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

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We would like to thank Klouwer and associates for their thoughtful comments regarding our recently published article, “Oral Cholic Acid is Efficacious and Well Tolerated in Patients with Bile Acid Synthesis and Zellweger Spectrum Disorders,” and would like to clarify a few of the points they raised (1). Although we agree that patients with single enzyme defects (SEDs) and Zellweger spectrum disorder (ZSD) represent 2 distinct and different classes of patients, our findings aim to provide a summary of the clinical information gathered that culminated in the approval of cholic acid (CA) by the Food and Drug Administration (FDA) in March 2015. The information reported included all patients who had been treated before approval of the new drug application. This includes a group of ZSD patients whose initial cohort was studied under an FDA Orphan Drug Grant (2) and subsequently individual patients who were enrolled with a final cohort of 20 ZSD patients included in the intent-to-treat analysis of CA. We do present the outcomes of urinary bile acid excretion, liver chemistries, and height/weight separately for the ZSD and SED cohorts in Figures 1–3.
The choice of the worst-to-best comparison was chosen because of the nature of the data, the rarity of the disease, and was based upon agreement between the sponsors and the FDA during the drug review process. The worst to best analysis provides patients and caregivers with information as to what type of efficacy they may be able to anticipate. This is critical as the natural history of ZSD is not well understood and our data provide important long-term insights into the clinical outcomes with CA treatment. Because this was not a randomized trial, participants did not have regularly scheduled study visits and were followed at a variety of sites throughout the United States and Canada. One of the goals was to determine the greatest potential impact that CA would have. As a consequence we utilized the worst baseline to the best post-treatment values. In addition, we added sensitivity analysis of best-to-best, worst-to-worst, and median to median; however, to best illustrate the true potential efficacy of the drug, we felt that the worst-to-best analysis was the best method available.
Our experience with CA treatment in 20 ZSD patients provides insight into long-term outcomes that may be anticipated with treatment of CA and varies from that of published experience of Berendse et al (3). Our findings report long-term outcomes of treated patients over a span of 18 years, whereas those of Berendse et al reported on 9 months of treatment. With 9 months of treatment, the Berendse study describes their group 1 patients as responding well to CA treatment, with a significant decline in C27-bile acid intermediate levels in plasma and urine, and our review of Fig. 2 suggests liver function stabilized and was maintained during the study period in these patients. The authors also state in their discussion that the treatment period of 9 months was too short to be able to conclude whether CA had an effect on clinical progression.
Furthermore, the populations from the 2 cohorts were different in age. The median age of participants at initiation of treatment in the Berendse study was 14 years versus a median age of 10 months in our study. In addition, in contrast to the participants in the study of Berendse et al, of whom only 21% had increased serum alanine aminotransferase at baseline, 59% had elevated serum alanine aminotransferase at entry in our study, which normalized with CA treatment in 52%.
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