An open, non-randomized, parallel-group pharmokinetic and -dynamic, investigator-initiated study on effects of obeticholic acid (OCA) in bile of patients with primary biliary cholangitis (PBC) and non-alcoholic steatohepatitis (NASH) in comparison to healthy controls

Obeticholic acid (OCA) is a semi-synthetic bile acid analogue, being 100 times
more potent than the endogenous bile acid chenodeoxycholic acid (CDCA) as a
farnesoid X receptor (FXR) activator. (7) OCA has shown anti-cholestatic,
anti-inflammatory and anti-fibrotic effects in pre-clinical and clinical
studies. (8) OCA is being developed in the United States and Europe for the
treatment of primary biliary cholangitis (PBC), nonalcoholic fatty liver
disease (NAFLD) associated with type 2 diabetes, non-alcoholic steatohepatitis
(NASH), primary sclerosing cholangitis (PSC), and biliary atresia. The exact
working mechanism of OCA is still unclear.

To explore the exact working mechnism of OCA in PBC / NASH patients in
comparison with healthy volunteers

11 patients suffering from PBC (treated with ursodeoxycholic acid 15mg/kg
daily), 11 patients with NASH and 11 healthy volunteers matched at best in term
of demographic characteristics will take obeticholic acid at a dosage of 10
mg/day during a treatment period of 28 days. Prior to intake of the study
medication and 24 hours after intake of the last dose of study medication, an
endoscopy of the upper gastrointestinal tract will be performed. During both
endoscopies, cystic bile samples and biopsies of the duodenum will be taken. In
addition, blood samples for pharmacokinetic analyses of bile acids and bile
acid metabolites in serum will be drawn during 24 hours after intake of the
last dose of study medication.

Obeticholic acid 10mg once daily

- Study medicine:

In randomized controlled trials, obeticholic acid has shown to be safe and
effective in PBC and NASH patients.

- Other interventions:

At the baseline visit and at day 30 a gastroscopy will be performed. The
gastroscopy will be performed under conscious sedation (with midazolam).

In this short investigation the esophagus, stomach and proximal duodenum are
visualized with an endoscope. Duodenal biopsies are taken during this
endoscopy. A rare but potentially severe risk of a biopsy is a perforation. In
some cases perforation can be treated conservatively or endoscopically. In a
minority of cases, surgery has to be performed to close the perforation
(extremely rare, high burden).

Another very rare risk of an duodenal biopsy is bleeding, which can be treated
endoscopically. (rare, intermediate burden)

Sedation carries the risk of aspiration (rare, intermediate burden).

Sampling of peripheral venous blood will be performed and carries the risk of
hematoma (common, low burden) and phlebitis (rare, low intermediate burden).

During 4 weeks patients are asked to fill in a diary, the burden is low and the
risk is zero.