Research Communication: Real-World Clinical Experience With Seladelpar in Primary Biliary Cholangitis.

New treatments/targets for primary biliary cholangitis.

Treatment for primary biliary cholangitis (PBC) was defined by its singular relationship with ursodeoxycholic acid (UDCA) for decades. However, nearly 40% of patients fail to achieve adequate biochemical response with UDCA, necessitating second-line therapies. The aim of our review was to assess the efficacy and safety of second-line therapies for PBC from phase three trials. We conducted a systematic review of PubMed, Medline, and ClinicalTrials.gov for published phase three trial data of second-line PBC therapies. Four phase three clinical trial evaluating obeticholic acid, bezafibrate, seladelpar, and elafibranor, were identified. All trials but one defined the treatment endpoints of an alkaline phosphatase (ALP) less than 1.67 times the upper limit of normal (ULN), a 15% decrease of ALP from baseline, and normal total bilirubin (TB) after 12months. All therapies demonstrated statistically significant achievement of primary endpoints relative to placebo. Reduction in ALP from baseline ranged from 113 to 133.9 U/L (-34.6% to -50%) across all trials. Primary endpoint treatment differences relative to placebo ranged between 31 and 47%. ALP normalization rates were described for three treatments and varied between 15 and 67% in treatment cohorts,compared to 0% to 2% of placebo cohorts. Only elafibranor and seladelpar demonstrated significant reduction in total 5D itch scale scores. Discontinuation rates across studies ranged from 1 to 14% due to adverse effects. All reviewed therapies met their respective study endpoints. Effective second-line therapies area available and continue to receive long-term evaluation in patients with PBC.

Primary biliary cholangitis is a chronic inflammatory, autoimmune cholestatic liver disease, which untreated will usually progress to end-stage biliary cirrhosis. The aims of treatment and management of primary biliary cholangitis are the amelioration of associated symptoms, particularly pruritis and fatigue, and the prevention of end-stage liver disease. The presentation, natural history and clinical course are variable. Recent published European and UK clinical guidelines have emphasized the need for risk stratification and an individualized approach to patient management in primary biliary cholangitis. The bile acid, ursodeoxycholic acid, is established as the first-line treatment of primary biliary cholangitis. Assessment of clinical response to treatment is based on specified improvements in serum liver tests including near normalization of the serum alkaline phosphatase level at 1 year. At least two thirds of patients with primary biliary cholangitis should respond to ursodeoxycholic acid after 1 year's treatment. The correct dosage of ursodeoxycholic acid is determined by body weight viz 13-15 mg/kg/day. A significant number of patients with primary biliary cholangitis in the UK are being underdosed. Over a third of ursodeoxycholic acid partial responders become responders within 2 years after increasing the ursodeoxycholic acid doses to recommended levels. While transplant rates for primary biliary cholangitis have halved over the last 20 years, it is clear that optimizing the dose of ursodeoxycholic acid in partial responders would further decrease morbidity, mortality and the need for liver transplantation.

To review the published data including the pharmacology, efficacy, and safety of seladelpar, a peroxisome proliferator-activated receptor delta (PPARδ) agonist leading to the Food and Drug Administration (FDA) accelerated approval for the treatment of primary biliary cholangitis (PBC). A PubMed (January 1, 1985 to January 27, 2025) literature search was performed using the terms seladelpar, MBX-8025, peroxisome proliferator-activated receptor agonist, and PBC. Other data sources included Google Scholar and the National Institutes of Health Clinical Trials Registry. All English-language literature evaluating the pharmacology, pharmacokinetics, safety, and efficacy of seladelpar in the treatment of PBC was reviewed. Seladelpar is the first PPARδ agonist in the treatment of PBC that has shown a significant reduction across biochemical response, alkaline phosphatase (ALP) normalization, and pruritus as compared to placebo while demonstrating safety and tolerability.Relevance to patient care and clinical practice in comparison to existing drugs:While existing drug treatments for PBC are efficacious, there remains an unmet need due to an incomplete biochemical response in many patients. Patients frequently suffer from symptoms, including pruritus, impacting their quality of life. Seladelpar could have a beneficial role in PBC as add-on therapy in improving biochemical response as well as alleviating pruritus. Seladelpar is a safe and effective treatment for PBC and fills a significant unmet need. Seladelpar's clinical benefit predicted by improvement in surrogate endpoints may need confirmation for traditional FDA approval.

IntroductionObeticholic acid (OCA) is a licensed second-line therapy approved for use by NHS England for patients with primary biliary cholangitis (PBC) that have inadequate response or intolerance to ursodeoxycholic acid....

Introduction National guidelines on the management of primary biliary cholangitis (PBC) were published by the BSG and UKPBC in 2018.1 We examined a database of all patients who had undergone anti-mitochondrial antibody (AMA) testing over a five year period in a single centre (a district general hospital serving a population of 220,000), to examine adequacy of PBC diagnosis, ursodeoxycholic acid (UDCA) dosing, biochemical response, and referral for second line therapy in cases of UDCA intolerance or failure, using the thresholds and recommendations set out in the BSG UKPBC 2018 guidelines. Methods A laboratory database search was carried out to capture all AMA test results from 01 April 2014–31 March 2019. Laboratory records for all patients with a positive AMA at any titre were cross referenced, and a registry created of all patients with positive AMA and biochemical evidence of cholestasis (elevated alkaline phosphatase (ALP) above the upper limit of normal), or a pre-existing diagnosis of PBC regardless of ALP. Medical records were examined of all patients on this registry to establish history of diagnosis of PBC, treatment history, dosing of UDCA in mg/kg, adequacy of response to UDCA, and referral for second line therapy with obeticholic acid (OCA) where relevant. Results 20783 AMA tests were carried out with positive results for AMA at any titre recorded in 155 individual patients; 45 had evidence of cholestasis at the time of index AMA testing, 23 of whom had been diagnosed with PBC by the end of the study period. A further 6 AMA positive patients had an existing diagnosis of PBC with normalised ALP on treatment, giving a total PBC population of 29 patients. 25/29 (86%) of PBC patients were treated with UDCA, which was adequately dosed in 23/25 (92%). 15/19 (79%) of patients who had completed at least one year of adequately dosed UDCA responded adequately (ALP Conclusions AMA testing was commonly carried out in a district general hospital setting, but the cohort of PBC patients identified was small. In those diagnosed with PBC, UDCA dosing was done well overall, but more than 20% of patients did not respond adequately or could not tolerate UDCA. Even in a small PBC cohort such as this, there are likely to be patients who may benefit from second line therapy with OCA. Such cases can be identified through simple audit of UDCA dosing and biochemical response. Reference Hirschfield G et al. The British Society of Gastroenterology/UKPBC primary biliary cholangitis treatment and management guidelines. Gut 2018;0:1–27

Introduction Primary biliary cholangitis (PBC) is a progressive inflammatory autoimmune cholestatic liver disease. Without treatment, it may result in fibrosis and eventually end stage liver disease. In addition to the disease burden, the symptom impact on the quality of life for PBC patients is significant. Ursodeoxycholic acid, and the second-line therapy, Obeticholic acid, are the only available licensed treatments. Although there has been rapid development of novel therapies in recent years for the treatment of PBC, there are very few symptoms directed therapies. Area covered This literature review aims to review the current treatment landscape in PBC and to explore how the next few years may unfold in the field. The current guidelines and emerging therapies in phase 2, 3 and 4 clinical trials have been included. Expert opinion The currently available therapies are effective, but their use has limitations and challenges and there is still significant unmet need. Although there have been promising therapeutic interventions in recent years, further research into personalizing therapeutic strategies with available treatments and new agents is needed.

Background:Glioblastoma (GB) treatment remains challenging because of recurrence and poorly defined treatment options after first-line therapy. To better understand real-world application of treatment paradigms and their impact on outcomes, we describe patterns of treatment, outcomes, and use of cancer-related healthcare resource for glioblastoma in the USA.Methods:A retrospective, online chart-abstraction study was conducted; each participating oncologist contributed ≤5 charts. Patients were ≥18 years with biopsy-confirmed primary or secondary newly diagnosed GB on or after 1 January 2010, had received first- and second-line therapies, and had information collected for ≥3 months after initiation of second-line therapy or until death. Assessments were descriptive and included Kaplan– Meier analyses from initiation to end of second-line therapy, disease progression, or death.Results:One hundred sixty physicians contributed information on 503 patient charts. During first-line therapy, patients most commonly underwent temozolomide monotherapy (76.5%). During second-line therapy, patients most commonly underwent bevacizumab monotherapy (58.1%). Median duration of second-line therapy was 130 days; median time to disease progression was 113 days. Median survival was 153 days. Use of supportive care was observed to be numerically higher in first- compared with second-line therapy except for anti-depressants, growth factors, and stimulants. Frequently used resources included corticosteroids (78.8% of patients in first-line and 62.6% in second-line therapies), anti-epileptics (45.8% and 41.5%) and narcotic opioids (45.3% and 41.4%).Conclusions:Most GB patients received temozolomide during first-line therapy and bevacizumab monotherapy or combination therapy during second-line therapy. Use of supportive care appeared to be higher in first- compared with second-line therapy for some agents.

Primary biliary cholangitis (PBC) is an enigmatic, autoimmune disease targeting the small intralobular bile ducts resulting in cholestasis and potentially progression to biliary cirrhosis. Primarily affecting middle-aged women, the diagnosis of PBC is typically straightforward, with most patients presenting with cholestatic liver tests and the highly specific antimitochondrial antibody. For decades, the foundational treatment of PBC has been ursodeoxycholic acid, which delays disease progression in most patients but has no impact on PBC symptoms. Large cohort studies of patients with PBC have established the benefit of maximizing the reduction in serum alkaline phosphatase levels with ursodeoxycholic acid and the need to add second-line agents in patients who do not achieve an adequate response. Advances in the understanding of bile acid physiology have led to the development of new agents that improve cholestasis in patients with PBC and are predicted to reduce the risk of disease progression. Obeticholic acid, the first second-line therapy to be approved for PBC, significantly improves liver biochemistries and has been associated with improved long-term clinical outcomes but is limited by its propensity to induce pruritus. Elafibranor and seladelpar are peroxisome proliferator-activated receptor agonists recently approved for use in patients with PBC, whereas bezafibrate and fenofibrate are available as off-label therapies. They also have shown biochemical improvements among patients with an inadequate response to ursodeoxycholic acid but may improve symptoms of pruritus. Herein, we review the patient features to consider when deciding whether a second-line agent is indicated and which agent to consider for a truly personalized approach to PBC patient care.

Primary biliary cholangitis (PBC) is a rare immune-mediated chronic cholestatic liver disease that can progress to liver fibrosis and, ultimately, cirrhosis if left untreated. Since the pathogenesis of PBC is not well understood, curative therapies have yet to be established. Ursodeoxycholic acid (UDCA), the standard of care treatment for PBC, has been proven to reduce disease progression and improve transplant-free survival. However, one third of patients have no response or partial biochemical response to UDCA and are at increased risk for disease progression. In such cases, second-line therapy with obeticholic acid (OCA) or peroxisomes proliferator-activated receptors (PPARs) should be considered in conjunction with UDCA. In this review article, we aim to provide an overview of the most recent data on PBC treatment in patients with inadequate response to UDCA, as well as novel therapies in the early stages of development.

Fibrates, which are agonists of peroxisome proliferator-activated receptor alpha, have received increasing attention in the treatment of primary biliary cholangitis. Reduced alkaline phosphatase levels and improved clinical outcomes were observed in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid (UDCA) monotherapy4 when treated with bezafibrate or fenofibrate combined with UDCA. In contrast to obeticholic acid, which exacerbates pruritus in patients, fibrates have been shown to relieve pruritus. Clinical trial outcomes show potential for the treatment of primary biliary cholangitis by targeting peroxisome proliferator-activated receptors. It is currently agreed that primary biliary cholangitis is an autoimmune-mediated cholestatic liver disease, and peroxisome proliferator-activated receptor is a nuclear receptor that regulates the functions of multiple immune cells, thus playing an important role in regulating innate and adaptive immunity. Therefore, this review focuses on the immune disorder of primary biliary cholangitis and summarizes the regulation of hepatic immunity when peroxisome proliferator-activated receptors are targeted for treating primary biliary cholangitis.

Peroxisome proliferator-activated receptor (PPAR) agonists are recognised as a promising treatment for primary biliary cholangitis (PBC). However, the effects and safety of these agonists on PBC remain unexplored. Our study aimed to investigate the efficacy and safety of PPAR agonists in treating PBC. We searched Cochrane Library, and Web of Science, PubMed, and Embase databases from inception to 15 March 2024 for randomised controlled studies (RCTs) that enrolled individuals with PBC treated with PPAR agonists compared with placebo. The primary outcomes were biochemical response and normalization of the alkaline phosphatase (ALP) level. Eight RCTs involving 869 participants in total were included. The meta-analysis revealed that compared to placebo, PPAR agonists increased the rate of biochemical response (RR: 5.53; 95% CI: 3.79, 8.06) and normalization of the ALP level (RR: 17.18; 95% CI: 5.61, 52.61). In addition, PPAR agonists can also reduce alanine aminotransferase (ALT) (MD: -12.69 U/L; 95% CI: -18.03, -7.35), aspartate aminotransferase (AST) (MD: -4.18 U/L; 95% CI: -7.28, -1.08), ALP (MD: -142.95 U/L; 95% CI: -167.29, -118.60), γ-glutamyltransferase (GGT) (MD: -63.03 U/L; 95% CI: -92.08, -33.98), and total cholesterol (TC) levels (SMD: -0.71; 95% CI: -1.38, -0.04), and there was no significant difference in overall adverse reactions (RR: 0.99; 95% CI: 0.92, 1.05), serious adverse reactions (RR: 1.10; 95% CI: 0.70, 1.72) between the two groups. PPAR agonists are safe and well-tolerated in patients with PBC and are effective in improving the rate of biochemical response and related biomarkers.

Introduction In primary biliary cholangitis (PBC), approximately 40% of the patients respond incompletely to first-line treatment with ursodeoxycholic acid (UDCA), resulting in a poorer prognosis. Although obeticholic acid (OCA) is approved as a second-line therapy, it is not well-tolerated by patients with significant itching or advanced cirrhosis. Peroxisome proliferator-activated receptor (PPAR) agonists, including fibrates traditionally known as antihyperlipidemic agents, have emerged as potent alternatives for treating PBC patients with an incomplete response to UDCA. Areas covered This article provides a detailed overview of the mechanisms of PPAR agonists and evaluates their efficacy and adverse events, focusing on findings from recent phase III clinical trials. Expert opinion PPAR agonists are significant alternatives in the treatment of PBC, showing the potential to enhance biochemical responses, reduce mortality, and alleviate pruritus. Long-term outcomes for PBC patients, particularly those with advanced disease, and longitudinal data on the antipruritic effects of PPAR agonists require further investigation. Combining PPAR agonists with other treatments and advancing personalized approaches may enhance therapeutic efficacy and patient outcomes. This study provides future perspectives on the roles of PPAR agonists in PBC management.

Background: Primary biliary cholangitis (PBC) is an autoimmune disease and is often accompanied by thyroid dysfunction. Understanding the potential causal relationship between PBC and thyroid dysfunction is helpful to explore the pathogenesis of PBC and to develop strategies for the prevention and treatment of PBC and its complications. Methods: We used a two-sample Mendelian randomization (MR) method to estimate the potential causal effect of PBC on the risk of autoimmune thyroid disease (AITD), thyroid-stimulating hormone (TSH) and free thyroxine (FT4), hyperthyroidism, hypothyroidism, and thyroid cancer (TC) in the European population. We collected seven datasets of PBC and related traits to perform a series MR analysis and performed extensive sensitivity analyses to ensure the reliability of our results. Results: Using a sensitivity analysis, we found that PBC was a risk factor for AITD, TSH, hypothyroidism, and TC with odds ratio (OR) of 1.002 (95% CI: 1.000–1.005, p = 0.042), 1.016 (95% CI: 1.006–1.027, p = 0.002), 1.068 (95% CI: 1.022–1.115, p = 0.003), and 1.106 (95% CI: 1.019–1.120, p = 0.042), respectively. Interestingly, using reverse-direction MR analysis, we also found that AITD had a significant potential causal association with PBC with an OR of 0.021 (p = 5.10E−4) and that the other two had no significant causal relation on PBC. Conclusion: PBC causes thyroid dysfunction, specifically as AITD, mild hypothyroidism, and TC. The potential causal relationship between PBC and thyroid dysfunction provides a new direction for the etiology of PBC.

Primary Biliary Cholangitis (PBC) is a chronic liver disease that significantly impacts patients, leading to cirrhosis and associated complications in a considerable number of individuals. The British Society of Gastroenterology...