Apical sodium-dependent bile acid transporter inhibition in children with Alagille syndrome

In The Lancet, Emmanuel Gonzales and colleagues 1 Gonzales E Hardikar W Stormon M et al. Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 study. Lancet. 2021; 398: 1581-1592 Google Scholar present the findings of the phase 2 placebo-controlled, randomised withdrawal period, open-label, extension ICONIC study of the apical sodium-dependent bile acid transporter (ASBT) inhibitor, maralixibat, in paediatric patients with Alagille syndrome. Alagille syndrome is a cholestatic liver disease that leads to pruritus, xanthomas, and impaired quality of life. Surgical interventions to interrupt the enterohepatic bile acid circulation or liver transplantation are often pursued 2 Wang KS Tiao G Bass LM et al. Analysis of surgical interruption of the enterohepatic circulation as a treatment for pediatric cholestasis. Hepatology. 2017; 65: 1645-1654 Google Scholar , 3 Kamath BM Ye W Goodrich NP et al. Outcomes of childhood cholestasis in Alagille syndrome: results of a multicenter observational study. Hepatol Commun. 2020; 4: 387-398 Google Scholar because there are no approved medical therapies. ASBT has a key role in the enterohepatic circulation of bile acids because it absorbs approximately 95% of bile acids from the terminal ileum. Because intrahepatic bile acids are thought to be the main driver behind hepatocellular injury in cholestatic diseases, pharmacological inhibition of ASBT has the potential to not only improve pruritus, but also disease trajectory. Studies in mouse models of cholestasis have shown that ASBT inhibition can decrease intrahepatic bile acid concentrations and improve fibrosis and disease progression. 4 Miethke AG Zhang W Simmons J et al. Pharmacological inhibition of apical sodium-dependent bile acid transporter changes bile composition and blocks progression of sclerosing cholangitis in multidrug resistance 2 knockout mice. Hepatology. 2016; 63: 512-523 Google Scholar , 5 Baghdasaryan A Fuchs CD Osterreicher CH et al. Inhibition of intestinal bile acid absorption improves cholestatic liver and bile duct injury in a mouse model of sclerosing cholangitis. J Hepatol. 2016; 64: 674-681 Google Scholar Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): a randomised phase 2 studyIn children with Alagille syndrome, maralixibat is, to our knowledge, the first agent to show durable and clinically meaningful improvements in cholestasis. Maralixibat might represent a new treatment paradigm for chronic cholestasis in Alagille syndrome. Full-Text PDF