Dear Editor,
We extend our gratitude to Dr. Bitao Jiang and colleagues for their insightful editorial on our recent study evaluating HK-660S as a treatment option for primary sclerosing cholangitis (PSC) [
1]. Their editorial highlight key points and provide constructive criticism on various aspects, from trial design to potential clinical implications, that will enhance the scope and direction of future research [
2]. Here, we aim to clarify our study’s rationale and address the valuable points they raised.
The study allows the use of low-dose ursodeoxycholic acid (UDCA, ≤23 mg/kg/day) as a concomitant medication, by AASLD guidelines recommending UDCA at 13–23 mg/kg/day for the treatment of PSC [
3], and EASL guidelines recommending 13–15 mg/kg/day for PSC [
4].
Furthermore, the study protocol states that “PSC patients deemed unsuitable for participation at the investigator’s discretion, or those who received herbal medicines for fatty liver disease within 2 weeks prior to screening,” are excluded. Additionally, “a history of medication for steatohepatitis within five times the half-life of the respective drug before screening” was also excluded. All medications potentially related to PSC, except low-dose UDCA, azathioprine, and prednisone, were prohibited.
Given the existing treatment recommendations for PSC, administering only a placebo in the control group could raise ethical concerns, despite the absence of an approved drug for PSC. Therefore, under current clinical practice, patients who were already receiving UDCA before screening were allowed to continue at a stable dose. The mean±SD UDCA dose was 10.7±6.33 mg/kg/day (n=15) in the study group and 9.6±5.92 mg/kg/day (n=6) in the control group.
Regarding efficacy, our study data indicate that HK-660S, when used in combination with UDCA, is more effective in reducing alkaline phosphatase (ALP) levels compared to UDCA treatment alone. Only two patients (one in each group) did not receive UDCA, as they were not taking it at the time of screening. Regarding safety, no adverse drug reaction (ADR) developed in the control group, whereas the study group showed an ADR rate of 18.8%, observed in three patients. The most frequent ADRs—gastrointestinal symptoms such as abdominal pain, distension, diarrhea and nausea—are consistent with the known mechanism of action of HK-660S.
Regarding the drug interaction, HK-660S may inhibit CYP1A2, COX-1, protein tyrosine kinase (Fyn), and protein tyrosine phosphatase (CD45) based on our off-target study data. Therefore, we believe that HK-660S has no drug interaction with UDCA based on our current information. However, your suggestion is highly valuable and will be carefully considered in a pharmacokinetic study of the combination treatment of HK-660S and UDCA in the future.
From a statistical perspective, considering the limited sample size and the distributional characteristics of the data, the analysis method pre-specified in the study protocol was employed. According to ICH E9, statistical methods should be chosen based on the study objectives and data characteristics, rather than applying a universal standard. Nonparametric approaches are specifically recommended when data do not meet the assumptions required for parametric methods [
5], as is often the case with smallsample, skewed distributions, or outlier-prone clinical variables such as ALP, enhanced liver fibrosis score and inflammatory biomarkers.
While model-based methods like mixed model for repeated measures (MMRM) can be powerful, ICH E9 cautions that their validity depends on correct model specification and sufficient sample size. In small samples, MMRM may yield unstable or biased results. Nonparametric methods, in contrast, offer robustness, transparency, and clinically interpretable outcomes, aligning with ICH E9’s emphasis on scientific justification and pre-specification.
Therefore, we believe our use of nonparametric methods is consistent with ICH E9 guidance and appropriate for our study’s data and objectives. Nonetheless, we acknowledge that the MMRM may offer a more robust and precise evaluation of treatment effects over time. Accordingly, the method of MMRM will be considered in future analyses or study designs.
We thank Dr. Bitao and colleagues for their detailed reviews and for underscoring the importance of addressing the complexities of PSC through innovative trial designs and robust endpoints. By expanding our methodological approach and refining the trial protocols in accordance with their recommendations, we hope to contribute to the development of a safe and effective treatment for PSC. We remain committed to advancing research on HK-660S, confident that future studies will further substantiate its potential as a promising therapeutic option.
FOOTNOTES
-
Authors’ contribution
Original draft and critical revision: W.H.P., H.S.J. and D.H.P.
-
Conflicts of Interest
Heon Se Jeong is a Curome Biosciences Co., Ltd employee. The other authors have no conflicts to disclose.
Abbreviations
mixed model for repeated measures
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. Jiang B, Zhang S, Bao L. Letter to the editor on “Safety and efficacy of HK-660S in patients with primary sclerosing cholangitis: A randomized double-blind phase 2a trial”. Clin Mol Hepatol 2026;32:e129-e130.
- 3. Bowlus CL, Arrivé L, Bergquist A, Deneau M, Forman L, Ilyas SI, et al. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology 2023;77:659-702.
- 4. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 2009;51:237-267.
- 5. ICH Topic E 9 Statistical Principles for Clinical Trials. European Medicines Agency (EMA). ICH E9 statistical principles for clinical trials - Scientific guideline. EMA web site, <https://www.ema.europa.eu/en/ich-e9-statistical-principles-clinical-trials-scientific-guideline>. Accessed 7 Jul. 2025.
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