects associated with UDCA to a once-daily, 80-mg dose of elafibranor or placebo for a year.

At week 52, approximately half of the elafibranor patients (51%) met the primary endpoint of an alkaline phosphatase level of < 1.67 times the upper limit of normal, with a reduction of at least 15% from baseline, and normal total bilirubin levels.

Adverse events reported in more than 10% of patients in each group were mainly gastrointestinal, including nausea, vomiting, diarrhea, and abdominal pain; these occurred more frequently in elafibranor patients than in placebo patients. Most adverse events across both groups were mild-to-moderate, with similar percentages of adverse events deemed treatment-related or leading to treatment discontinuation.

“We should remember that seladelpar and elafibranor are not recommended for patients with decompensated cirrhosis,” Muir added. “These medications are for patients before they get to that point. Once at the more advanced stage, we need to consider liver transplantation,” he said.

In addition to seladelpar and elafibranor, old-school fibrates such as fenofibrate and bezafibrate are off-label second line alternatives when response to UDCA is inadequate. Fenofibrate, for example, a widely used lipid-lowering medication, is a broad PPAR activator with anti-inflammatory and antifibrotic properties. In decompensated cirrhosis, however, its potential to worsen disease has led the American Society for the Study of Liver Diseases (AASLD), to discourage its use.

As to drug affordability issues, financial barriers to second line PBC treatments have not been common in practice, Saab noted. “And pharmaceutical companies have a number of programs to increase access to newer therapies if there are insurance issues.”

Added Assis, “For patients unable to afford or obtain insurance coverage for the PPAR agonists, off-label treatment with fenofibrate is a very reasonable option and is endorsed by the current version of the AASLD Guidelines for PBC.”

Immunosuppression Therapy

Although PBC is an autoimmune disease, its response to traditional immunosuppressive therapies has to date been disappointing, Swain said. “However, newer approaches that focus instead on generating immune tolerance are being explored and include nanoparticle-based therapies that target immune dysregulation and destruction of the biliary epithelium.”

One possible target is regulatory T cells (Tregs), for example, which are critical regulators of autoimmunity, and PBC is associated with dysfunctional Treg responses. Newer therapies designed to augment these cells’ response within the liver are being actively explored and may emerge as new treatment options.

Counteracting Depression

Depressive symptoms are common in PBC, although depression does not appear to impact disease outcomes, noted Swain. “However, the atypical antidepressant mirtazapine is significantly protective in patients with PBC, reducing the risk for poor liver outcomes such as decompensated cirrhosis transplant, and death by 77%.”

Fatigue and itch can have a massive effect on well-being and can persist even despite successful resolution of liver inflammation with treatment, noted Assis. “This can, in turn, lead to reduced quality of life and predispose to depression. There’s a great amount of research underway to better understand and hopefully modify the underlying mechanisms that generate fatigue in persons with PBC.”

And moderate-to-severe pruritus may be mitigated with newer iBat [ileal bile acid transporter inhibitors] drugs, which are designed to significantly reduce liver-related itching.

While modest aerobic exercise and stretching can help reduce fatigue in PBC, pharmacologic approaches are currently lacking, Assis added. “But there’s no contraindication to receiving antidepressant treatment while on PBC therapies.”

On the Horizon

Future therapy in PBC will involve individualized approaches with both early patient phenotyping to predict response to traditional therapies and earlier use of second line and immunomodulatory therapies at critical time points in disease progression. “Clinical care decisions will be based on personalized assessments and risk characteristics as well as dynamic assessment of treatment responses,” said Swain. “Symptom control will be an overlapping target for treatment strategies that focus on improving quality of life.”

Fortunately, said Assis, PBC is a slowly progressing condition compared with some chronic liver diseases. “However, as noted in the review article, there are efforts to identify patients who will ultimately need second-line therapies earlier than at the 1-year mark of UDCA treatment. Initiation of second-line treatments up front, however, is generally not recommended since most patients will respond to UDCA alone.”

Medical writing and editorial support for this statement were funded by Gilead Sciences, Inc. Saab reported speaking for Ipsen, Intercept, and Gilead, as well as consulting for Ipsen Intercept and Gilead. Other coauthors disclosed similar ties. Muir reported serving as an investigator on studies of both seladelpar and elafibranor, but not those referenced in this story. Assis disclosed having no relevant conflicts of interest. Swain disclosed consulting for Gilead, Ipsen, Novo Nordisk, Advanz, Abbott, GSK, Mirum, and Boehringer Ingelheim; speaking for Ipsen, Gilead, Umecrine, and Abbott, as well as clinical trial funding from Gilead, GSK, Cymabay, Intercept, Kowa, Novo Nordisk, Pfizer, Ancella, Merck, Galectin, Ipsen, Madrigal, Roche, Altimmune, 89Bio, Inventiva, Boehringer Ingelheim, and Lilly. Bowlus reported serving as a consultant for Gilead, and his institution has received research funds from the company.