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 |