Dear Editor,
We have carefully read the results of the randomized, placebo-controlled phase II clinical trial of HK-660S for the treatment of primary sclerosing cholangitis (PSC) by Paik et al. recently published in your journal [
1]. This study is a critical step forward in the field of PSC, a disease with extremely limited treatment options, and deserves high attention. However, some of the methodological issues in the paper need to be further elucidated to enhance the interpretability and reproducibility of the study results.
The study did not explicitly report the subjects’ baseline medication use, nor did it indicate whether medications with possible drug-durg interactions (e.g., UDCA, etc.) were uniformly discontinued or controlled prior to randomization. Although the trial allowed for the continuation of “stabilized doses of UDCA,” I do not understand the actual intent of such a move, which demonstrates my concern. Indeed, it has been shown that UDCA may affect the expression and function of the CYP3A4 enzyme system and transporters such as P gp and OATP1B1, thereby altering the level of exposure to the relevant substrate drugs [
2,
3]. If it is through these pathways that the pharmacokinetics and efficacy of HK 660S are regulated, it is highly likely that uncontrolled co-administration will have an impact on the assessment of HK 660S efficacy and safety outcomes. If HK-660S efficacy is partially attributable to UDCA, this may lead to overly optimistic estimates of its independent efficacy. A review on the design of PSC clinical trials [
4] states, “Comorbid medications must be adequately documented and controlled, especially those that may cross over with the study drug in biliary excretion or metabolic pathways.”
In terms of statistics, nonparametric methods were used for the primary comparative analyses in this article. Although these methods are robust to distributional assumptions, they may lack sufficient statistical efficacy in the context of small sample sizes, especially for longitudinal data with multiple time points such as ALP, ELF, and inflammatory biomarkers. In this context, the use of repeated-measures mixed-effects models (MMRM), which are more sensitive to capturing intra-individual changes over time and estimating “treatment-time” interaction effects, may better identify subtle but clinically significant trends that are missed by nonparametric tests.
We believe that data reanalysis, disclosure of regimen details, or clarification in future studies would help to strengthen the community’s confidence in the evidence for HK-660S’s efficacy. We thank the authors for their contribution to the field of PSC therapy and look forward to further results from this drug in subsequent studies.
FOOTNOTES
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Authors’ contributions
Bitao Jiang and Song Zhang wrote the manuscript, Lingling Bao provided methodological and theoretical support, and Lingling Bao and Bitao Jiang revised the manuscript.
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Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
primary sclerosing cholangitis
REFERENCES
- 1. Paik WH, Park JK, Chung MJ, Huh G, Park CH, Lee SH, et al. Safety and efficacy of HK-660S in patients with primary sclerosing cholangitis: A randomized double-blind phase 2a trial. Clin Mol Hepatol 2025;31:119-130.
- 2. Becquemont L, Glaeser H, Drescher S, Hitzl M, Simon N, Murdter TE, et al. Effects of ursodeoxycholic acid on P-glycoprotein and cytochrome P450 3A4-dependent pharmacokinetics in humans. Clin Pharmacol Ther 2006;79:449-460.
- 3. Hempfling W, Dilger K, Beuers U. Systematic review: ursodeoxycholic acid--adverse effects and drug interactions. Aliment Pharmacol Ther 2003;18:963-972.
- 4. Ponsioen CY, Lindor KD, Mehta R, Dimick-Santos L. Design and endpoints for clinical trials in primary sclerosing cholangitis. Hepatology 2018;68:1174-1188.
Citations
Citations to this article as recorded by
- Correspondence to letter to the editor on “Safety and efficacy of HK-660S in patients with primary sclerosing cholangitis: A randomized double-blind phase 2a trial”
Woo Hyun Paik, Heon Se Jeong, Do Hyun Park
Clinical and Molecular Hepatology.2026; 32(2): e233. CrossRef
