Commentary: Efficacy and safety of HSK21542 for pruritus management in hemodialysis patients: a multicenter, randomized, double-blind, placebo-controlled trial

statistical difference. In summary, the "superior efficacy" claim is may be misleading. In addition, the claim of superior safety for HSK21542 is also unsubstantiated. The safety relative to placebo was comparable: the incidence of treatment-emergent adverse events in the 0.3 μg/kg group (76.7%) was similar to placebo (73.3%). Thus, asserting an overall superior safety is incorrect. The 0.3 μg/kg HSK21542 appears to have a safety/tolerability profile similar to placebo, which is reassuring, but not "superior".High-dose (HSK21542 0.6 μg/kg) results: The findings for the higher 0.6 μg/kg dose which showed less itch relief vs placebo is under-addressed. The group difference was +1.03 points vs placebo, with a 95% CI of +0.01 to +2.07. Notably, this CI excludes zero, which implies a statistically significant worse result of the high dose vs placebo. The authors do not explicitly acknowledge this but simply describe the 0.6 μg/kg effect as "less pronounced" than that of 0.3 μg/kg and "although various efficacy endpoints in the 0.6 μg/kg dose group showed improvement from baseline, no significant dose-response relationship was observed compared to the 0.3 μg/kg dose group". These statements appear to understate the findings, as the data show a less favorable effect compared with placebo. These are understatements considering the data showed a worse effect compared to placebo. This is a relevant finding (possible U-shaped dose-response) that would be important to explore. I also note an omission in Table 2: the 5-D Itch score value is blank for the LS mean difference vs placebo for the 0.6 μg/kg group, with only the CI provided, which may be a formatting error. In summary, the significant worse lower itch improvement at 0.6 μg/kg vs placebo is an important result that warrants emphasis. In review BUSINESS USE Cross-Trial comparisons: In the discussion section, the outcomes of this Phase II trial are compared with difelikefalin trials for CKD-aP. They The authors report, that 62.1% of patients in the HSK21542 0.3 μg/kg group achieved ≥3-point WI-NRS improvement at 12 weeks, versus 49.1% and 53.4% in the Phase 3 KALM-1 and KALM-2 studies of difelikefalin, respectively. While these figures were correctly cited (2,4), cross-trial comparisons are potentially misleading. The patient population and study conditions differed and no matching or statistical comparison was performed. Contextualization is crucial important asand as directly comparing the responder percentages in separate trials without adjustment can may be misleading. The authors also draw parallels to the dose-response findings of difelikefalin's Phase II trial. They state that the lack of a dose-response (0.6 vs 0.3) in HSK21542 "mirrors the findings from the phase II study of difelikefalin, where the 0.5 μg/kg dose group exhibited better efficacy than the 1 μg/kg dose group". This comparison is may be imprecise because asthere was no statistical difference was observed between these groups, and the difelikefalin phase II trial showed a significant benefit or a trend towards a benefit of the drug vs placebo at all doses tested (0.5 μg/kg being optimal)(3). Given that the HSK21542 0.6 μg/kg dose group showed a statistically significant diminshed effect compared to placebo, drawing an analogy to difelikefalin may be misleading.Thus, considering the lack of efficacy for all HSK21542 dose groups, the analogy to difelikefalin seems misleading.Discussion: I urge recommend caution in interpreting the results of Pan et al.'s 2025 manuscript. The data do not demonstrate a significant benefit of HSK21542 0.3 μg/kg over placebo. I recommend that the authors and researchers ensure that statements in the abstract, discussion, and conclusion are fully supported by the results presented. Inadvertent mistakes, such as the missing number or minus symbol should may be corrected to avoid confusion. Comparing results to other studies without direct comparative data should be avoidedmade with caution. Accurate reporting of results with substantiated claims, will ultimately benefit the scientific community and patients by setting the stage for credible and reproducible findings in future trials. In summary, HSK21542 could be an interesting therapeutic candidate for CKD-aP, but the evidence from this Phase II study is not sufficient to prove superior efficacy and safety. We look forward to further studies that address these topics and clarify the role of HSK21542 in managing CKD-aP.In summary, authors must use care in the reporting of results. The repeated miststatements asserting efficacy in this study, when the results do not demonstrate significant efficacy vs. placebo, can be misleading for readers.