Obeticholic acid for the treatment of primary biliary cholangitis in adult patients: clinical utility and patient selection

Abstract

Primary biliary cholangitis (PBC), previously known as primary biliary “cirrhosis”, is a rare autoimmune liver disease characterized by the hallmark autoantibodies to mitochondrial antigens and immune-mediated destruction of small bile duct epithelial cells leading to cholestasis and cirrhosis. Surprisingly, while immune modulators have not been effective in the treatment of PBC, supplementation with the hydrophilic bile acid (BA) ursodeoxycholic acid (UDCA) has been demonstrated to slow the disease progression. However, a significant minority of PBC patients do not have a complete response to UDCA and remain at risk of continued disease progression. Although the mechanisms of action are not well understood, UDCA provided proof of concept for BA therapy in PBC. Obeticholic acid (OCA), a novel derivative of the human BA chenodeoxycholic acid, is a potent agonist of the nuclear hormone receptor farnesoid X receptor, which regulates BA synthesis and transport. A series of clinical trials of OCA in PBC, primarily in combination with UDCA, have established that OCA leads to significant reductions in serum alkaline phosphatase that are predicted to lead to improved clinical outcomes, while dose-dependent pruritus has been the most common adverse effect. On the basis of these studies, OCA was given conditional approval by the US Food and Drug Administration with plans to establish the long-term clinical efficacy of OCA in patients with advanced PBC.

Bile Acid Receptor Therapeutics Effects on Chronic Liver Diseases

“…Ursodeoxycholic acid (UDCA), an epimer of CDCA, was the first FDA-approved treatment for PBC. Despite increased bile flow, lower liver enzyme levels, and decreased serum BA levels, one in three PBC patients will have a limited or no response to treatment, strengthening the need for effective therapeutic intervention of PBC progression (33,(40)(41)(42)(43)(44)(45).…”

Autoimmunassoziierte Gallenwegserkrankungen

“…Begonnen wird mit einer Dosis von 5 mg einmal täglich, welche nach 6 Monaten bei unzureichendem Ansprechen auf 10 mg pro Tag gesteigert werden kann [9]. Ist bereits eine Leberzirrhose im Child-Pugh Stadium B oder C bekannt, so darf OCA aufgrund der Gefahr eines akuten Leberversagens nur in deutlich geringerer Dosierung (5 mg einmal wöchentlich) und nur unter engmaschiger Kontrolle der Leberwerte eingesetzt werden [50]. Ist keine fortgeschrittene Leberzirrhose bekannt, wird OCA in der Regel gut vertragen.…”

Nuclear receptors and liver disease: Summary of the 2017 basic research symposium

“…Human studies are ongoing with the BA‐derivative agonist obeticholic acid (OCA), which improves insulin resistance and decreases liver fibrosis markers 78. OCA has also been approved for treatment of primary biliary cholangitis79 and is in late clinical studies for NASH.…”