Alagille syndrome is a rare genetic disease affecting many organs and systems in the body. It is characterized by bile duct paucity, leading to bile acid accumulation in the liver and causing progressive liver disease, damage, and failure. It is caused by mutations in the Jagged 1 (JAG1) or Notch 2 (Notch2) genes, leading to problems with the Notch signaling pathway, causing development disorder with facial features, the heart, spinal cord, and bile ducts.1
There is currently no cure for Alagille syndrome (ALGS) and treatment options focus on alleviating symptoms and increasing patients’ quality of life. Vitamins and supplements may also be used to support patients’ growth and development. In more serious cases, biliary diversion procedures can be performed to lower blood bile levels. Finally, a liver transplant may be performed to improve liver function in some patients with end-stage liver disease. 2
There are also experimental treatments that are currently in clinical trials for patients with ALGS and other cholestatic liver diseases. They include maralixibat and odevixibat. Both treatments aim to reduce the transport of bile acid back to the liver from the digestive system to reduce its accumulation in the liver and consequential liver problems.
Maralixibat is an oral compound from Mirum Pharmaceuticals that inhibits the apical sodium-dependent bile acid transporter (ASBT).3 ASBT is expressed in the small intestine. It plays a role in the uptake of bile acids in the intestines, recycling them back to the liver.4 Inhibiting ASBT results in more bile acid being excreted in the feces instead of being returned to the liver. This could reduce bile acid accumulation in the liver and improve liver function, as well as delaying or preventing liver disease, damage, and failure. It can also treat hypercholesterolemia, cholestasis, and diseases associated with enterohepatic circulation of bile acids.
Maralixibat has been tested in a phase 2 clinical trial in children with ALGS aged 1 year and above. Results showed that maralixibat could reduce serum bile acid levels, pruritus, and xanthomas compared to a placebo. It also led to accelerated growth in the long term. The treatment was well-tolerated and only led to mild or moderate symptoms, the most common ones being fever, cough, diarrhea, and abdominal pain.5
This treatment is also being tested in infants with ALGS to evaluate its safety and tolerability in this age group.6 An expanded access program is currently available for patients, aged 1 year and above, in the US, Canada, Australia, and Europe.7
Maralixibat has been granted Breakthrough Therapy, Rare Pediatric Disease, and Orphan Drug designations by the US Food and Drug Administration (FDA) for the treatment of ALGS and other cholestatic liver diseases.8,9
Read more about Maralixibat.
Odevixibat is an ileal bile acid transport inhibitor being developed by Albireo to treat cholestatic liver diseases in children with ALGS, biliary atresia, and progressive familial intrahepatic cholestasis.10 Like maralixibat, it reduces bile acids returning to the liver by inhibiting the ileal bile acid transporter. It is hoped that this could treat cholestatic liver diseases like ALGS.
A phase 3 clinical trial in patients with progressive familial intrahepatic cholestasis has shown that odevixibat reduced serum bile acids and improved pruritus. An open-label phase 3 extension study showed that the treatment led to reductions in bile acids in a continued and durable manner and improved pruritus. Patients in both studies tolerated odevixibat well, and treatment-emergent adverse events were mostly mild or moderate.
Another phase 3 trial is evaluating the safety and efficacy of odevixibat in relieving pruritus in patients with ALGS.11
The FDA and the European Medicines Agency (EMA) have granted odevixibat Orphan Drug designation for the treatment of ALGS and other cholestatic liver diseases.10
Read more about Odevixibat.
Participation in Clinical Trials
Patients and families who are eligible for and willing to participate in clinical trials should be apprised about the pros and cons. They should be given information about the possible side effects an experimental treatment can have and informed about the fact that they could be in the placebo arm of the study.
Requests about the expanded access program for maralixibat can only be made by a licensed physician. Physicians in the US, Canada, Australia, Austria, Belgium, Denmark, France, Germany, Greece, Italy, the Netherlands, Poland, Spain, Sweden, and the UK who are interested in the expanded access program should contact Mirum Pharmaceuticals to register.7
- Alagille syndrome. MedlinePlus. Updated April 7, 2021. Accessed June 18, 2021.
- Alagille syndrome. Genetic and Rare Diseases Information Center. Accessed June 18, 2021.
- Programs. Mirum Pharma. Accessed June 18, 2021.
- Xiao L, Pan G. An important intestinal transporter that regulates the enterohepatic circulation of bile acids and cholesterol homeostasis: the apical sodium-dependent bile acid transporter (SLC10A2/ASBT). Clin Res Hepatol Gastroenterol. 2017;41(5):509-515. doi:10.1016/j.clinre.2017.02.001
- Mirum Pharmaceuticals presents new data demonstrating durable improvements in clinical outcome measures in patients with PFIC2 and Alagille syndrome treated with maralixibat. News release. Mirum Pharma; April 15, 2019.
- A study to evaluate the safety and tolerability of maralixibat in infant participants with cholestatic liver diseases including progressive familial intrahepatic cholestasis (PFIC) and Alagille syndrome (ALGS). (RISE). ClinicalTrials.gov. January 28, 2021. Updated June 11, 2021. Accessed June 18, 2021.
- Maralixibat Expanded Access Program for patients with Alagille syndrome (ALGS). Mirum Pharma. Accessed June 18, 2021.
- Mirum Pharmaceuticals announces breakthrough therapy designation for maralixibat for the treatment of pruritus associated with Alagille syndrome. News release. Mirum Pharma; October 28, 2019.
- FDA grants Mirum Rare Pediatric Disease Designation for maralixibat in Alagille syndrome. Global Genes. December 16, 2019. Accessed June 18, 2021.
- Odevixibat. Albireo. Accessed June 18, 2021.
- Efficacy and safety of odevixibat in patients With Alagille syndrome (ASSERT). ClinicalTrials.gov. December 19, 2020. Updated June 15, 2021. Accessed June 18, 2021.
Reviewed by Debjyoti Talukdar, MD, on 7/1/2021.