Second-line therapies in PBC-related cirrhosis: balancing efficacy and safety

Ursodeoxycholic acid (UDCA) remains the cornerstone of treatment for primary biliary cholangitis (PBC). However, approximately 30–40% of patients fail to achieve a complete biochemical response, a factor associated with increased risk of disease progression and liver-related complications (1). This emphasizes the importance of early assessment of therapeutic response and the implementation of individualized treatment strategies based on risk stratification and disease stage. In this context, the recent multicenter study by Ampuero et al. offers valuable real-world insights into the safety and effectiveness of second-line treatments in patients with PBC-related cirrhosis—a population typically excluded from pivotal clinical trials, yet at the highest risk of decompensation (2).

Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, was the first second-line therapy formally recommended in international guidelines for patients with an inadequate response or intolerance to UDCA. It received Food and Drug Administration (FDA) approval in 2016 based on the POISE [Phase 3 study of obeticholic acid in patients with primary biliary cirrhosis (NCT01473524)] trial, which demonstrated significant biochemical improvement in UDCA non-responders (3). In the same year, the European Medicines Agency (EMA) granted conditional approval, which was later withdrawn in 2024 following the results of the confirmatory COBALT [Phase 4 study of obeticholic acid evaluating clinical outcomes in patients with primary biliary cholangitis (NCT02308111)] trial (4). This randomized controlled study did not show clinical benefit of OCA over placebo in the primary composite outcome, partly due to treatment crossover and functional unblinding. However, analyses using well-matched external control groups demonstrated a significant reduction in the risk of serious and life-threatening outcome events. OCA remains available outside the European Union and is still used, including in combination with fibrates. Real-world data, including the HEROES [Real-world data study to evaluate the effectiveness of OCA on hepatic outcomes in PBC patients (NCT04526665)] study, have further supported its potential benefits, showing improved transplant-free survival and a lower risk of liver-related complications in appropriately selected patients (5). Importantly, its use is restricted to patients with compensated liver disease, due to potentially increased risk of hepatic adverse events—particularly in those with prior decompensation or portal hypertension (6).

In 2024, the therapeutic landscape expanded further with FDA approval of two new peroxisome proliferator-activated receptor (PPAR) agonists: elafibranor (PPAR-α/δ) and seladelpar (PPAR-δ), following the results of the ELATIVE [Study of elafibranor in patients with primary biliary cholangitis (NCT04526665)] and RESPONSE [Response to Seladelpar in subjects with primary biliary cholangitis (PBC) and an inadequate control to or an intolerance to ursodeoxycholic acid (NCT04620733)] trials, respectively (7,8). Both agents demonstrated robust biochemical efficacy and favorable safety profiles in patients with inadequate response to UDCA. However, their clinical use remains limited to non-cirrhotic or compensated patients, as safety data in those with decompensated liver disease are lacking.

Bezafibrate, although not formally licensed for PBC, is frequently prescribed off-label in Europe (9). Clinical trials have shown that bezafibrate, when added to UDCA, can improve cholestatic markers and reduce pruritus. However, its use in patients with advanced liver disease remains a subject of debate due to concerns about renal safety and the limited availability of long-term outcome data.

These therapeutic developments are comprehensively addressed in several high-quality, recently published reviews that critically appraise current and emerging treatment options in PBC (10-13). These articles provide up-to-date perspectives on the role of FXR and PPAR agonists, IBAT inhibitors, combination strategies, and future directions toward individualized therapy.

The study by Ampuero et al. addresses a critical gap in the current evidence base by focusing specifically on patients with PBC-related cirrhosis—a population systematically underrepresented in clinical trials. Whereas most data on second-line therapies derive from non-cirrhotic cohorts, this large multicenter study prospectively evaluated nearly 400 patients with cirrhosis enrolled in the Spanish ColHai registry. To date, it represents the largest real-world analysis of second-line treatment in this high-risk subgroup. Notably, 15% of patients receiving OCA were already decompensated at baseline, illustrating real-world prescribing practices prior to the introduction of regulatory restrictions. This is particularly relevant considering ongoing concerns regarding the safety of both OCA and fibrates in advanced liver disease. Beyond evaluating the impact of second-line therapies on the risk of hepatic decompensation, the study also identified baseline factors associated with poor clinical outcomes. These insights offer practical guidance for managing high-risk patients who are most in need of effective and safe therapeutic interventions.

The study offers several clinically meaningful observations. First, both OCA and fibrates achieved a biochemical response in approximately half of the patients with cirrhosis, indicating that these therapies retain efficacy even in advanced stages of disease. Importantly, patients who fulfilled the POISE response criteria had a substantially lower risk of hepatic decompensation, underscoring the prognostic utility of these criteria in cirrhotic populations. In contrast, non-responders experienced a nearly fourfold higher incidence of complications, supporting the rationale for discontinuing ineffective therapy in this subgroup.

Second, hepatic decompensation was uncommon among patients without clinically significant portal hypertension (CSPH), even in those receiving OCA or fibrates, highlighting the value of identifying this low-risk subgroup. Among patients treated with OCA, risk of decompensation was associated with lower serum albumin, thrombocytopenia, presence of diabetes, and lack of biochemical response. In the fibrate group, the key predictors were CSPH, low albumin, and failure to achieve treatment response. These readily available clinical and laboratory parameters may aid in stratifying risk and guiding the safer use of second-line therapies. Notably, bilirubin alone did not consistently predict outcomes in this cohort.

Finally, although higher rates of decompensation were initially observed among patients receiving second-line therapy, this association was no longer significant after adjustment for confounding factors—suggesting that the elevated risk was attributable to baseline disease severity rather than treatment-related toxicity.

These findings underscore the importance of close monitoring of treatment response in all patients with PBC. It is the lack of response to second-line therapy—rather than the treatment itself—that appears to be the principal driver of hepatic decompensation (14). In addition to on-treatment risk stratification, recent data from the Global PBC Study Group demonstrate that nearly half of patients with early-stage disease progress to a more advanced biochemical stage within five years, and such progression is strongly associated with clinical events (15). This highlights the need for long-term surveillance, even in patients initially considered low risk. Taken together, these observations emphasize the importance of individualizing therapeutic decisions based on baseline risk factors and early response, both in patients receiving OCA and those treated with fibrates. Dose titration of OCA may enhance tolerability, especially given that pruritus is a dose-dependent adverse effect leading to treatment discontinuation in up to 25% of patients. Moreover, FXR activation is known to adversely affect lipid metabolism by lowering high density lipoprotein (HDL) and increasing low density lipoprotein (LDL) cholesterol levels. In this context, combination therapy with low-dose OCA and fibrates—which can improve both pruritus and lipid parameters—may represent a rational strategy for selected patients, although supporting evidence remains limited.

Despite the availability of second-line therapies, up to 50% of patients with an inadequate response to UDCA may fail to achieve biochemical improvement or may discontinue treatment due to intolerance. This underscores the need for additional therapeutic options. Recently approved peroxisome proliferator-activated receptor (PPAR) agonists, such as elafibranor and seladelpar, offer new possibilities for this difficult-to-treat subgroup. In parallel, pruritus-targeted agents like linerixibat—an apical sodium-dependent bile acid transporter (ASBT) inhibitor—have shown promise in improving quality of life and may soon become the first approved therapy specifically for cholestatic pruritus in PBC.

In summary, while UDCA remains the mainstay of treatment in PBC, several second-line therapies are now available for patients with an inadequate response. The approval of new PPAR agonists and development of symptom-focused agents reflect important progress. The study by Ampuero et al. provides valuable real-world evidence on treatment outcomes in patients with PBC-related cirrhosis—a group often underrepresented in trials. Their findings highlight the need for early risk assessment, close monitoring of treatment response, and individualized therapy based on disease stage, tolerance, and symptoms.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article has undergone external peer review.

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-329/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-329/coif). The authors have no conflicts of interest to declare.

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References

1. EASL Clinical Practice Guidelines. The diagnosis and management of patients with primary biliary cholangitis. J Hepatol 2017;67:145-72. [Crossref] [PubMed]
2. Ampuero J, Lucena A, Berenguer M, et al. Predictive factors for decompensating events in patients with cirrhosis with primary biliary cholangitis under different lines of therapy. Hepatology 2024;80:791-806. [Crossref] [PubMed]
3. Nevens F, Andreone P, Mazzella G, et al. A Placebo-Controlled Trial of Obeticholic Acid in Primary Biliary Cholangitis. N Engl J Med 2016;375:631-43. [Crossref] [PubMed]
4. Kowdley KV, Hirschfield GM, Coombs C, et al. COBALT: A Confirmatory Trial of Obeticholic Acid in Primary Biliary Cholangitis With Placebo and External Controls. Am J Gastroenterol 2025;120:390-400. [Crossref] [PubMed]
5. Brookhart MA, Mayne TJ, Coombs C, et al. Hepatic real-world outcomes with obeticholic acid in primary biliary cholangitis (HEROES): A trial emulation study design. Hepatology 2025;81:1647-59. [Crossref] [PubMed]
6. John BV, Schwartz K, Levy C, et al. Impact of Obeticholic acid Exposure on Decompensation and Mortality in Primary Biliary Cholangitis and Cirrhosis. Hepatol Commun 2021;5:1426-36. [Crossref] [PubMed]
7. Kowdley KV, Bowlus CL, Levy C, et al. Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis. N Engl J Med 2024;390:795-805. [Crossref] [PubMed]
8. Hirschfield GM, Bowlus CL, Mayo MJ, et al. A Phase 3 Trial of Seladelpar in Primary Biliary Cholangitis. N Engl J Med 2024;390:783-94. [Crossref] [PubMed]
9. Corpechot C, Chazouillères O, Rousseau A, et al. A Placebo-Controlled Trial of Bezafibrate in Primary Biliary Cholangitis. N Engl J Med 2018;378:2171-81. [Crossref] [PubMed]
10. Jallouli I, Doulberis M, Kountouras J. Primary biliary cholangitis: a summary of pathogenesis and therapies. Ann Gastroenterol 2025;38:121-32. [Crossref] [PubMed]
11. Fiorucci S, Urbani G, Di Giorgio C, et al. Current Landscape and Evolving Therapies for Primary Biliary Cholangitis. Cells 2024;13:1580. [Crossref] [PubMed]
12. McNally BB, Carey EJ. Cholestatic liver diseases: modern therapeutics. Expert Rev Gastroenterol Hepatol 2025;19:365-70. [Crossref] [PubMed]
13. Cumpian NA, Choi G, Saab S. Review of Current and Upcoming Second-Line Treatments for Primary Biliary Cholangitis. Dig Dis Sci 2025;70:100-10. [Crossref] [PubMed]
14. De Vincentis A, D'Amato D, Cristoferi L, et al. Predictors of serious adverse events and non-response in cirrhotic patients with primary biliary cholangitis treated with obeticholic acid. Liver Int 2022;42:2453-65. [Crossref] [PubMed]
15. Gatselis NK, Goet JC, Zachou K, et al. Factors Associated With Progression and Outcomes of Early Stage Primary Biliary Cholangitis. Clin Gastroenterol Hepatol 2020;18:684-692.e6. [Crossref] [PubMed]