Dear Editor,
We read with interest the phase 2a trial by Paik et al. [
1] investigating HK-660S in patients with primary sclerosing cholangitis (PSC). While the study highlights promising reductions in alkaline phosphatase (ALP) levels and improvements in magnetic resonance cholangiopancreatograph (MRCP) Anali scores, several methodological and mechanistic limitations warrant deeper scrutiny to contextualize these findings.
The trial design utilized placebo as a comparator, yet 93.3% of HK-660S recipients and 83.3% of placebo patients received concomitant ursodeoxycholic acid (UDCA). UDCA itself exhibits dose-dependent effects on ALP and disease progression in PSC, with high doses (>28 mg/kg/day) linked to adverse outcomes [
2]. Notably, two HK-660S patients received UDCA doses exceeding 900 mg/day (16.9 mg/kg), while others received ≤900 mg/day. This heterogeneity introduces confounding, as UDCA’s variable efficacy could mask or amplify HK-660S effects. A stratified analysis by UDCA dose (e.g., <15 vs. ≥15 mg/kg/day) is critical to isolate HK-660S-specific responses, akin to norUDCA trials where UDCA-naïve cohorts were prioritized [
3].
The Anali score was a key endpoint, yet inter- and intra-observer variability of MRCP in PSC remains a concern. While two radiologists independently scored images, the study omitted kappa statistics or intraclass correlation coefficients to quantify agreement. Prior work demonstrated only moderate inter-reader reliability for Anali scores (κ=0.45–0.60) [
4]. Without transparency on scoring consistency, improvements in Anali scores (13.3% vs. 0%) may reflect measurement error rather than true therapeutic effect. Incorporating quantitative MRCP metrics (e.g., stricture length/volume) or secondary validation via endoscopic retrograde cholangiopancreatograp could strengthen structural outcome assessments.
ALP reduction was emphasized, yet its utility in PSC is contested. ALP fluctuations unrelated to disease activity are common, and a ≥40% reduction—not 20%—is increasingly adopted as a clinically meaningful threshold [
5]. The reported 15.2% ALP reduction with HK-660S falls short of this benchmark. Furthermore, ALP lacks specificity for cholangiocyte injury; concurrent declines in CCL-2 (monocyte chemoattractant) and enhanced liver fibrosis (ELF) scores suggest broader anti-inflammatory effects. Integrating bile acid composition (e.g., conjugated/unconjugated ratios) or cholangiocyte-specific biomarkers (e.g., cytokeratin-19 fragments) could better delineate HK-660S’s mechanism.
HK-660S purportedly attenuates fibrosis via SIRT1 activation, yet histopathological validation is absent. Transient elastography liver stiffness measurement (LSM) and ELF scores are indirect proxies; liver biopsy remains the gold standard for fibrosis staging [
6]. In the NGM282 trial, biopsy-proven fibrosis regression validated serum biomarker trends [
7]. Similarly, HK-660S requires paired biopsies to confirm antifibrotic efficacy, particularly given discrepancies between ELF improvements (26.7%) and LSM changes (3/15 patients).
Stratification by 1, NAD(P)H quinone dehydrogenase 1 (NQO1) genotype (T/T, C/T, C/C) was performed but not leveraged in efficacy analyses. NQO1 polymorphisms significantly influence beta-lapachone metabolism and NAD+ modulation [
8]. For example, C/C genotypes exhibit 30–50% lower enzymatic activity, potentially blunting HK-660S effects. Subgroup analyses by genotype could identify responders, mirroring precision approaches in PPAR-δ agonist trials [
9].
In conclusion, while HK-660S shows tentative promise, the trial’s conclusions are constrained by methodological gaps. Future studies should: (1) control for UDCA dose effects through stratification or enrichment of UDCA-naïve cohorts; (2) validate MRCP outcomes with quantitative imaging and inter-reader metrics; (3) incorporate histopathology and cholangiocyte-specific biomarkers; and (4) leverage NQO1 genotyping for personalized dosing. Such refinements will clarify whether HK-660S truly modifies PSC progression or merely modulates surrogate endpoints.
FOOTNOTES
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Authors’ contribution
Y-Z. X. conceived the work. All authors contributed substantially to discussion of the content. Y-Z. H. wrote the article. All authors reviewed and/or edited the manuscript before submission. All authors approve the final version of the manuscript.
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Acknowledgements
This study is funded by the Hunan Provincial Natural Science Foundation of China (Grant No. 2025JJ60567 and 2025JJ50527).
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Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
magnetic resonance cholangiopancreatograph
NAD(P)H quinone dehydrogenase 1
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