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Table 1 Summary of key clinical studies of CA therapy in patients with ZSD

From: Cholbam® and Zellweger spectrum disorders: treatment implementation and management

Study Design Patients CA dosage Study duration Major findings Conclusions Limitations
Berendse et al. [17] Open-label, pretest-postest study 19 patients with ZSD (mean age 14 years) 15 mg/kg/day (with dose adjustments, as needed) 36 weeks Signficant increases in plasma CA levels
Signficant decreases in plasma levels of C27-bile acid intermediates
No changes in:
AST, ALT, or conjugated bilirubin
Fibroscan® liver stiffness values
Concentrations of fat-soluble vitamins
Weight
Subset of patients with advanced liver disease at baseline (n = 4) showed evidence of increased liver damage with CA therapy
CA therapy can be used in the majority of patients with ZSD, leading to at least partial supression of bile acid synthesis
Caution is needed in patients with advanced liver disease because of possible hepatotoxic effects
Small size of the cohort
Short duration of treatment
Mild disease severity at start of treatment
Klouwer et al. [20] Extension of Berendse et al. 2016 pretest–posttest study 22 patients with ZSD (mean age 13 years) 15 mg/kg/day (with dose adjustments, as needed) Additional 12 months (total duration 21 months) Significant decreases in plasma C27-bile acid intermediates
No changes in:
AST, ALT, or conjugated bilirubin
Liver elasticity
Concentrations of fat-soluble vitamins
Weight
Subset of patients with advanced liver disease at baseline (n = 6) had progressive increases in conjugated bilirubin levels with CA therapy
Although CA therapy resulted in lower C27-bile acid intermediate levels in plasma and urine, no clincial benefit was observed
CA therapy can be harmful to ZSD patients with cirrhosis
Small size of the cohort
Short duration of treatment
Mild disease severity at start of treatment
Heubi et al. [19] Phase 3, open-label, single-arm, nonrandomized, noncomparative study 70 patients
SED, n = 50
ZSD, n = 20 (mean age 3 years)
10–15 mg/kg/day 18 years Significant improvements in FAB-MS scores
Significant reductions in AST, ALT, and serum direct bilirubin levels
Significantly improved weight profiles
Improvement in nearly all histological parameters
TEAEs generally mild to moderate
CA therapy is an effacious, safe, and well-tolerated treatment for patients with ZSD Lack of a placebo control group
Collection of laboratory data and urine FAB-MS was not defined at specific and rigid times during the study period
Heubi and Setchell [21] Phase 3, open-label, single-arm extension study of Heubi et al. [19] 53 patients (31 previously treated, 22 treatment naïve)
SED, n = 41
ZSD, n = 12 (mean age 9 years)
10–15 mg/kg/day Additional 6 years Significant improvements in urinary bile acids, height, and weight
AST and ALT levels decreased in treatment-naïve patients and remained stable in previously treated patients
TEAEs predominantly mild to moderate
Findings reinforce the short-term (in treatment-naïve patients) and long-term (in previously treated patients) efficacy and safety of CA therapy in patients with ZSD Lack of systematic follow-up
Small number of treatment-naïve patients with ZSD
Use of urine vs serum for assessing DHCA and THCA may have compromised ability to detect changes with treatment in patients with ZSD
  1. ALT alanine aminotransferase, AST aspartate aminotransferase, CA cholic acid, DHCA 3α,7α- dihydroxycholestanoic acid, FAB-MS fast atom bombardment ionization mass spectrometry, SED single enzyme defect, TEAE treatment-emergent adverse event, THCA 3α,7α,12α-trihydroxycholestanoic acid, ZSD Zellweger spectrum disorder