RTY-406

FVB.129P2-Abcb4tm1Bor/J (ABCB4 heterozygous) (9-10-week-old female; toxic bile-induced model fed lithogenic diet)^[1]

15 mg/kg; 30 mg/kg; 60 mg/kg

p.o.; b.i.d.; 6 weeks

Increased biliary phospholipid levels relative to vehicle control at all tested doses.
Reduced gallbladder cholesterol crystal formation relative to vehicle control at all tested doses.
Reduced 6-week serum total bile acid levels relative to vehicle control at 30 mg/kg and 60 mg/kg.
Reduced 2-week serum alkaline phosphatase levels relative to vehicle control at all tested doses.
Reduced liver taurocholic acid (TCA) levels relative to vehicle control at all tested doses.
Reduced mRNA levels of ductular reaction, fibrosis, and cholangitis markers: 15 mg/kg: Ck19 (-9%), Vcam (-1%), Itgb6 (-7%), Spp1 (-13%), Timp-1 (-6%), Col1a1 (0%), Col1a2 (0%); 30 mg/kg: Ck19 (-21%), Vcam (-14%), Itgb6 (-54%), Spp1 (-44%), Timp-1 (-30%), Col1a1 (-10%), Col1a2 (-18%); 60 mg/kg: Ck19 (-76%), Vcam (-27%), Itgb6 (-95%), Spp1 (-79%), Timp-1 (-25%), Col1a1 (-20%), Col1a2 (-37%).
Reduced protein levels of proinflammatory mediators: 15 mg/kg: Cxcl-1 (-17%), Mcp-1 (-23%); 30 mg/kg: Cxcl-1 (-37%), Mcp-1 (-44%); 60 mg/kg: Cxcl-1 (-35%), Mcp-1 (-57%).
Reduced biliary Ck19+, Vcam+, Cd11b+ area, and picrosirius red-stained fibrotic area relative to vehicle control at all tested doses.

Cynomolgus monkeys (3 to 5 years old)^[2]

5 mg/kg; 10 mg/kg

p.o.; daily; 28 days

Reduced serum alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and total cholesterol levels dose-dependently from baseline after 28 days.
Kept serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels within normal limits without increasing them.