Effective treatments for patients with primary biliary cholangitis are limited. Seladelpar, a peroxisome proliferator-activated receptor delta agonist, has potential benefits.
ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA).
Abstract Treatment of primary biliary cholangitis (PBC) with ursodeoxycholic acid (UDCA) is not always sufficient to prevent progression to hepatic decompensation and/or need for liver transplant. Adjuvant therapy with obeticholic acid may provide additional biochemical improvements in some patients, but it is not well‐tolerated by patients with significant itch or advanced cirrhosis. Thus, new and creative approaches to treating patients with PBC are important to identify. This review discusses major potential therapeutic targets in PBC and provides examples of some specific agents currently in development for the treatment of PBC. Targets are broadly classified into those which strive to modify bile, inflammation, cell survival, or fibrosis. In bile, shrinking the size of the bile acid pool or modifying the quality of the bile by making it more hydrophilic or enriched in phosphatidylcholine may ameliorate cholestatic injury. Biliary epithelial cell survival may be extended by fortifying the bicarbonate umbrella or improving cell membrane integrity. Autoimmunity and cholangitis have the potential to be improved via regulation of the immune system. Targeting cytokines, immune checkpoints, and anti‐mitochondrial antibodies are examples of a more focused immunosuppression approach. Stem cell therapy and lymphocyte trafficking inhibition are more novel methods of broad immune regulation. Anti‐fibrotic therapies are also potentially useful for preventing progression of PBC. The nuclear hormone receptors, farnesoid X receptor (FXR) and peroxisome proliferator–activated receptor (PPAR) regulate many of these pathways: cholestasis, inflammation, and fibrosis, which is why they are being enthusiastically pursued as potential therapeutic targets in PBC.
Introduction: The Global PBC Study Group have developed and validated the GLOBE score: a prognostic algorithm (calculated from: age, ALP, total bilirubin, platelets and albumin) to predict risk of liver transplantation and all-cause mortality (http://www.globalpbc.com). A GLOBE score ≤0.3 is associated with a liver transplant-free survival similar to that of a sex and age matched normal population, whereas a GLOBE score >0.3 is associated with significantly diminished liver transplant-free survival. POISE was a placebo-controlled, double-blind, 12-month Phase 3 study which assessed the efficacy of daily 5-10 mg obeticholic acid (OCA) in patients with PBC. The aim of this analysis was to use data from POISE trial to assess if OCA treatment had an effect on categorical shifts in the GLOBE score. Methods: POISE inclusion criteria: PBC diagnosis, ALP ≥1.67x ULN and/or total bilirubin >ULN to < 2x ULN, stable UDCA dose or unable to tolerate UDCA. 216 patients were randomized and dosed with Placebo (PBO, n=73), OCA 5-10 mg (n=70; titration from daily 5 mg to 10 mg at month 6 based on response or tolerability), or OCA 10 mg (n=73). The GLOBE score was calculated at baseline and month 12 to assess disease progression. Results: At baseline there were a similar number of patients across treatment groups who had a GLOBE score above or below 0.3. After 12 months of treatment, patients receiving OCA 5-10 mg (27%, p < 0.05) were significantly more likely to shift from above to below a GLOBE score of 0.3, as compared to PBO (6%). Additionally, after 12 months of treatment, more PBO patients (33%) compared to OCA-treated patients (OCA 5-10 mg: 13%, p= 0.06; OCA 10 mg: 3%, p < 0.01) progressed from a baseline GLOBE score below 0.3 to a GLOBE score above 0.3. Conclusion: OCA treatment resulted in a significantly greater number of patients achieving a GLOBE score ≤0.3, associated with survival that is similar to age and sex matched individuals as compared to PBO treatment. Also, fewer patients progressed to a GLOBE score >0.3, associated with diminished survival. These changes indicate a potential effect of OCA after only 12 months of treatment to delay disease progression in PBC patients who are insufficiently responding to UDCA; however, further evaluation is required. A Phase 3 study evaluating clinical outcomes with OCA in patients with PBC (COBALT) is ongoing to confirm the clinical benefit of OCA and may be used to test the utility of the GLOBE score with OCA.Figure
Primary biliary cholangitis (PBC) is a rare chronic cholestatic liver disease that may progress to biliary cirrhosis if left untreated. The first‐line therapy for PBC is ursodeoxycholic acid (UDCA). Unfortunately, 1 of 3 patients does not respond to UDCA. These patients are at risk for developing clinical events, including cirrhosis, complications of portal hypertension, hepatocellular carcinoma, liver transplant, or death. Recently, the U.S. Food and Drug Administration approved obeticholic acid to be used in certain patients with PBC. Off‐label therapies are also used, and several other therapies are currently under evaluation. Real‐world effectiveness of newly approved and off‐label therapies remains unknown. TARGET‐PBC is a 5‐year, longitudinal, observational study of patients with PBC that will evaluate the effectiveness of clinical practice interventions and provide practical information unobtainable in registration trials. Enrollment will take place at both academic and community sites. In addition to consenting to medical records review, participants will be asked to provide an annual blood sample and complete patient reported outcome surveys at predetermined intervals. Any available liver biopsies will be digitally preserved. Conclusion: Key study outcomes will be the evaluation of the safety and effectiveness of PBC interventions and the assessment of disease progression under real‐world conditions. ( Hepatology Communications 2018;2:484‐491)
Extrahepatic immunological manifestations of hepatitis C virus (HCV) are well described. In addition, antiglutamic acid decarboxylase (GAD) antibody-associated cerebellar ataxia is well-established entity. However, there have been no reports in the literature of anti-GAD antibody-associated ataxia as an extrahepatic manifestation of HCV infection. We report the case of a young woman with chronic hepatitis C virus and multiple extrahepatic autoimmune diseases including Sjögren syndrome and pernicious anemia who presented with subacute midline cerebellar syndrome and was found to have positive antiglutamic acid decarboxylase (GAD) antibody in the serum and cerebrospinal fluid. An extensive diagnostic workup to rule out neoplastic growths was negative, suggesting the diagnosis of nonparaneoplastic antiglutamic acid decarboxylase antibody-associated cerebellar ataxia as an additional extrahepatic manifestation of hepatitis C virus infection. The patient failed to respond to high-dose steroids and intravenous immunoglobulin. Treatment with the monoclonal antibody rituximab stabilized the disease. We postulate that anti-GAD associated ataxia could be an extrahepatic manifestation of HCV infection.
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