Alagille Syndrome (ALGS)


Livmarli™ (maralixibat) is a medication approved by the US Food and Drug Administration (FDA) for the treatment of patients with Alagille syndrome (ALGS).1 Developed by Mirum Pharmaceuticals to treat cholestatic liver diseases such as ALGS, Livmarli is an oral solution indicated for the treatment of cholestatic pruritus in people with ALGS aged 1 year or older.11  

Prior to approval, the FDA granted maralixibat Breakthrough Therapy designation for the treatment of Alagille syndrome-associated pruritus in patients aged 1 year and older, as well as for patients with progressive familial intrahepatic cholestasis.2 The treatment was also granted Rare Pediatric Disease designation (a disease that is serious or life-threatening in which the serious or life-threatening manifestations primarily affect individuals aged from birth to 18 years) for ALGS and Orphan Drug designation for the treatment of ALGS and progressive familial intrahepatic cholestasis.3

Get full prescribing information about Livmarli on MPR

Mirum Pharmaceuticals completed the submission of its New Drug Application for maralixibat to the FDA in February 2021 for the treatment of cholestatic pruritus in patients with ALGS aged 1 year and older.4 Livmarli was approved by the FDA almost 2 years to the day that the medication received Breakthrough Therapy designation.

Maralixibat
Molecular structure of maralixibat

Alagille Syndrome

ALGS is a rare genetic disease caused by mutations in the Jagged 1 (JAG1) or Notch 2 (NOTCH2) genes.5 This impairs the Notch signaling pathway, which plays a key role in many developmental processes including certain facial features, the spinal column, heart, and bile ducts.

Patients with ALGS have a wide range of symptoms including pruritus, jaundice, xanthoma, dark urine and light, loose, and greasy stools, hepatomegaly, and splenomegaly.

The disease is characterized by intrahepatic bile duct paucity (the hallmark of the disease) causing chronic cholestasis. Patients may also have congenital heart defects, posterior embryotoxon, and skeletal abnormalities such as butterfly vertebrae.

Livmarli’s Mechanism of Action

Livmarli is a minimally absorbed oral compound that inhibits the apical sodium-dependent bile acid transporter (ASBT).1 ASBT is a protein that is expressed at the apical membrane of enterocytes in the ileum, colon, jejunum, and duodenum.6 It plays a key role in the enterohepatic circulation of bile acids. 

ASBT inhibition results in more bile acids being excreted in the feces, which reduces levels of systemic bile acids. It is hoped that this can reduce bile acid-mediated liver damage and lead to improvements in liver function. This, in turn, could reduce pruritus and inhibit or delay complications associated with cholestasis such as progressive liver disease, liver injury, fibrosis, cirrhosis, and end-stage liver disease.1

Efficacy in Clinical Trials

A phase 2b randomized placebo-controlled clinical trial called ICONIC tested maralixibat in 31 children (mean age 5.4 years) with ALGS.7 The primary endpoint of the study was the change in serum bile acids in patients with reduced serum bile acids at week 12 or week 18. Secondary endpoints included improvements in the caregiver Itch Reported Outcome score (0 = none; 4 = severe itch), clinician xanthoma severity scale, pediatric quality of life inventory (PedsQL), and safety parameters. 

Patients were given up to 400 mg/kg of maralixibat per day for 18 weeks and then were randomized to either continue receiving the treatment at the same dose or a placebo for 4 weeks. This was followed by 48 weeks of maralixibat treatment for all patients. 

The results showed that patients who received maralixibat had significant reductions in serum bile acids and pruritus compared to those given the placebo. They also had reductions in xanthomas and accelerated growth in the long term.

Participants tolerated maralixibat generally well, with 30 patients showing treatment-emergent adverse events (TEAE), most of which were mild or moderate and mainly included diarrhea and abdominal pain. Four patients had serious treatment-emergent adverse events, but these were all considered unrelated to maralixibat.

An expanded Livmarli access program is available for patients aged 1 year and older with cholestatic pruritus associated with ALGS in the US, Canada, Australia, and regions throughout Europe, including Austria, Belgium, Denmark, France, Germany, Greece, Italy, the Netherlands, Poland, Spain, Sweden, and the UK.8 This is an open-label, single-arm, multicenter program that will evaluate the safety and tolerability of the treatment on an ongoing basis.9 Requests for expanded access must be made by a licensed physician.

An open-label, phase 2 clinical trial called RISE is currently recruiting as of October 2021, and will evaluate the safety and tolerability of maralixibat in infants with cholestatic liver diseases, including ALGS.10 The primary endpoint of this study is the frequency of treatment-emergent adverse events (TEAE). The secondary outcome is the change in fasting serum bile acid (sBA) levels. 

The trial aims to recruit 6 participants with ALGS and 6 participants with familial intrahepatic cholestasis, aged from birth to 1 year. Participants with ALGS will be given up to 400 μg/kg of maralixibat once a day over 13 weeks in the core study and for the duration of the long-term extension where applicable. The trial is not yet recruiting participants. It is estimated to be completed in January 2023.

References

  1. Programs. Mirum Pharmaceuticals. Accessed June 18, 2021.
  2. Mirum Pharmaceuticals announces Breakthrough Therapy designation for maralixibat for the treatment of pruritus associated with Alagille syndrome. News release. Mirum Pharmaceuticals; October 28, 2019. 
  3. FDA grants Mirum Rare Pediatric Disease designation for maralixibat in Alagille syndrome. Global Genes. December 16, 2019. Accessed June 18, 2021.
  4. Mirum Pharmaceuticals announces completion of rolling NDA submission for maralixibat in Alagille syndrome. News release. Mirum Pharmaceuticals; February 1, 2021.
  5. Alagille syndrome. MedlinePlus. Updated April 7, 2021. Accessed June 18, 2021. 
  6. 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
  7. 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 Pharmaceuticals; April 15, 2019. 
  8. Maralixibat Expanded Access Program for patients with Alagille syndrome (ALGS). Mirum Pharmaceuticals. Accessed June 18, 2021.
  9. A maralixibat expanded access program for patients with cholestatic pruritus associated with Alagille syndrome (ALGS). ClinicalTrials.gov. August 28, 2020. Updated May 27, 2021. Accessed June 18, 2021.
  10. 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.
  11. U.S. FDA approves LIVMARLI (maralixibat) as the first and only approved medication for the treatment of cholestatic pruritus in patients with Alagille syndrome one year of age and older. News release. Mirum Pharmaceuticals; October 29, 2021. 

Reviewed by Debjyoti Talukdar, MD, on 10/1/2021.