Editor's Note:
Primary Biliary Cholangitis (PBC) is an autoimmune liver disease that predominantly affects middle-aged women. The exact cause and mechanism of its onset are not yet fully understood. It is thought to be related to genetic factors and their interaction with environmental factors leading to immune dysregulation. Currently, there are few effective medications available for clinical treatment. However, ongoing basic and clinical research has been shedding light on the role of bile acid metabolism, nuclear receptors, surface receptors, and transport proteins in the development and progression of PBC, leading to encouraging progress in new drug development. In this issue, we have invited Professor Jia JidongDr. Jidong Jia from the Capital Medical University affiliated Beijing Friendship Hospital to share the latest advancements in the clinical diagnosis and treatment of PBC.

01 Latest Developments in the Clinical Diagnosis of PBC

The clinical features of PBC include high titers of anti-mitochondrial antibodies (AMA) in the serum, elevated biliary enzymes, and characteristic liver pathology changes. Biochemical features include increased serum alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT); immunologically, there is an elevated serum immunoglobulin M (IgM), especially in AMA or AMA-M2 positive cases. The latter has significant diagnostic value in clinical populations, with both sensitivity and specificity exceeding 90% (Figure 1). The characteristic liver pathology of PBC is non-suppurative destructive cholangitis in small bile ducts[1].

Figure 1. Clinical, Biochemical, Immunological, and Pathological Characteristics of PBC[1]

In recent years, with a deeper understanding of the disease and the development and widespread availability of autoantibody testing techniques, the reported overall incidence of PBC has shown an increasing trend annually. Currently, China lacks population-based epidemiological data on PBC. It is estimated that the prevalence of PBC in China is around 20.5 per 100,000, ranking second in the Asia-Pacific region, just behind Japan[2-3].

The diagnosis of PBC requires a comprehensive assessment based on biochemical, immunological, imaging, and histological examinations. The 2022 version of the APASL (Asia-Pacific Association for the Study of the Liver) Clinical Practice Guidelines for PBC[4] recommends that a diagnosis of PBC can be made when at least two of the following three criteria are met: 1) Elevated biochemical markers indicative of cholestasis (primarily ALP and GGT) and imaging studies ruling out intrahepatic and extrahepatic biliary obstruction; 2) Positive AMA, or other PBC-specific antinuclear antibodies (ANA) such as anti-sp100 or anti-gp210 antibodies; 3) Liver biopsy showing non-suppurative destructive cholangitis primarily involving the small interlobular bile ducts.

Figure 2. Clinical Diagnostic Pathway for PBC

The “Diagnosis and Treatment Guidelines for Primary Biliary Cholangitis (2021)”[5] in China also suggest that a diagnosis of PBC can be confirmed if two of the following three criteria are met: 1) Elevated ALP and GGT, with imaging studies excluding intrahepatic or extrahepatic large bile duct obstruction; 2) Positive AMAs/AMA M2, or positive anti-gp210 or anti-sp100 antibodies; 3) Liver biopsy showing histological evidence of non-suppurative destructive cholangitis and destruction of small bile ducts.

It is important to note that serum AMA is a specific biomarker for diagnosing PBC, but the presence of AMAs/AMA M2 alone is not sufficient for diagnosis. Studies have shown[6] that AMAs/AMA M2 positivity can occur in various intrahepatic and extrahepatic diseases, but the titers of AMA-M2 in other diseases are lower than in PBC. Moreover, AMA/AMA-M2 positivity does not necessarily progress to PBC: the overall cumulative incidence of PBC development at 3, 5, and 10 years is only 1.63% (95%CI: 0.48-2.81), 4.2% (95%CI: 2.1-8.58), and 7.5% (95%CI: 4.32-17.20), respectively. Elevated IgM is a risk factor for progression to PBC in AMA/AMA-M2 positive individuals. For those with positive AMA but normal liver biochemical indices, enhanced follow-up is recommended, with annual re-evaluation of serological markers and liver biopsy if necessary for definitive diagnosis. Recent studies have found that even if AMA positivity accompanies elevated ALP and/or GGT, it is not necessarily indicative of PBC, as elevated ALP and/or GGT with AMA positivity can also occur in various intrahepatic and extrahepatic diseases. With effective treatment of the primary disease, ALP and GGT levels can improve or even return to normal without ursodeoxycholic acid (UDCA) treatment[7].

02 Clinical Treatment Strategies for PBC

First-line Treatment
The “Diagnosis and Treatment Guidelines for Primary Biliary Cholangitis (2021)”[5] in China recommend long-term oral administration of ursodeoxycholic acid (UDCA) at a dose of 13-15 mg/kg/day, either in divided doses or as a single daily dose for PBC patients. During treatment, it’s necessary to monitor changes in body weight and adjust the UDCA dosage accordingly (A1). The APASL guidelines[4] suggest that the standard treatment for all PBC patients should be oral UDCA at 13-15 mg/kg/day, with a commitment to long-term medication and monitoring of patient compliance (I, 1).

Second-line Treatment
When using UDCA for 6-12 months, biochemical response should be assessed using common standards. If the response criteria are met, there will be significant improvements in liver pathology and long-term survival. Conversely, if there is a poor or no biochemical response after 6-12 months or longer of treatment, consideration should be given to adding second-line medications such as obeticholic acid (OCA), bile acid sequestrants, or budesonide[4].

Figure 3. Clinical Treatment Pathway for PBC

Regarding the choice between OCA and bile acid sequestrants in second-line treatments, which is better? A UK observational cohort study conducted from August 2017 to June 2021 found that in the PBC patient population, the biochemical response rates and discontinuation rates for treatment with OCA and bile acid sequestrants (such as bezafibrate or fenofibrate) seem to be similar[8].

03 New Developments in PBC Drug Research

Currently, up to 40% of PBC patients do not respond well to UDCA treatment. Hence, there is an urgent need to identify new drug targets and develop novel therapeutic agents. Bile acid metabolism has several key regulatory targets, such as the farnesoid X receptor (FXR), peroxisome proliferator-activated receptors (PPARs), and the ileal bile acid transporter (IBAT). These targets can achieve therapeutic or symptomatic improvement in PBC through various pathways, making them the most promising drug targets at present.

The PBC treatment drugs currently undergoing clinical trials include (see Table 1) PPARδ agonists like Seladelpar, as well as Elafibranor and Saroglitazar, which have a broader PPAR activation effect[9]. All of these are in phase II or III clinical trials and have shown potential in improving biochemical markers in the blood. In terms of alleviating itching, both PPAR agonists and IBAT inhibitors (such as Linerixibat) have shown promise. For patients with severe liver fibrosis, the effectiveness of NOX inhibitors is being evaluated. Early treatment strategies also include methods for immune modulation in patients, as well as the use of MrgprX4 antagonists and other methods for treating itch. Overall, the prospects for treating PBC are exciting. With increasingly proactive and individualized treatment goals, our aim is to quickly normalize serum tests, improve the quality of life for patients, and prevent the onset of end-stage liver disease.

Table 1. New PBC Drugs Entering Phase III Clinical Trials[9]

PPAR Agonists

PPARs (Peroxisome Proliferator-Activated Receptors) consist of three subtypes: PPARα, PPARγ, and PPARδ. PPAR agonists, known for regulating bile acid metabolism, anti-inflammatory, and anti-fibrotic actions[10], have been proven to alleviate symptoms of itching.

Elafibranor is an oral PPARα/δ agonist. In a multinational, phase III, double-blind, placebo-controlled clinical trial[11], patients were randomly assigned in a 2:1 ratio to either the Elafibranor group or a placebo group. The primary endpoint was the biochemical response at 52 weeks, with key secondary endpoints including normalization of ALP levels at 52 weeks and changes in itch intensity measured by the Worst Itching Numeric Rating Scale (WI-NRS) from baseline to weeks 52 and 24. The results showed that 51% (55/108) of patients in the Elafibranor group achieved the primary endpoint compared to only 4% (2/53) in the placebo group, a difference of 47% (95%CI: 32~57; P<0.001), as shown in Figure 4. Additionally, 15% of patients in the Elafibranor group had normalized ALP levels at 52 weeks compared to 0% in the placebo group (difference 15%; 95%CI: 6~23; P=0.002). Furthermore, among patients with moderate to severe itching (44 patients on Elafibranor and 22 on placebo), there was no significant difference in the least squares mean change in WI-NRS from baseline to week 52 between the two groups.

Figure 4. Improvement in Biochemical Markers and Itching with Elafibranor + UDCA[11]

Seladelpar is an oral PPAR-δ agonist. The phase III ENHANCE study[12] assessed the efficacy and safety of Seladelpar in treating patients with PBC. Patients were randomly assigned in a 1:1:1 ratio to receive oral Seladelpar 5 mg (n=89), 10 mg (n=89), or placebo (n=87) once daily (UDCA could be added as needed). The primary endpoint was the rate of composite biochemical response at 3 months. The results indicated that a higher proportion of patients in the Seladelpar groups achieved the primary endpoint (Seladelpar 5mg group: 57.1%, 10mg group: 78.2%, placebo group: 12.5%; P<0.0001); 5.4% (P=0.08), 27.3% (P<0.0001), and 0% of patients, respectively, had normalized ALP levels. Seladelpar treatment continuously improved biochemical markers over 6 months, as shown in Figure 5.

Figure 5. Continuous Improvement in Biochemical Markers with Seladelpar Treatment at 3 Months and 6 Months[12]

In an open-label, international, long-term extension study[13], PBC patients who completed the Seladelpar induction study continued to receive treatment. The results showed that among 106 patients who received Seladelpar treatment for up to 2 years, no severe treatment-related adverse events were observed. Among the 53 patients who completed 2 years of Seladelpar treatment, the response rate for the composite endpoint (ALP<1.67×ULN, ALP reduction ≥15%, total bilirubin ≤ULN) and the proportion of patients with normalized ALP increased from 66% to 79% and from 26% to 42%, respectively, from year 1 to year 2 (Figure 6).

Figure 6. Results of the Seladelpar Open-Label 2-Year Study[13]

Saroglitazar is a PPARα/δ agonist. In a double-blind, phase 2 proof-of-concept trial[14], 37 PBC patients were randomly assigned to the 4 mg Saroglitazar group (n=13), 2 mg Saroglitazar group (n=14), or placebo group (n=10), and were treated daily for 16 weeks. The primary efficacy endpoint was the reduction in ALP levels at week 16. The results showed that the average ALP levels in the 4 mg and 2 mg Saroglitazar groups were significantly reduced at week 16 compared to baseline, while there was no significant reduction in the placebo group. The percentage reduction in ALP for the three groups was 49%, 51%, and 3%, respectively. Patients treated with Saroglitazar experienced a rapid reduction in ALP levels at week 4, which was maintained throughout the study period (Figure 7). In all three groups, the proportion of patients who experienced at least one treatment-emergent adverse event by week 4 was 84.6%, 85.7%, and 80%. Four patients (3 in the 4 mg group and 1 in the 2 mg group) discontinued the study drug due to elevated transaminases but rapidly returned to baseline values after discontinuation.

Figure 7. Rapid Reduction in ALP Levels with Saroglitazar Treatment[14]

NOX1/4 Inhibitor

Setanaxib is a NOX1/4 inhibitor that has demonstrated anti-fibrotic effects in in vitro and animal studies. A phase 2 randomized multicenter study evaluated the efficacy and safety of Setanaxib in PBC patients[15]. PBC patients were randomly assigned in a 1:1:1 ratio to receive oral Setanaxib 400 mg (once daily, twice daily, or placebo) for 24 weeks while also receiving UDCA treatment. The primary endpoint was the percentage change in GGT at week 24, with secondary endpoints including ALP and liver stiffness (LS) measured by transient elastography at week 24. At 24 weeks, the average GGT changes for the three groups were -4.9% (59.6%), -19.0% (28.9%), and -8.4% (21.5%), respectively; P=0.31. Patients treated with Setanaxib 400 mg once daily and twice daily had average LS percentage increases of 3.3% (35.0%) and 7.9% (43.7%) at week 24, while the placebo group had an increase of 10.1% (33.1%; P=0.65, Figure 8). The results indicated that Setanaxib could improve bile stasis markers and fibrosis.

Figure 8. Effects of Setanaxib on Liver Stiffness (LS)[15]

IBAT Inhibitor

Linerixibat is an investigational IBAT inhibitor medication used to treat itching in PBC. The GLIMMER study is a multicenter, randomized, parallel-group study[16] that included adults with PBC and moderate to severe itching (NRS≥4). The primary objective was to investigate dose-related changes in the Mean Worst Daily Itch Score (MWDI). A total of 147 patients received either placebo (n=36) or Linerixibat treatment.

The Linerixibat treatment group had a reduction of at least 2 points in MWDI compared to baseline at week 16. However, the difference compared to placebo was not significant. Post hoc analysis revealed significant differences between Linerixibat doses administered once daily at 180 mg (P=0.0424), twice daily at 40 mg (P=0.0105), and twice daily at 90 mg (P=0.0370) when compared to placebo (Figure 9). Post hoc analysis in the per-protocol population showed a significant relationship between the total daily dose and response (P=0.0542). Additionally, diarrhea was the most common side effect, with an increased incidence with higher doses. Diarrhea and abdominal pain were the main reasons for discontinuation.

Figure 9. Effects of Linerixibat on MWDI in PBC Patients[16]

Future Outlook

The future of PBC treatment is likely to involve combination therapy targeting different molecular pathways. Phase II clinical studies have already shown that combination therapy with OCA and phenzabart can better improve ALP and TBIL levels in PBC patients[17]. Therefore, combination therapy may become an effective treatment strategy. Furthermore, research has shown that PBC patients who respond adequately to UDCA but still have ALP levels persistently between 1.1 and 1.5×ULN, especially those with advanced fibrosis or young enough, still face a risk of poor prognosis[18]. Therefore, future treatment goals should aim for stricter treatment criteria, such as defining more specific biochemical response criteria, to improve treatment efficacy and reduce the risk of adverse outcomes. In summary, future treatment trends should be based on rigorous scientific research and adopt a multidisciplinary, multi-target comprehensive treatment approach to enhance treatment effectiveness and better meet the treatment needs of patients.

References: (Scroll up and down to view more)

  1. Lindor KD, Bowlus CL, Boyer J, et al. Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019 Jan;69(1):394-419.
  2. Lv T, Chen S, Li M, et al. Regional variation and temporal trend of primary biliary cholangitis epidemiology: A systematic review and meta-analysis. J Gastroenterol Hepatol. 2021 Jun;36(6):1423-1434.
  3. Zeng N, Duan W, Chen S, et al. Epidemiology and clinical course of primary biliary cholangitis in the Asia-Pacific region: a systematic review and meta-analysis. Hepatol Int. 2019 Nov;13(6):788-799.
  4. You H, Ma X, Efe C, et al. APASL clinical practice guidance: the diagnosis and management of patients with primary biliary cholangitis. Hepatol Int. 2022 Feb;16(1):1-23.
  5. 中华医学会肝病学分会. 自身免疫性肝炎诊断和治疗指南（2021）.中华内科杂志. 2021; 60(12):1024-1037
  6. Duan W, Chen S, Li S, et al. The future risk of primary biliary cholangitis (PBC) is low among patients with incidental anti-mitochondrial antibodies but without baseline PBC. Hepatol Commun. 2022 Nov;6(11):3112-3119.
  7. Zeng X, et al. Patients with Pbc-Specific Antibodies and Cholestasis May Not Be Primary Biliary Cholangitis. APASL 2024 Poster
  8. Abbas N, Culver EL, Thorburn D, et al. UK-Wide Multicenter Evaluation of Second-line Therapies in Primary Biliary Cholangitis. Clin Gastroenterol Hepatol. 2023 Jun;21(6):1561-1570.e13.
  9. Levy C, Manns M, Hirschfield G. New Treatment Paradigms in Primary Biliary Cholangitis. Clin Gastroenterol Hepatol. 2023 Jul;21(8):2076-2087.
  10. Kowdley KV, Bowlus CL, Levy C, et al. Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis. N Engl J Med. 2023 Nov 13. Epub ahead of print. PMID: 37962077.
  11. Hirschfield GM, Shiffman ML, Gulamhusein A, et al. Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study. Hepatology. 2023 Aug 1;78(2):397-415.
  12. Mayo MJ, Vierling JM, Bowlus CL, et al. Open-label, clinical trial extension: Two-year safety and efficacy results of seladelpar in patients with primary biliary cholangitis. Aliment Pharmacol Ther. 2024 Jan;59(2):186-200.
  13. Vuppalanchi R, Caldwell SH, Pyrsopoulos N, et al. Proof-of-concept study to evaluate the safety and efficacy of saroglitazar in patients with primary biliary cholangitis. J Hepatol. 2022 Jan;76(1):75-85. doi: 10.1016/j.jhep.2021.08.025. Epub 2021 Sep 4. PMID: 34487750.
  14. Invernizzi P, Carbone M, Jones D, et al. Setanaxib, a first-in-class selective NADPH oxidase 1/4 inhibitor for primary biliary cholangitis: A randomized, placebo-controlled, phase 2 trial. Liver Int. 2023 Jul;43(7):1507-1522.
  15. Levy C, Kendrick S, Bowlus CL, et al. GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus. Clin Gastroenterol Hepatol. 2023 Jul;21(7):1902-1912.e13.
  16. Two randomized, double-blind, active-controlled, phase 2 trials (studies 213 and 214) assessed the effects of combination OCA/BZF vs BZF monotherapy on safety and tolerability, as well as on serum biomarker levels and rates of biochemical remission. AALSD 2023 Poster
  17. Corpechot C, Lemoinne S, Soret PA, et al. Adequate versus deep response to ursodeoxycholic acid in primary biliary cholangitis: To what extent and under what conditions is normal alkaline phosphatase level associated with complication-free survival gain? Hepatology. 2024 Jan 1;79(1):39-48.
  18. Lindor KD, Bowlus CL, Boyer J, et al. Primary Biliary Cholangitis: 2018 Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019 Jan;69(1):394-419.2. Lv T, Chen S, Li M, et al. Regional variation and temporal trend of primary biliary cholangitis epidemiology: A systematic review and meta-analysis. J Gastroenterol Hepatol. 2021 Jun;36(6):1423-1434.3. Zeng N, Duan W, Chen S, et al. Epidemiology and clinical course of primary biliary cholangitis in the Asia-Pacific region: a systematic review and meta-analysis. Hepatol Int. 2019 Nov;13(6):788-799.4. You H, Ma X, Efe C, et al. APASL clinical practice guidance: the diagnosis and management of patients with primary biliary cholangitis. Hepatol Int. 2022 Feb;16(1):1-23.5. 中华医学会肝病学分会. 自身免疫性肝炎诊断和治疗指南（2021）.中华内科杂志. 2021; 60(12):1024-10376. Duan W, Chen S, Li S, et al. The future risk of primary biliary cholangitis (PBC) is low among patients with incidental anti-mitochondrial antibodies but without baseline PBC. Hepatol Commun. 2022 Nov;6(11):3112-3119.7. Zeng X, et al. Patients with Pbc-Specific Antibodies and Cholestasis May Not Be Primary Biliary Cholangitis. APASL 2024 Poster8. Abbas N, Culver EL, Thorburn D, et al. UK-Wide Multicenter Evaluation of Second-line Therapies in Primary Biliary Cholangitis. Clin Gastroenterol Hepatol. 2023 Jun;21(6):1561-1570.e13.9. Levy C, Manns M, Hirschfield G. New Treatment Paradigms in Primary Biliary Cholangitis. Clin Gastroenterol Hepatol. 2023 Jul;21(8):2076-2087.10. Kowdley KV, Bowlus CL, Levy C, et al. Efficacy and Safety of Elafibranor in Primary Biliary Cholangitis. N Engl J Med. 2023 Nov 13. Epub ahead of print. PMID: 37962077.11. Hirschfield GM, Shiffman ML, Gulamhusein A, et al. Seladelpar efficacy and safety at 3 months in patients with primary biliary cholangitis: ENHANCE, a phase 3, randomized, placebo-controlled study. Hepatology. 2023 Aug 1;78(2):397-415.12. Mayo MJ, Vierling JM, Bowlus CL, et al. Open-label, clinical trial extension: Two-year safety and efficacy results of seladelpar in patients with primary biliary cholangitis. Aliment Pharmacol Ther. 2024 Jan;59(2):186-200.13. Vuppalanchi R, Caldwell SH, Pyrsopoulos N, et al. Proof-of-concept study to evaluate the safety and efficacy of saroglitazar in patients with primary biliary cholangitis. J Hepatol. 2022 Jan;76(1):75-85. doi: 10.1016/j.jhep.2021.08.025. Epub 2021 Sep 4. PMID: 34487750.14. Invernizzi P, Carbone M, Jones D, et al. Setanaxib, a first-in-class selective NADPH oxidase 1/4 inhibitor for primary biliary cholangitis: A randomized, placebo-controlled, phase 2 trial. Liver Int. 2023 Jul;43(7):1507-1522.15. Levy C, Kendrick S, Bowlus CL, et al. GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus. Clin Gastroenterol Hepatol. 2023 Jul;21(7):1902-1912.e13.16. Two randomized, double-blind, active-controlled, phase 2 trials (studies 213 and 214) assessed the effects of combination OCA/BZF vs BZF monotherapy on safety and tolerability, as well as on serum biomarker levels and rates of biochemical remission. AALSD 2023 Poster17. Corpechot C, Lemoinne S, Soret PA, et al. Adequate versus deep response to ursodeoxycholic acid in primary biliary cholangitis: To what extent and under what conditions is normal alkaline phosphatase level associated with complication-free survival gain? Hepatology. 2024 Jan 1;79(1):39-48.

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Last updated on 2024.03.13