Cholbam® and Zellweger spectrum disorders: treatment implementation and management

Abstract

Background: Zellweger spectrum disorders (ZSDs) are a rare, heterogenous group of autosomal recessively inherited disorders characterized by reduced peroxisomes numbers, impaired peroxisomal formation, and/or defective peroxisomal functioning. In the absence of functional peroxisomes, bile acid synthesis is disrupted, and multisystem disease ensues with abnormalities in the brain, liver, kidneys, muscle, eyes, ears, and nervous system.

Main body: Liver disease may play an important role in morbidity and mortality, with hepatic fibrosis that can develop as early as the postnatal period and often progressing to cirrhosis within the first year of life. Because hepatic dysfunction can have numerous secondary effects on other organ systems, thereby impacting the overall disease severity, the treatment of liver disease in patients with ZSD is an important focus of disease management. Cholbam® (cholic acid), approved by the U.S. Food and Drug Administration in March 2015, is currently the only therapy approved as adjunctive treatment for patients with ZSDs and single enzyme bile acid synthesis disorders. This review will focus on the use of CA therapy in the treatment of liver disease associated with ZSDs, including recommendations for initiating and maintaining CA therapy and the limitations of available clinical data supporting its use in this patient population.

Conclusions: Cholbam is a safe and well-tolerated treatment for patients with ZSDs that has been shown to improve liver chemistries and reduce toxic bile acid intermediates in the majority of patients with ZSD. Due to the systemic impacts of hepatic damage, Cholbam should be initiated in patients without signs of advanced liver disease.

Keywords: Cholic acid therapy; Hepatic injury; Peroxisome biogenesis disorder; Zellweger disease; Zellweger spectrum disorder.

Fig. 1

Disrupted bile acid synthesis in patients with ZSD and CA mechanism of action. CA, cholic acid; CDCA, chenodeoxycholic acid; CYP7A1, cytochrome P450 7A; LRH-1, liver receptor homolog 1; SHP-1, small heterodimeric partner 1. A Disrupted bile acid synthesis in patients with ZSD. In the absence of functional peroxisomes, there is a deficiency of primary C₂₄-bile acids, which subsequently results in the disruption of the negative feedback loop (dotted lines) that maintains bile acid homeostasis under normal physiological conditions. Increased transcription of CYP7A1 causes a build-up of C₂₇-bile acid intermediates, which have been shown to be cytotoxic. Additionally, deficiency in primary bile acids causes impaired bile flow and cholestasis, as well as reduced absorption of dietary fats and fat-soluble vitamins. B CA mechanism of action in patients with ZSD. Introduction of exogenous CA restores levels of the primary bile acids, improves bile flow and absorption, and reactivates the negative feedback loop, which, via repression of CYP7A1, reduces levels of the C₂₇-bile acid intermediates. Adapted from Gonzales et al. [13], with permission from Elsevier

Fig. 2

Klouwer et al. [20]: impact of cholic acid therapy on bile acid levels, and liver chemistry. A, B Tukey box plots showing the effect of oral cholic acid (CA) on plasma 3α,7α- dihydroxycholestanoic acid (DHCA) and 3α,7α,12α-trihydroxycholestanoic acid (THCA) after 1, 3, 9, 15 and 21 months of treatment. The control reference range for THCA is < 0.05–0.1 μmol/L and levels of DHCA are undetectable (< 0.05 μmol/L) in control individuals. C, D Tukey box plots showing the levels of plasma DHCA and THCA at baseline, study end (after 9 or 21 months of CA treatment) and at follow-up (6–12 months after discontinuation of CA). Only the levels of patients for which follow-up values were available are shown (n = 16). E, F Graphs showing the individual courses of alanine transaminase (ALT) and aspartate transaminase (AST) levels during oral CA treatment (n = 22). The patients with liver cirrhosis are depicted in red. The upper control reference ranges of ALT (40 U/L) and AST (45 U/L) are indicated by the dotted lines. *P<0.05, **P<0.01, ***P<0.005, ****P<0.001, ns, not significant. Reprinted from Klouwer et al. [20]; with permission from John Wiley and Sons. This is an open access article distributed under the terms of the Creative Commons CC BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Fig. 3

Heubi et al. [19]: impact of cholic acid therapy on bile acid levels, liver chemistry, and height and weight. ALT, alanine transaminase; AST aspartate transaminase; NS, not significant; SED, single enzyme defect; SEM, standard erroor of the mean; ULN, upper limit of normal. A Impact of cholic acid treatment on urinary bile acid excretion patients with Zellweger spectrum disorder (ZSD) (n = 27)—worst-to-best analysis, modified intent-to-treat (mITT) population. B Impact of cholic acid treatment on liver chemistries in patients with ZSD (n = 27)—worst-to-best analysis, mITT population. C Mean height and weight percentiles from pretreatment to post-treatment in the mITT population (N = 70), worst-to-best analysis. Numbers in bars represent absolute percentiles for each group. Reprinted from Heubi et al. [19]. This is an open access article distributed under the terms of the Creative Commons CCBY-NC-ND license, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal

Fig. 4

Heubi et al. [21]: impact of cholic acid therapy on bile acid levels, liver chemistry, and height and weight. ALT, alanine transaminase, AST, aspartate transaminase. A Urinary bile acids at baseline, worst postbaseline response, and best postbaseline response (total population). B Height and body weight: baseline, worst postbaseline response, and best postbaseline response (total population). Change from baseline over time in C serum alanine aminotransferase and D serum aspartate aminotransferase. In panels A, C, and D, numbers within the bars indicate n values. Reprinted from Heubi and Setchell [21]. This is an open access article distributed under the terms of the Creative Commons CCBY-NC-ND license, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal