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Obeticholic acid By Mohamed Fathy Bakosh Demonstrator of hepatology
Obeticholic acid (OCA) 6α-ethyl chenodeoxycholic acid Obeticholic acid (OCA) is the 6 -ethyl derivative of naturally occurring chenodeoxycholic acid (CDCA) with about 100 times higher potency than CDCA itself.
Mechanism of actions • Obeticholic acid is a farnesoid x receptor (FXR) agonist , and reduces hepatic exposure to bile acids by reducing the amount of circulating bile acid. • FXR is expressed in the liver and intestine, and is reponsable for regulating bile acid, inflammatory, fibrotic, and metabolic pathways.
Enterohepatic Bile Acid Circulation & Signaling
Bile acid homeostasis • The total bile acid pool in humans is tightly controlled by a coordinated regulation of expression of genes involved with synthesis, secretion, reabsorption and reuptake of bile acids by the liver. • The major components of the bile acid pool are cholic and chenodeoxycholic acid with lesser amounts deoxycholic and lithocholic acid and minor amounts of ursodeoxycholic acid • CDCA as the most potent FXR activator, while DCA and LCA activated FXR with a lower efficacy than CDCA Hydrophilic unconjugated BAs, such as CA and UDCA, could not activate FXR.
FXR-mediated pharmacological actions of OCA
UDCA and OCA properties
OCA –key properties
Indication • Treatment of primary biliary cholangitis in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA or as monotherapy in adults unable to tolerate UDCA.
Adverse reactions • Common Dermatologic: pruritis (up to 70%). Endocrine and metabolic: dose-dependant reductions in HDL-C levels. Others: Fatigue(19% to 25%) • Serious Hepatic : hepatic decompensation, Ascites and jaundice
Dosage & adminstration
Dosage & adminstration Intolerable pruritis : 1. Consider adding an antihistamine or bile acid binding resin. 2. Consider interrupting obeticholic acid treatment for 2 weeks, then restart at reduced dosage. 3. If intolerant to 5 mg once daily, consider dosage reduction to 5 mg every other day. 4. If intolerant to 10 mg once daily, consider dosage reduction to 5 mg every other day.
Future indication-NASH • REGENERATE, a pivotal phase 3 study of obeticholic acid (OCA) by Intercept Pharmaceuticals, Inc. , has demonstrated positive results in patients with liver fibrosis from nonalcoholic steatohepatitis (NASH). • The primary efficacy analysis indicated that treatment with once-daily OCA 25 mg met the primary endpoint of fibrosis improvement (≥ 1 stage) with no worsening of NASH after 18 months.
Future indication-PSC • The AESOP trial was a 24 -week, double-blind, placebo-controlled , phase 2 trial including 77 patients with PSC who received either 1. 5 mg to 3 mg of obeticholic acid, 5 mg to 10 mg of obeticholic acid, or placebo. Compared with a 1% increase of alkaline phosphatase in the control group, both groups who received obeticholic acid treatment had a mean reduction of 22% (P <. 05).