Oral Cholic Acid Is Efficacious and Well Tolerated in Patients With Bile Acid Synthesis and Zellweger Spectrum Disorders

• Published in: Journal of pediatric gastroenterology and nutrition Vol. 65; no. 3; pp. 321 - 326
• Main Authors: Heubi, James E., Bove, Kevin E., Setchell, Kenneth D.R.
• Format: Journal Article
• Language: English
• Published: United States by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology 01-09-2017; Lippincott Williams & Wilkins
• Subjects: Administration, Oral; Adolescent; AKR1D1 deficiency; Bile Acids and Salts - metabolism; Child; Child, Preschool; Cholic Acid - therapeutic use; Drug Administration Schedule; Female; HSD3B7 deficiency; Humans; inborn errors of bile acid synthesis; Infant; Infant, Newborn; Intention to Treat Analysis; Male; Original : Hepatology; peroxisomal disorders; Steroid Metabolism, Inborn Errors - drug therapy; Steroid Metabolism, Inborn Errors - metabolism; Treatment Outcome; Zellweger Syndrome - drug therapy
• ISSN: 0277-2116; 1536-4801
• DOI: 10.1097/MPG.0000000000001657

ABSTRACT
Objectives:
Patients with bile acid synthesis disorders (BASDs) due to single enzyme defects (SEDs) or Zellweger spectrum disorders (ZSDs) accumulate hepatotoxic atypical bile acids resulting in potentially fatal progressive liver disease. We evaluated the efficacy and safety of oral cholic acid in patients with BASD.
Methods:
In this phase 3, open‐label, single‐arm, nonrandomized, noncomparative study conducted over 18 years, patients were administered cholic acid orally 10 to 15 mg · kg−1 · day−1. The primary efficacy variables were changes from pre‐ to post‐treatment in atypical urinary bile acids, liver chemistries (serum aspartate aminotransferase, alanine aminotransferase), and height and weight. Additional efficacy variables included changes in serum bilirubin and liver histology.
Results:
Of the 85 enrolled patients (63 with SED and 22 with ZSD), 79 received at least 1 dose of study medication; 70 patients (50 with SED and 20 with ZSD) were included in the modified intent‐to‐treat dataset. Cholic acid significantly improved urine bile acid metabolite scores (P < 0.0001) and serum aspartate aminotransferase and alanine aminotransferase (P < 0.0001) in patients with SED and ZSD. Cholic acid also improved height and weight percentiles in both groups, but only the change in weight was significant (P < 0.05). Serum direct bilirubin decreased significantly post‐treatment (P < 0.001) in the intent‐to‐treat population, and liver biopsies showed either stable findings or histologic improvement in all parameters except bridging fibrosis. The overall safety profile of cholic acid was favorable, with no study drug‐related serious adverse events or drug‐related deaths reported.
Conclusions:
Oral cholic acid is a safe, efficacious, and well‐tolerated treatment for BASD due to SED and ZSD.