Odevixibat

Progressive familiar intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders leading to cholestasis, fibrosis, and eventually a need for liver transplantation. Patients with PFIC require liver transplants or develop hepatocellular carcinomas in their first few years of life. Many of these patients experience severe pruritus. The exact mechanism of pruritus is PFIC is not known, but lower concentrations of bile acids have been shown to reduce pruritus. Patients with certain forms of PFIC type 2, associated with a non-functional or absent bile salt export pump, are not expected to benefit from odevixibat treatment.

The ileal sodium/bile acid cotransporter is a transport glycoprotein responsible for reabsorption of 95% of bile acids in the distal ileum. Odevixibat is a reversible inhibitor of the ileal sodium/bile acid contransporter. Patients taking odevixibat for a week experienced a 56% reduction in bile acid area under the curve with a 3 mg once daily dose. A 1.5 mg daily dose lead to a 43% reduction in bile acid area under the curve.

The decreased reabsorption of bile acids, leads to reduced stimulation of FXR, which reduces expression of FGF19, reducing binding of FGF19 to FGF4R, decreasing inhibition of bile acid synthesis. Further synthesis of bile acids that will not be reabsorbed in the intestine contributes to lowering low density lipoprotein levels.