Maralixibat

In trials of maralixibat in children with Alagille syndrome, serum ALT levels rose to greater than 3 times the upper limit of normal (ULN) in 24% of patients and above 5 times ULN in 2%. The ALT elevations led to dose modification, interruption or therapy or early discontinuation in up to 10% of patients. In trials of maralixibat in children with PFIC, at least 4 cases of suspected drug-induced liver injury were reported by the FDA, one of which led to emergent liver transplantation. Children with Alagille syndrome and PFIC typically have serum aminotransferase elevations in the range of 2 to 5 times the upper limit of normal (ULN), and it is can be difficult to distinguish between spontaneous fluctuations in enzyme levels due to the underlying disease vs effects of maralixibat therapy. In many instances, therapy can be continued despite the serum enzyme elevations, at least at a reduced dosage. While there have been reports of worsening liver disease and hepatic decompensation in patients receiving maralixibat, the role of therapy in causing these complications is not always clear. There have been no published reports of acute, clinically apparent liver injury with jaundice attributed to maralixibat therapy, but it has had limited general clinical use.

Maralixibat is indicated in the treatment of cholestatic pruritus in patients with Alagille syndrome who are at least 1 year old. It has a moderate duration of action as it is given once daily, and a wide therapeutic index as patients have safely tolerated single doses up to 18 times the normal dose. Patients should be counselled regarding the risks of liver test abnormalities, gastrointestinal adverse reactions, and fat-soluble vitamin deficiencies.

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.