Second-line treatment of primary biliary cholangitis: To whom, which molecule, and when

Abstract

Ursodeoxycholic acid (UDCA) is the first-line treatment of primary biliary cholangitis (PBC). Approximately two-thirds of patients have a biochemical response to UDCA, but only one-third of treated patients achieve a complete biochemical response. UDCA nonresponse is associated with hepatic decompensation and higher liver-related mortality; therefore, UDCA nonresponders should be considered for second-line PBC treatment. Nonfibrate peroxisome proliferator-activated receptor (PPAR) agonists elafibranor and seladelpar are approved for second-line PBC treatment in UDCA nonresponders and in UDCA treatment intolerance. Fibrates are an alternative second-line PBC therapy, but they are not approved for second-line treatment. A significant benefit of PPAR receptor agonists therapy is the alleviation of pruritus in some patients. Second-line PBC treatment is usually indicated after 1 year of UDCA therapy; however, it may be considered after 6 months of UDCA treatment in high-risk PBC patients. The selection of drug for second-line PBC treatment and the timing of therapy initiation should be individualized. Many factors, including PBC complications, especially pruritus, should also be considered in the decision-making algorithm. It will be necessary in the coming years to evaluate the efficacy of PPAR agonists in real-world clinical practice, including monitoring the incidence of decompensated liver cirrhosis and liver-related mortality.

Key Words: Primary biliary cholangitis; Ursodeoxycholic acid; Second-line treatment; Elafibranor; Seladelpar; Therapeutic response

Core Tip: Primary biliary cholangitis (PBC) is a disease with increasing prevalence, particularly in developed countries. First-line treatment of choice is ursodeoxycholic acid (UDCA), but only about two-thirds of patients achieve biochemical response. UDCA nonresponders have a higher risk of liver cirrhosis decompensation and poorer transplant-free survival. These patients should be considered for second-line therapy. This review provides a comprehensive overview of second-line treatment indications, selection of the most appropriate medication, timing of therapy initiation, benefits, and adverse effects of therapy, as well as the administration of second-line treatment in specific groups of PBC patients.

INTRODUCTION

Primary biliary cholangitis (PBC) is a nonsuppurative autoimmune liver disease. PBC is associated with destruction of the bile ducts, and liver fibrosis. PBC progresses to liver cirrhosis in some patients, and hepatocellular carcinoma is a rare complication in PBC[1,2]. PBC is a rare disease that occurs significantly more often in women. The PBC prevalence and incidence in recent years have been increasing in developed countries[3,4]. Two of the three criteria listed below are required to diagnose PBC: Increased alkaline phosphatase (ALP) above the upper limit of the normal lasting for ≥ 6 months; AMA M2 positivity in a titer of at least 1: 40 or specific ANA positivity (anti-sp100 or anti-gp210) in case of AMA negativity; histological findings consistent with PBC[1].

PBC may overlap with other autoimmune liver diseases including primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH). These patients have a worse clinical course than patients with PBC alone. Patients with PBC/AIH overlap must meet the histological criteria for both diseases[5,6]. Pruritus, fatigue, dyslipidemia, and osteoporosis are the most common extrahepatic manifestations of PBC, and their presence worsens the quality of life of PBC patients[7].

The goals of PBC treatment include: (1) improvement of biochemical findings; (2) improvement of histological findings (reduction of inflammation and fibrosis); (3) reduction in the incidence of liver cirrhosis and decompensated liver cirrhosis; (4) reduction in the incidence of hepatocellular carcinoma; (5) improvement in the course of extrahepatic complications or their reduction; (6) improvement in quality of life; and (7) improvement in survival[8].

Today, we have effective treatments for PBC, which should be started immediately after diagnosis. If first-line treatment for PBC fails, second-line treatment should be considered. This is a narrative review summarizing current and emerging second-line therapies for PBC, with emphasis on patient selection, drug choice and timing of treatment escalation.

FIRST-LINE TREATMENT OF PBC

Ursodeoxycholic acid (UDCA) is the drug of choice in the first-line treatment of PBC. UDCA has been used in the treatment of PBC for almost four decades[9]. UDCA is a 7-β-epimer of chenodeoxycholic acid with hepatoprotective and choleretic effects[10]. UDCA reduces the absorption of toxic hydrophobic endogenous bile acids, stabilizes the hepatocyte membrane against toxic bile acid salts, and suppresses interleukin (IL)-2 production. During treatment, UDCA partially replaces hepatotoxic cholic, chenodeoxycholic, deoxycholic, and lithocholic acids. UDCA levels in bile correlate with biochemical findings in PBC patients[11]. UDCA leads to a reduction in fibrogenesis in the liver[12]. Treatment with UDCA in PBC patients is associated with a reduction in total cholesterol (TC) and low-density cholesterol (LDL-C); high-density cholesterol (HDL-C) and triglyceride (TG) levels do not change significantly during treatment[13].

The recommended dose of UDCA for the treatment of PBC is 13-15 mg/kg/day[1]. PBC patients tolerate UDCA treatment well. Rare adverse effects include pruritus, which is usually transient, diarrhea, and upper right abdominal quadrant pain[14]. Reduction of UDCA dose or premature discontinuation of treatment is rare[15].

An analysis of the Global PBC Study Group database, which included 3902 patients (90.4% were treated with UDCA) with mean follow-up of 7.8 (4.1-12.1) years, showed that UDCA improved transplant-free survival compared to untreated patients [hazard ratio (HR): 0.46; 95% confidence interval (CI): 0.40-0.52; P < 0.001]. Patients who had an inadequate response to UDCA treatment after 1 year of treatment had a significantly better transplant-free survival rate compared to the untreated patients (HR: 0.56; 95%CI: 0.45-0.69; P < 0.001)[16].

The definition of therapeutic response to UDCA in PBC patients is not clearly defined. Biochemical response to UDCA is evaluated by different qualitative binary scoring systems using simple laboratory parameters. Apart from the EHIME and Rotterdam Scoring System, these scoring systems evaluate ALP as a marker of cholestasis, and approximately half of them also evaluate bilirubin levels when assessing therapeutic response. The Toronto criteria are the most used in clinical practice. Approximately 70% of PBC patients treated with UDCA achieve a biochemical response according to the modified Toronto criteria: ALP ≤ 1.67 × upper limit of normal (ULN) after 1 year, and approximately one-third of patients have normal bilirubin and ALP levels[4]. Patients who achieve low ALP and bilirubin levels during UDCA treatment have the best outcome. In an evaluation of > 2000 patients from the Global PBC Study Group database, the best survival rates were seen in patients who had normal ALP and bilirubin ≤ 0.6 × ULN after 1 year of UDCA treatment[17]. An overview of the most used qualitative binary scoring systems is provided in Table 1[17-26].

Table 1 Overview of the most commonly used qualitative binary scoring systems in primary biliary cholangitis patients treated with ursodeoxycholic acid.

Name of scoring system	Duration of treatment (mo)	Type of PBC population	UDCA treatment response definition	Ref.
Rochester	6	American	ALP < 2 × ULN and Mayo Risk Score < 4.5	[18]
Barcelona	12	European	Decrease in ALP > 40% or ALP ≤ × 1 ULN	[19]
Paris-I	12	European	ALP < 3 × ULN and AST < 2 × ULN and bilirubin ≤ 1 mg/dL	[20]
Paris-II	12	European	ALP ≤ × 1.5 ULN and AST ≤ × 1.5 ULN and bilirubin ≤ 1 × ULN	[21]
Rotterdam	12	European	Bilirubin ≤ 1 × ULN and albumin ≥ 1 × ULN	[22]
Ehime	6	Asian	Decrease in GGT > 70% or GGT ≤ 1 × ULN	[23]
Toronto	24	American	ALP ≤ 1.67 × ULN	[24]
Xi’an	1	Asian	ALP ≤ 2.5 × ULN, AST ≤ 2 × ULN and total bilirubin ≤ 1 × ULN	[25]
Monza	12	European	GGT < 3.2 × ULN or ALP < 2 × ULN	[26]
Global PBC study group	12	International	Bilirubin ≤ 0.6 × ULN and ALP ≤ 1 × ULN	[17]

ALP: Alkaline phosphatase; AST: Aspartate aminotransferase; GGT: Gamma glutamyl transferase; mo: Months; PBC: Primary biliary cholangitis; UDCA: Ursodeoxycholic acid; ULN: Upper limit of normal.

Carbone et al[27] constructed the UDCA Response Score, which uses parameters prior to the start of UDCA treatment. The authors included the following parameters in the scoring system: Age; bilirubin; aminotransferases; ALP, time from diagnosis to treatment; and worsening of ALP in the time interval between diagnosis and treatment. Modified Toronto criteria (ALP ≤ 1.67 × ULN after 1 year of treatment) were used to evaluate therapeutic response. The area under the receiver operating characteristic for the UDCA response score after 1 year of UDCA treatment was 0.83 (95%CI: 0.79-0.87).

Continuous scoring systems predict therapeutic response and patient prognosis more accurately than qualitative binary scoring systems. UK-PBC Risk Score uses the following variables: Pretreatment albumin and thrombocytes; 12 months post-treatment bilirubin; aminotransferase levels; and ALP[28]. GLOBE score evaluates pretreatment age and 12 months post-UDCA treatment bilirubin, ALP, albumin, and platelets[29]. GLOBE score and UK-PBC Risk Score are the most suitable for the real-world allocation of second-line therapies. However, ALP and total bilirubin normalization should be the primary outcome in clinical trials in PBC[30].

However, biochemical improvement in PBC patients does not correspond to histological improvement during long-term UDCA treatment. Paired liver biopsies showed that only a quarter of patients with a biochemical response according to the Toronto criteria had an improvement in fibrosis stage after 10 years of treatment. A quarter of patients had progression of fibrosis despite a biochemical response and approximately half had no change in fibrosis stage. Almost all UDCA nonresponders experienced fibrosis progression after 10 years[24].

Patients who do not achieve a biochemical response to UDCA treatment have a poorer prognosis and progress significantly more often to decompensated liver cirrhosis[4]. Findings of advanced fibrosis or even liver cirrhosis are associated with poor response to UDCA[24]. The presence of anti-sp 100 or anti-gp 210 antibodies is associated with poorer prognosis[31,32]. Younger PBC patients have poorer response to UDCA therapy and lower transplant-free survival compared to older patients[33]. Patients with PBC/AIH overlap have a poorer response to UDCA and a worse prognosis than patients with PBC alone[34].

Some factors are associated with poorer clinical course in treated PBC patients. As described above, nonresponders to UDCA treatment, patients with overlap PBC/AIH and young women with PBC have a worse prognosis. Histopathological or elastographic findings of advanced fibrosis or even liver cirrhosis are associated with poor response to UDCA and poor prognosis[24,35]. Fibrosis stage is an independent predictor of the outcome in PBC despite biochemical treatment response[36]. Transient elastography is an excellent method for assessing fibrosis stage. In a meta-analysis of 13 studies of PBC patients, sensitivity and specificity were estimated to be 0.76 and 0.93, 0.88 and 0.9, and 0.91 and 0.95 for ≥ F2, ≥ F3, and ≥ F4, respectively[37]. The 8- and 15-kPa cutoffs in vibration-controlled transient elastography selected low-, medium-, and high-risk groups of PBC patients[38]. Ductopenia, found by histological examination, is an independent risk factor for the occurrence of liver-related adverse events in PBC patients[39]. In men with PBC, the disease is diagnosed later than in women due to the absence of clinical symptoms. Men with PBC have a worse clinical course than women have[40,41]. However, the response to UDCA treatment is comparable in both sexes[33].

SECOND-LINE TREATMENT IN PBC

Progression of fibrosis and worse prognosis are observed in PBC complete and partial nonresponders to UDCA treatment. The loss of biochemical response to UDCA at any time is associated with worse prognosis in PBC patients[42]. These patients are indicated for the second-line PBC treatment. The most promising drugs in second-line treatment of PBC are peroxisome proliferator-activated receptor (PPAR) agonists, including fibrates which are still used off-label in this indication.

PPAR agonists in the second-line treatment of PBC

Nonfibrate PPAR agonists and fibrates are used in the management of PBC. Nonfibrate PPAR agonists include elafibranor, seladelpar, and saroglitazar, while fibrates used in the treatment of PBC include bezafibrate, fenofibrate, and ciprofibrate[43,44]. PPAR agonists, after binding to their ligands, form heterodimers with the retinoid X receptor and interact with specific DNA sequences to regulate the expression of target genes. Three isotypes of PPAR agonists may be identified: PPAR-α, PPAR-γ, and PPAR-β/δ agonists. PPAR-α agonists act on hepatocytes, reduce inflammation, regulate lipid and bile acid metabolism, and reduce liver fibrosis in rat models. PPAR-γ agonists act on Kupfer cells, reduce inflammation and liver fibrosis, but may increase fat accumulation. PPAR-β/δ agonists act on hepatocytes, Kupfer cells, hepatic stellate cells, and cholangiocytes; reduce inflammation and fat accumulation; and protect against carcinogenesis. Table 2 describes PPAR agonists used in the treatment of PBC.

Table 2 Overview of peroxisome proliferator-activated receptor agonists used in the treatment of primary biliary cholangitis.

Name of PPAR agonist	Fibrate/non-fibrate	Isotypes of PPAR	Status of regulatory approval	Clinical results
Elafibranor	Non-fibrate	PPAR-α and PPAR-β/δ	Approved	Improvement of cholestasis
				Biochemical response and ALP normalization
				Reduction of pruritus
				Improvement of fatigue and sleep disturbance
Seladelpar	Non-fibrate	PPAR-β/δ	Approved	Improvement of cholestasis
				Biochemical response
				ALP normalization
				Reduction of pruritus
				Improvement of fatigue and sleep disturbance
Saroglitazar	Non-fibrate	PPAR-α and PPAR-γ	Phase 3 study complete	Improvement of cholestasis
				Biochemical response and ALP decrease
Bezafibrate	Fibrate	PPAR-α, PPAR-γ and PPAR-β/δ	Off-label	Improvement of cholestasis
				Biochemical response and ALP normalization
				Reduction of pruritus
Fenofibrate	Fibrate	PPAR-α	Off-label	Improvement of cholestasis
				Biochemical response and ALP normalization
				Reduction of pruritus

ALP: Alkaline phosphatase; PPAR: Peroxisome proliferator-activated receptor.

Nonfibrate PPAR agonists in second-line treatment of PBC

Elafibranor is a pan-PPAR agonist. It led to an ~50% decrease in ALP after 12 weeks of treatment at a dose of 80 or 120 mg/day in a Phase 2 clinical study. The therapy was well tolerated[45]. Elafibranor at a dose of 80 mg daily was added to UDCA in nonresponders to UDCA treatment in the Phase 3 clinical trial ELATIVE. This was a randomized, double-blind, placebo-controlled trial where the primary outcome was defined as follows: ALP < 1.67 × ULN, with a decrease of ≥ 15% from baseline; and a normal total bilirubin level, assessed after 52 weeks of treatment. Primary endpoint was reached in 51% of patients treated with elafibranor and in 4% of patients in the placebo arm (P < 0.001). ALP normalization was present in 15% of patients in the elafibranor group and in any patient from the placebo group (P = 0.002). The intensity of pruritus in patients with baseline moderate-to-severe pruritus was comparable in both groups at the end of treatment[46]. Interim results from the open label extension up to 3 years showed sustained biochemical response in elafibranor-treated PBC patients. The intensity of pruritus was reduced in patients who were switched from placebo to elafibranor after 52 weeks of follow-up. Long-term treatment with elafibranor led to further significant improvement in fatigue and sleep disorders in patients with baseline moderate to severe fatigue or excessive sleepiness[47].

Seladelpar is a PPAR-β/δ agonist that has demonstrated clinical efficacy in UDCA nonresponders in a Phase 2 clinical trial[48]. The registration Phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial also included nonresponders to UDCA. Seladelpar was added to UDCA treatment at a dose of 10 mg daily. The primary objective was to achieve a biochemical response after 12 months of treatment. The biochemical response was defined in the same way as in the ELATIVE trial with elafibranor. Secondary objectives were normalization of ALP after 12 months of treatment and improvement in itching intensity. The primary outcome was achieved by 61.1% of patients treated with seladelpar and in 20% of patients in the placebo group (P < 0.001). ALP normalization was achieved by a quarter of patients in the seladelpar group, but by none of the patients in the placebo group (P < 0.001). Treatment with seladelpar led to a significant reduction in pruritus intensity[49]. The effect of seladelpar in second-line treatment of PBC lasts a long time[50]. After 30 months of treatment, 81% of patients treated with seladelpar achieved a biochemical response and 41% of patients achieved normalization of ALP[51]. Real-world clinical experience confirmed the efficacy of seladelpar as a second-line treatment for PBC. More than half of the patients achieved a biochemical response, and nearly one-third of the patients had normalized ALP levels after just 1 month of treatment with seladelpar[52].

A beneficial effect of seladelpar treatment is a reduction in pruritus intensity, which was associated with a decrease in IL-31 and serum bile acid levels[53]. Seladelpar treatment for PBC led to a reduction in pruritus intensity, and to improved sleep. No patient treated with seladelpar developed de novo pruritus[54]. Seladelpar also reduces fatigue in PBC patients[54,55].

Elafibranor and seladelpar were approved by the Food and Drug Administration and European Medicines Agency (EMA) for second-line PBC treatment.

Saroglitazar is a dual PPAR agonist (α and γ). It is approved for treatment of metabolic dysfunction-associated steatotic liver disease and noncirrhotic metabolic dysfunction-associated steatohepatitis in India. The cost of the drug is relatively low[56]. Saroglitazar was evaluated for second-line treatment of PBC in a Phase 2 clinical trial. Treatment with saroglitazar at a dose of 2 or 4 mg led to a rapid decrease in ALP after 4 weeks of treatment and persisted at the end of the study after 16 weeks of treatment. In four of 17 patients, treatment was discontinued prematurely due to aminotransferase elevation, which promptly resolved after discontinuation of treatment[57].

Fibrates in the second-line treatment of PBC

Fibrates are a group of drugs developed for the treatment of dyslipidemia. They have a strong agonistic effect on PPAR-α, leading to a significant reduction in serum TG levels and a slight increase in HDL-C. This is associated with the cardioprotective effect of fibrates. Creatinine increase is the most common adverse effect of fibrate treatment, occurring mainly in diabetics, elderly patients, men, and patients with cardiovascular disease[58]. Fibrates, like statins, have many pleiotropic effects. One of the most important is the reduction of cholestasis, hepatic inflammation, and fibrosis[8].

Corpechot et al[59] conducted the double-blind, placebo-controlled, randomized BEZURSO trial comparing combination therapy with UDCA + bezafibrate at a dose of 400 mg daily vs UDCA + placebo in PBC nonresponders to first-line UDCA treatment. The duration of the study was 24 months. The primary outcome was a complete biochemical response (CBR), which was defined as normal levels of total bilirubin, ALP, aminotransferases, and albumin, as well as a normal prothrombin time at the end of follow-up. The primary outcome was achieved in 31% of patients in the bezafibrate vs 0% patients in the placebo group (P < 0.001). ALP normalization at the end of treatment was observed in 67% of patients treated with bezafibrate vs 2% of patients in the placebo group. Creatinine level increase and myalgia were the most common adverse effects during treatment with bezafibrate[59].

A meta-analysis comparing combined treatment with UDCA + bezafibrate with UDCA alone, which included the BEZURSO trial and several Japanese studies, was recently published[59-65]. Combined treatment with UDCA and bezafibrate significantly reduced ALP and-glutamyl transferase (GGT) levels, but not total bilirubin and IgM, compared with UDCA monotherapy. Insufficient data were available to assess mortality[60]. Data from the Japanese National PBC Database showed that long-term combination therapy with UDCA + bezafibrate reduces all-cause and liver-related mortality approximately threefold compared to UDCA monotherapy[66].

Nonresponse to combined treatment with UDCA and bezafibrate in PBC patients is associated with a higher incidence of decompensation of liver cirrhosis[67].

Bezafibrate is not available in some countries; a possible alternative is the use of fenofibrate in second-line treatment of PBC when bezafibrate is not available. A low dose of fenofibrate (80 mg daily) was comparably effective in treating PBC in one small study compared to bezafibrate at a dose of 200 mg daily[68]. Chinese authors compared combination therapy with UDCA and fenofibrate vs UDCA monotherapy. Patients receiving combination therapy achieved normalization of ALP and a CBR; defined as normalization of ALP, GGT, and bilirubin, after 1 year of treatment significantly more often compared to PBC patients treated with UDCA monotherapy[69].

A meta-analysis showed that combined treatment with UDCA + fibrate improves laboratory findings and pruritus compared to UDCA monotherapy. Combined treatment does not result in more frequent adverse effects[70]. Despite the beneficial effect of fibrates on biochemical findings in PBC patients and on mortality data in multiple studies, fibrates have not yet been approved for the treatment of PBC and their use remains off-label.

Obeticholic acid in the second-line treatment of PBC

Obeticholic acid (OCA) is semisynthetic derivate of chenodeoxycholic acid (6α-ethyl-chenodeoxycholic acid), it acts as an agonist of the farnesoid X receptor (FXR). OCA regulates impaired enterohepatic circulation and bile acid composition through FXR activation[71]. OCA activates sinusoidal endothelial cells in the liver and Kupffer cells, leading to an anti-inflammatory effect and, through reduced stellate cell activity, also to an antifibrotic effect[71,72]. OCA modulates fibroblast growth factor (FGF)-19, which is associated with hepatoprotective and anticholestatic effects[73].

PBC nonresponders to UDCA were enrolled in the POISE Phase 3 registration study. One group was treated with a combination of OCA at a dose of 5-10 mg daily + UDCA, while the control group received UDCA + placebo. The primary outcome was the same as in the ELATIVE study mentioned above and was achieved by almost half of the patients treated with OCA + UDCA and only by 10% of patients in the placebo control group (P < 0.001). The most serious adverse effect of OCA treatment was pruritus. Patients treated with OCA suffered from pruritus more frequently, with pruritus being more common at a dose of 10 mg/day than at 5 mg/day[74]. The biochemical response to OCA treatment persisted after 4 years of treatment, but paired biopsies showed improvement in fibrosis stage in approximately one quarter of patients and worsening in approximately another quarter of patients, with no change in fibrosis stage after 3 years in half of the treated patients[75,76].

Three randomized placebo-controlled studies were included in a meta-analysis[74,77,78] documenting the superiority of combined OCA + UDCA treatment compared to UDCA and placebo in achieving therapeutic response. Combined treatment led to partial correction of dyslipidemia[79].

Data from real-world clinical practice using OCA as second-line treatment for PBC showed poorer results, especially in patients with compensated liver cirrhosis, and confirmed the frequent occurrence of pruritus in treated patients[80-83].

OCA is contraindicated in advanced cirrhosis because it increases the risk of decompensation of liver cirrhosis and liver-related mortality[2,84].

COBALT, a double-blind, randomized, Phase 3b/4 clinical trial compared UDCA nonresponders who were treated with OCA and placebo. The primary composite endpoint was time to death, liver transplant, model for end-stage liver disease score ≥ 15, uncontrolled ascites, or hospitalization for hepatic decompensation. The study did not demonstrate a difference in the achievement of the primary endpoint between the two groups of PBC patients. Among PBC patients in the COBALT trial treated with OCA, the primary endpoint occurred less frequently compared to the external control arm from the Komodo Healthcare Map database: PBC patients who did not respond to UDCA treatment and were not treated with OCA (HR = 0.39; 95%CI: 0.22-0.69; P = 0.001)[85]. However, a limitation of the COBALT trial was its short duration and small number of enrolled patients (< 170 in each trial arm). Another significant limitation of the study was the advanced stage of the disease at the time of enrollment in the OCA arm. The original inclusion criteria were mean ALP > 5 × ULN and mean total bilirubin > ULN and ≤ 3 × ULN. Subsequently, these criteria were revised to ALP > 3 × ULN and mean total bilirubin > ULN and ≤ 5 × ULN. All patients treated with OCA in the COBALT trial had elevated baseline bilirubin levels, which are associated with a poorer biochemical response to OCA treatment[86]. The HEROES trial used real clinical data from the Komodo Healthcare Map and demonstrated superiority of the OCA treatment compared to non-OCA treatment. OCA treatment reduced the risk of hospitalization for hepatic decompensation, liver transplantation, or death by 63% compared to untreated patients[87].

OCA is not currently a routine second-line option, as the adverse effects of treatment may outweigh its benefits, especially in patients with advanced PBC. Based on the results of the COBALT trial, EMA revoked the conditional marketing authorization for OCA. The European Union General Court upheld the revocation of the conditional authorization of OCA on November 26, 2024. OCA is currently officially listed in the Union-register of nonactive medicinal products. OCA was officially withdrawn from the US market on November 14, 2025. OCA remains licensed and available in many other regions, including Canada (conditional notice of compliance was granted by Health Canada on May 25, 2017) and the UK (conditional marketing authorization was recommended by National Institute for Health and Care Excellence on March 2, 2017). Second-line treatment for PBC should begin with PPAR agonists in these countries as well.

Budesonide in second-line treatment of PBC

Budesonide is a combined glucocorticoid receptor and pregnane X receptor agonist with higher affinity for the glucocorticoid receptor compared to prednisolone[88]. PBC nonresponders to UDCA with liver inflammatory activity confirmed by liver biopsy treated with budesonide achieved biochemical response more frequently than nonresponders treated with placebo[89]. Combined treatment with UDCA + budesonide is recommended in first line for patients with PBC/AIH overlap based on the results of a meta-analysis published by Chinese researchers[90]. The initial dose of budesonide for PBC/AIH overlap syndrome is 9 mg daily (divided into three doses) in combination with UDCA and azathioprine. Once biochemical remission is achieved, the dose may be reduced to 3 mg over a period of 6 months. In cases of long-term remission, budesonide may be withdrawn while continuing treatment with UDCA and azathioprine; however, this approach will need to be confirmed in clinical studies[91].

Novel molecules in second-line treatment of PBC

Several molecules are being studied as second-line treatment for PBC: Nonsteroidal FXR agonists, nor-UDCA, fibroblast growth factor 19 (FGF-19) modulators, and dual nicotinamide adenine dinucleotide phosphate oxidase 1/4 (NOX 1/4) inhibitors. Tropifexor and cilofexor are nonsteroidal FXR agonists, which improve cholestasis in the second-line PBC treatment. Common adverse effects that limit the potential use of both molecules are pruritus and atherogenic dyslipidemia, which are dose dependent. TQA3526 and ASC42 are other promising molecules for the treatment of PBC from this group[92]. Nor-UDCA is a side-chain-shortened derivative of UDCA; it has anti-inflammatory, anti-cholestatic, and anti-fibrotic properties[93]. FGF-19 analogs decrease toxic bile acids production and have anti-inflammatory, anticholestatic and antifibrotic properties without pruritogenic effect[94].

Setanaxib is a dual NOX 1/4 inhibitor that improves cholestasis and alleviates fatigue in patients with PBC[95]. Patients treated with setanaxib experienced an improvement in quality of life compared with those receiving placebo[96].

An overview of drugs in clinical trials for PBC is summarized in Table 3. Phase 3 clinical trials are required for these drugs to be incorporated into clinical practice.

Table 3 Overview of drugs in clinical trials for primary biliary cholangitis.

Drug name	Drug class	Therapeutic indication	Study phase
Tropifexor	FXR agonist	PBC	Phase 2 complete
Cilofexor	FXR agonist	PBC	Phase 2 complete
TQA3526	FXR agonist	PBC	Phase 3 ongoing
ASC42	FXR agonist	PBC	Phase 2 closed prematurely
Nor-UDCA	UDCA homolog	PBC	Phase 2 ongoing
Aldafermin	FGF-19 analogue	PBC	Phase 2 complete
Setanaxib	NOX 1/4 inhibitor	PBC	Phase 2b complete
Linerixibat	IBAT inhibitor	Pruritus in PBC	Phase 3 complete; FDA approved for pruritus in PBC
Maralixibat	IBAT inhibitor	Pruritus in PBC	Phase 2 complete
Volixibat	IBAT inhibitor	Pruritus in PBC	Phase 2b ongoing

FDA: Food and drug administration; FGF: Fibroblast growth factor; FXR: Farnesoid X receptor; IBAT: Ileal bile acid transporter; NOX1/4: Dual nicotinamide adenine dinucleotide phosphate oxidase 1/4; PBC: Primary biliary cholangitis; UDCA: Ursodeoxycholic acid.

Personalized second-line treatment for PBC

Elafibranor and seladelpar are approved second-line options for selected patients with an inadequate response or intolerance to UDCA. Their approval is based primarily on biochemical endpoints; therefore, long-term data on clinical outcomes remain important.

Indirect comparisons suggest potential differences between agents. Elafibranor seems to be more effective in achieving a biochemical response, while seladelpar shows particularly consistent antipruritic effects; however, there is a lack of head-to-head comparative studies[97]. Data from real-world clinical practice in the future will need to be analyzed to confirm these preliminary findings. Cost-effectiveness, drug tolerance, and adverse effects will play a crucial role in the selection of a nonfibrate PPAR agonist for second-line treatment of PBC.

Fibrates are used as an off-label treatment, but may be indicated as a second-line therapy in low-income countries; countries where elafibranor or seladelpar are not available; and countries where the cost of these drugs is not reimbursed. Bezafibrate is the preferred fibrate PPAR agonist; if it is unavailable, fenofibrate or ciprofibrate may be administered as second-line treatment for PBC[43]. It should be noted that although fibrates have an anticholestatic and likely also an antipruritic effect, this is an off-label treatment with potential adverse effects - most commonly renal insufficiency and myalgia.

The question of how to manage PBC patients who do not achieve a therapeutic response to second-line treatment with PPAR agonists remains unanswered. A combination of UDCA, OCA, and PPAR agonists appears promising. Treatment with UDCA-OCA-fibrate led to normalization of ALP levels in 30% of nonresponders to first-line UDCA therapy after 6 months. The treatment was also effective in older patients. Triple therapy alleviated pruritus in 65% of patients, was associated with worsening of the pruritus in 12% of patients, and the remaining patients reported no change in the intensity of pruritus[98]. Another multicenter study evaluated the combination therapy of OCA and fibrates in nonresponders to second-line PBC treatment. In PBC patients with failure of second-line OCA therapy, addition of a fibrate (bezafibrate or fenofibrate) led to a significant decrease in ALP. In contrast, addition of OCA in nonresponders to fibrates did not significantly affect ALP levels. The results of this study may significantly limit the future use of OCA in patients who do not respond to UDCA and fibrate[99]. Recent observations suggest that seladelpar may improve cholestasis and pruritus in OCA or fibrate-experienced PBC patients[100].

Disease stage, PBC complications, comorbidities, and potential drug-drug interactions also play a role in the selection of second-line PBC treatment. OCA and nonfibrate PPAR agonists are contraindicated in decompensated liver cirrhosis[2,84,101]. Although there have been reports about the benefits of using fibrates in decompensated cirrhosis in PBC patients, no studies on the efficacy and safety of fibrates for this indication are available[102,103]. Nephrotoxicity is a serious adverse effect of fibrates and may limit their use in patients with advanced liver cirrhosis[59,102]. PBC patients with decompensated cirrhosis should be placed on the waiting list for liver transplantation. Prophylactic administration of UDCA following liver transplantation for PBC reduces the risk of recurrence of PBC and improves the prognosis of transplant recipients[104,105].

Although head-to-head comparisons of the antipruritic effects of PPAR agonists are lacking, available clinical data have described a strong antipruritic effect of seladelpar[97]. Ileal bile acid transporter (IBAT) inhibitors prevent reabsorption of bile acids from the intestine and decrease bile acid enterohepatic circulation. Linerixibat and maralixibat show promising antipruritic effects[106,107]. Treatment with linerixibat was associated with an improvement in pruritus without worsening of ALP levels in the randomized, multicenter, double-blind, placebo-controlled Phase 3 GLISTEIN trial. Nearly two-thirds of patients treated with linerixibat experienced gastrointestinal adverse effects, primarily diarrhea and abdominal pain, and 7% of patients discontinued treatment early due to adverse effects[108]. The discovery of a potent antipruritic effect in nonfibrate PPAR agonists and IBAT inhibitors will reduce the future use of currently prescribed pruritus-relieving medications (cholestyramine, rifampicin, naltrexone, and sertraline)[7].

Fibrates are used not only to treat PBC, but also to treat atherogenic dyslipidemia, which is often associated with PBC[7,109]. The use of statins in PBC has a protective effect on the prevalence of hepatic decompensation[110]. Statins have a low incidence of drug-induced liver injury and are safe for patients with PBC[110,111]. Treatment of osteoporosis in PBC is the same as in patients without PBC, and bisphosphonates are the drugs of choice[1].

UDCA is a safe medication during pregnancy, and the clinical course of PBC stabilizes or even improves during pregnancy[112]. Fibrates, elafibranor, and seladelpar are not generally recommended during pregnancy because of insufficient safety data[113-116].

Clinical aspects of second-line treatment for PBC patients

Treatment with PPAR agonists leads to an improvement in biochemical parameters: A decrease or even normalization of ALP and normalization of bilirubin; therefore, the evidence for newer drugs is currently based on surrogate endpoints. To date, there is no objective evidence linking treatment with PPAR agonists to improvements in histological findings, a reduction in the incidence of decompensated liver cirrhosis, and a decrease in liver-related mortality. To definitively assess the clinical efficacy of these drugs, long-term clinical trials will be needed that focus on laboratory parameters but primarily on the clinical endpoints mentioned above.

Patients receiving second-line treatment for PBC must be carefully monitored before and during treatment. Liver biochemistry bilirubin, total protein, albumin, renal parameters, creatine kinase, lipoprotein metabolism parameters, and blood count should be monitored regularly. The therapeutic response is evaluated every 6 months. An elastography examination should be performed once a year; an abdominal ultrasound should be performed every six months in patients with compensated cirrhosis; and a densitometry examination should be performed once every 2 years. It is important to actively look for clinical manifestations of the disease, such as pruritus and fatigue, as well as for treatment-related complications, such as myalgia. Decompensated cirrhosis should prompt transplant evaluation and specialist management rather than routine pharmacological escalation.

When should second-line PBC treatment be indicated?

Approximately one-third of PBC patients treated with UDCA achieve a CBR with normalization of ALP and bilirubin. Although another third of treated patients do not achieve a CBR, they do achieve a biochemical response according to the Toronto criteria, which can be described as an incomplete UDCA response[15]. Nonresponders to UDCA, according to the Toronto criteria, have poorer transplant-free survival compared to UDCA responders[117]. A loss of biochemical response at any time during UDCA treatment is associated with a poorer prognosis in PBC patients[42].

Second-line treatment for PBC is typically initiated in patients who have not responded to UDCA therapy after 12 months or in patients who did not tolerate UDCA therapy. However, in some UDCA nonresponders, the underlying disease may worsen over the course of a year. The risk of PBC progression is particularly high among young women; males; patients with positive anti-sp100 and anti-gp 210 antibodies; patients with overlap syndrome involving AIH or PSC; patients with high baseline ALP level; patients with ductopenic form of PBC; and patients with advanced fibrosis or even liver cirrhosis at the time of diagnosis.

Nonresponse to UDCA treatment can be predicted based on baseline parameters - the UDCA response score[27,118] or detected after a short course of treatment using the Xi’an score[25]; these patients are candidates for early second-line therapy. Determining the biochemical response to UDCA according to the modified Toronto criteria is the optimal approach at an earlier time frame for the assessment of the effectiveness of first-line treatment. UDCA nonresponders after 6 months of treatment have approximately a 12-fold increased risk of developing decompensated liver cirrhosis in the future[4]. UDCA nonresponders after 6 months of treatment have a minimal chance of achieving CBR[119], which is associated with the best prognosis[17]. Assessing the therapeutic response to UDCA treatment after 6 months may be the optimal time frame.

The indication for second-line treatment in cases of incomplete biochemical response remains unclear. On the one hand, these patients have a better chance of achieving a CBR, which may slightly improve their prognosis; on the other hand, there is a risk of treatment-related adverse effects, and the cost of treatment and monitoring is also significant. Second-line therapy for incomplete UDCA responders should be considered primarily in high-risk patients, as described above. PBC patients with fibrosis progression exceeding 2.1 kPa/year on repeated vibration-controlled transient elastography[35] and an incomplete UDCA response may also be considered for second-line treatment.

The consideration of the indication for second-line PBC treatment and its timing is summarized in Figure 1.

Figure 1 Considerations of the indication for second-line primary biliary cholangitis treatment and its timing. Elafibranor and seladelpar are approved drugs for second-line primary biliary cholangitis treatment. Fibrates should be considered in countries where approved agents are unavailable or not reimbursed. UDCA: Ursodeoxycholic acid.

CONCLUSION

PPAR agonists are approved for second-line treatment of PBC. The results of Phase 3 clinical trials are promising, but long-term clinical outcome data and real-world validation remain necessary. If these drugs are unavailable, replacing elafibranor or seladelpar with bezafibrate or other fibrates may be considered; however, this therapeutic option is off-label. No second-line treatment is available for PBC patients with decompensated cirrhosis or for pregnant patients. Second-line PBC treatment should be personalized, considering not only the benefits of treatment but also its side effects[120].