Maralixibat

Patients with Alagille syndrome experience potentially debilitating pruritus. The exact mechanism of cholestatic pruritus in Alagille syndrome is not well defined, however it is correlated with elevated total serum bile acid concentrations.

Enterohepatic circulation involves the synthesis of bile acid from cholesterol in the liver, conjugation with glycine or taurine, excretion into the duodenum, 95% resorption in the distal ileum through the ileal bile acid transporter (IBAT), return to the liver via the portal vein, and uptake into the liver by the sodium-dependent taurocholate co-transporting peptide (NTCP). It is important to note that unconjugated bile acids may freely diffuse across the intestinal mucosa or be transported across by other organic anion transporters.

Maralixibat reversibly inhibits IBAT to decrease bile acid resorption in the ileum, leading to decreased resorption of bile acids in the distal ileum, increased elimination of bile acids in the feces, and decreased serum bile acids. The mechanism of action of maralixibat also leads to increased rates of diarrhea in patients.

Under normal conditions, bile acids binding to the farnesoid X receptor (FXR) in the liver by via nuclear receptor small heterodimer partner (SHP) or in the ileum via fibroblast growth factor 19 (FGF19), triggers signal cascade that inhibits CYP7A1-mediated bile acid synthesis. Inhibition of IBAT by maralixibat, inhibits these negative feedback loops, leading to increased bile acid synthesis, and a reduction of low density lipoprotein cholesterol.

In one clinical trial (NCT02057692), not all dose strengths were associated with a clinically significant difference between maralixibat and placebo.