Advances in pharmacotherapy for primary biliary cirrhosis

Abstract

Introduction Primary Biliary Cirrhosis (PBC) is a chronic autoimmune liver disease mostly seen in middle aged women characterized by progressive non-suppurative destruction of small bile ducts resulting in intrahepatic cholestasis, parenchymal injury, and ultimately end stage liver disease. Despite major breakthroughs in our understanding of PBC, there remains only one FDA-approved agent for treatment: ursodeoxycholic acid (UDCA) to which one third of patients are unresponsive. Areas covered Biochemical response to treatment with UDCA is associated with excellent survival rates in PBC patients. However, there is a need for alternative treatments for non-responders. Results from human epidemiological and genetic studies as well as preclinical studies in PBC animal models have provided a strong impetus for the development of new therapeutic agents. In this review, we discuss the recent advances in translational research in PBC focusing on promising therapeutic approaches, namely immune-based targeted therapies and agents targeting the synthesis and circulation of bile acids. Expert opinion We are in a new era for the development of novel therapies for PBC. Data on fibrates, budesonide, and obeticholic acid offer encouragement for non-responders to UDCA.

Bile Acids and the Potential Role in Primary Biliary Cirrhosis

“…UDCA is the accepted therapy to treat these symptoms, to inhibit intestinal absorption of Bas, to increase biliary secretion of BAs rich in bicarbonate and to eliminate toxic substances from hepatocytes, thereby both enriching the BA pool with less toxic, hydrophilic BAs and relieving the cell necrosis and apoptosis. Besides this, clinical trials of drugs suggest that the administration of obeticholic acid, a 6α-ethyl derivative of CDCA, is well tolerated in patients with PBC and significantly reduces serum ALP levels [2] . It is definite that BAs assume the dispensable responsibility in PBC.…”

Primary Biliary Cholangitis: Disease Pathogenesis and Implications for Established and Novel Therapeutics

“…Preliminary results at 1 year have report percentage of patients meeting primary endpoint (reduction in serum ALP <1.67 times ULN with a 15% reduction from baseline levels and a normal serum bilirubin): 10% placebo group, 47%-10 mg OCA group, and 46%-5 to 10 mg OCA group (both treated groups highly significant vs. placebo arm). 36 Estimated completion is June 2018. A second phase III study (COBALT, NCT0230811) is currently ongoing evaluating clinical outcomes (including liver transplant and death) of PBC patients treated with OCA and is currently recruiting participants with estimated completion date of April 2023.…”

Primary biliary cholangitis: new treatments for an old disease

“…The farnesoid X receptor (FXR) is an important nuclear receptor. When activated, it regulates bile acid physiology and reduces their toxic accumulation 45 46. Obeticholic acid (OCA) is a therapeutic FXR agonist that has shown encouraging biochemical results.…”

“…Nuclear transcription factors of the peroxisome proliferator-activated receptors (PPARs) family appear to play some role 46. This results in a cascade of events which reduces toxic bile 24.…”

“…A recently discovered therapeutic target is TGR5, a transmembrane G-protein coupled receptor 46. Int-767, a dual FXR and TGR5 agonist, and Int-777 are two agents that are currently undergoing investigation 33–36.…”