Efficacy and safety of anrikefon in the treatment of diabetic hemodialysis patients with pruritus: a post hoc analysis

Abstract

Background

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease worldwide and diabetes predisposes patients to pruritus. Anrikefon is a novel selective peripherally restricted kappa-opioid receptor agonist. This post hoc analysis utilized data from phase 3 anrikefon-302 study to investigate the efficacy and safety of anrikefon in the treatment of diabetic hemodialysis patients with pruritus.

Methods

This is a post hoc analysis of data collected in a randomized, placebo-controlled phase 3 study. Diabetic hemodialysis patients were included (anrikefon n = 67 and placebo n = 79). The percentage of patients achieving at least a 4-point or 3-point reduction in weekly mean 24 hour worst itching intensity numerical rating scale (WI-NRS) score from baseline to week 12 were analyzed. The changes in itch related quality of life from baseline using the Skindex-10 and 5-D itch scales were also compared.

Results

The baseline demographics and characteristics were generally similar in the individual placebo and anrikefon treatment arms. Interestingly, significantly more patients reported a clinically meaningful ≥ 4-point (29.9% versus 15.2%; p = 0.033) and ≥3-point (41.8% versus 20.3%; p = 0.012) reduction from baseline to week 12 in WI-NRS for the anrikefon group versus placebo. Furthermore, the change in WI-NRS score was significantly greater in patients receiving anrikefon treatment than in those in the placebo control group [−2.86 (SE 0.26) versus −1.63 (SE 0.21); p = 0.001]. Moreover, the mean change from baseline in the Skindex-10 itch score at week 12 was −16.25 (SE 1.52) in the anrikefon group and −8.49 (SE 1.36) in the placebo group (p < 0.001). The mean change from baseline in the 5-D itch score at week 12 was −5.41 (SE 0.45) in the anrikefon group and −3.20 (SE 0.38) in the placebo group. Moreover, the incidence of treatment emergent adverse events was comparable between the two groups.

Conclusions

Anrikefon resulted in a noticeable reduction in itch intensity and an improvement in itch related quality of life in diabetic hemodialysis patients with pruritus.

Introduction

Chronic kidney disease-associated pruritus (CKD-aP) is a highly distressing condition affecting patients with CKD, particularly those with advanced or end-stage renal disease [1–3]. CKD-aP affects more than 60% of patients undergoing hemodialysis, with 33–50% reporting moderate to severe itching [3]. Accumulating evidence indicated that diabetes, a metabolic disorder frequently leading to CKD, predisposes patients to pruritus [4]. Indeed, pruritus is one of the most common cutaneous manifestations in diabetes mellitus, particularly among the diabetic kidney disease (DKD) population [5–7]. As a prevalent and underrecognized complication of diabetes, pruritus is characterized by persistent, intractable itching, which is directly associated with impaired quality of life and increased mortality risk [8, 9]. Thus, pruritus represents a particularly recalcitrant clinical challenge for diabetic patients.

The pathogenesis of pruritus in DKD is complex and remains incompletely elucidated. It is generally accepted that various pruritogens, receptors, neurons, and neurotransmitters is involved in the pathophysiology of itching [10, 11]. Notably, a cross-sectional analysis from the CKD Outcomes and Practice Patterns Study identified diabetes as a risk factor associated with higher prevalence ratios of moderate-to-severe pruritus [12]. Indeed, this finding was replicated in a separate study of the association between risk factors and incident pruritus [13]. These data suggest that pruritus in individuals with diabetes may exhibit distinct characteristics.

Anrikefon is a novel selective peripherally restricted kappa opioid receptor (KOR) agonist with antinociceptive and antipruritic properties [14, 15]. A recent randomized controlled trial involving 545 hemodialysis patients with moderate-to-severe CKD-aP confirmed that anrikefon has reliable clinical efficacy in the treatment of CKD-aP [16]. Moreover, the anrikefon group showed significant improvements in itch related quality of life. However, the efficacy of anrikefon on DKD population has never been evaluated. Given that DKD has become the primary etiology of CKD, accounting for more than 50% of CKD cases globally [15], exploring the efficacy of anrikefon in this special population is crucial for guiding precision-based clinical management. Therefore, the primary purpose of the current study was to rigorously investigate the efficacy of anrikefon for pruritus in diabetic hemodialysis patients though post hoc analysis of data from the phase 3 Anrikefon-302 study.

Methods

Study

This is a post hoc analysis of data collected in a randomized, placebo-controlled phase 3 study. Detailed methods of the studies (NCT05135390) have previously been described [16].

In brief, the randomized, placebo-controlled phase 3 study was a multicenter, double-blind, placebo-controlled study in patients with moderate-to-severe CKD-aP undergoing hemodialysis, randomized to receive 0.3 μg/kg anrikefon (n = 275) or placebo (n = 270) three times per week (following each hemodialysis session) for 12 weeks. Inclusion criteria were a weekly mean 24 hour worst itching intensity numerical rating scale (WI-NRS) score of > 5 during a 7-day run-in period (scores ranged from 0 to 10). All patients were from the China.

The phase 3 study were conducted in accordance with the principles of the Declaration of Helsinki. Institutional review boards or independent ethics committees reviewed and approved the protocols before studies were commenced.

Analysis of DKD population

In this analysis, the baseline and following-up data from the Anrikefon-302 study were used and analyzed. Diabetic hemodialysis patients were included based on the medical history during the screening period. Here, 67 participants were enrolled in the anrikefon treatment group, and 79 in the placebo group.

Statistical analysis

Because this is a post hoc analysis, all p values are exploratory and should be interpreted descriptively. Here, the Shapiro–Wilks test was performed to assess the Gaussian distribution of continuous variables. Continuous variables with normal distributions are expressed as means ± standard deviation (SD) or means ± standard error (SE). Those without normal distributions are presented as medians and interquartile ranges. The Student’s t-test or Mann-Whitney U test were used to compare continuous variables. Categorical variables are presented as numbers with percentages. The Chi-square test was used to compare the categorical variables. A p value < 0.05 was considered statistically significant. All statistical analyses were performed using R software (version 4.5.1, 2025–06-13, UCRT). A two-tailed p value < 0.05 was considered statistically significant.

Results

Baseline demographics and characteristics

In total, 146 participants in the Anrikefon-302 study were diabetic hemodialysis patients and were enrolled in the analyses. The baseline Skindex-10 scale score was higher (p = 0.04) in the anruikfen group compared with those in the placebo group. Demographics and other characteristics were generally similar (all p > 0.05) at baseline in the individual placebo and anrikefon treatment arms (Table 1).

Table 1.

Baseline characteristics of patients with diabetes in HSK21542-302 study

Characteristic	Overall（n = 146）	Anrikefon（n = 67）	Placebo（n = 79）	p
Age [M (Q1, Q3)]	58.50 (51.00, 63.75)	58.00 (51.00, 61.50)	59.00 (51.00, 64.50)	0.449
Age < 65 year (%)	114 (78.1)	55 (82.1)	59 (74.7)	0.380
Age ≥ 65 year (%)	32 (21.9)	12 (17.9)	20 (25.3)
Male (%)	115 (78.8)	52 (77.6)	63 (79.7)	0.911
Mean (SD) height (cm)	167.07 (7.75)	166.96 (8.27)	167.16 (7.33)	0.879
Mean (SD) dry body weight (kg)	65.77 (11.89)	66.82 (12.31)	64.88 (11.53)	0.331
Baseline anti-itch medication use, n (%) Yes	11 (7.5)	6 (9.0)	5 (6.3)	0.776
Weekly WI-NRS score (range 0–10) †	7.20 (1.16)	7.29 (1.15)	7.12 (1.17)	0.359
Moderate (<7)	61 (41.8)	24 (35.8)	37 (46.8)	0.239
Severe (≥7)	85 (58.2)	43 (64.2)	42 (53.2)
Baseline M (Q1, Q3) Skindex-10 scale score (range 0–60) ‡	29.00 (20.00, 39.00)	33.00 (23.50, 42.00)	27.00 (18.00, 36.00)	0.040
Baseline M (Q1, Q3) 5-D itch scale (range 5–25) ‡	16.00 (14.00, 18.00)	16.00 (14.00, 19.00)	16.00 (14.00, 18.00)	0.706
Blood glucose (mmol/L) [M (Q1, Q3)]	7.44 (5.60, 10.70)	8.12 (5.96, 11.16)	7.19 (5.37, 10.22)	0.170
Potassium (mmol/L) [mean (SD)]	5.00 (0.74)	4.91 (0.75)	5.08 (0.72)	0.171
Calcium (mmol/L) [mean (SD)]	2.23 (0.23)	2.20 (0.19)	2.25 (0.26)	0.136
Serum phosphate (mmol/L) [M (Q1, Q3)]	1.83 (1.42, 2.25)	1.87 (1.52, 2.28)	1.72 (1.33, 2.24)	0.276
Phosphate (%) >1.45 mmol/L	107 (73.3)	53 (79.1)	54 (68.4)	0.202
Phosphate (%) ≤1.45 mmol/L	39 (26.7)	14 (20.9)	25 (31.6)
iPTH (pg/mL) [M (Q1, Q3)]	29.88 (15.81, 43.94)	32.46 (15.42, 50.16)	28.18 (16.01, 40.68)	0.419
iPTH (%) >300 pg/mL	67 (45.9)	34 (50.7)	33 (41.8)	0.359
iPTH (%) ≤300 pg/mL	79 (54.1)	33 (49.3)	46 (58.2)
Hemoglobin (g/L) [mean (SD)]	113.93 (14.21)	114.24 (13.56)	113.67 (14.81)	0.809

SD = standard deviation; WI-NRS = worst itching intensity numerical rating scale; iPTH = intact parathyroid hormone. †Measures worst itching intensity during previous 24 hours; higher scores indicate greater intensity of itching. ‡Higher scores indicate worse itch related quality of life

Anrikefon treatment and reduction in WI-NRS score

Significantly more patients reported a clinically meaningful ≥ 4-point reduction from baseline to week 12 in WI-NRS for the diabetes group with anrikefon versus placebo (29.9% versus 15.2%; p = 0.033) (Fig. 1A). Meanwhile, significantly more patients reported a clinically meaningful ≥ 3-point reduction from baseline to week 12 in WI-NRS with anrikefon than placebo in this population (41.8% versus 20.3%; p = 0.012) (Fig. 1B).

Fig. 1.

Anrikefon treatment decreased the WI-NRS score of patients. A: significantly more patients reported a clinically meaningful ≥ 4-point reduction from baseline to week 12 in WI-NRS for the diabetes group with anrikefon versus placeb. B: significantly more patients reported a clinically meaningful ≥ 3-point reduction from baseline to week 12 in WI-NRS with anrikefon than placebo in this population

Anrikefon treatment and changed WI-NRS score

The change in the WI-NRS score was significantly greater in patients receiving anrikefon treatment than in those in the placebo control group [−2.86 (SE 0.26) versus −1.63 (SE 0.21); p = 0.001] (Fig. 2).

Fig. 2.

Anrikefon treatment was associated with greater in changed WI-NRS score. The change in the WI-NRS score was significantly greater in patients receiving anrikefon treatment than in those in the placebo control group

Anrikefon treatment and itch-related quality of life

The mean change from baseline in the Skindex-10 itch score at week 12 was −16.25 (SE 1.52) in the anrikefon group and −8.49 (SE 1.36) in the placebo group, with a between group difference of −7.76 (p < 0.001) (Fig. 3A). Meanwhile, the mean change from baseline in the 5-D itch score at week 12 was −5.41 (SE 0.45) in the anrikefon group and −3.20 (SE 0.38) in the placebo group, with a between group difference of −2.21 (p = 0.001) (Fig. 3B).

Fig. 3.

Anrikefon treatment improved the itch-related quality of life of patients. A: the mean change from baseline in the Skindex-10 itch score at week 12 in the anrikefon group and in the placebo group. B: the mean change from baseline in the 5-D itch score at week 12 in the anrikefon group and in the placebo group

Adverse events

For safety, the incidence of treatment emergent adverse events was comparable between the two groups (all p > 0.05) (Table 2). The relative risk for the incidence of treatment emergent adverse events was 1.048 for the comparison between the two groups.

Table 2.

Adverse events during double blind phase in diabetic patients with CKD-aP undergoing hemodialysis assigned to receive anrikefon or placebo

	HSK21542（n = 67）	Placebo（n = 79）
Any adverse event*	64 (95.5%)	72 (91.1%)
SAE	7 (10.4%)	7 (8.9%)
Treatment-related adverse events	5 (7.5%)	4 (5.1%)
TEAEs	64 (95.5%)	72 (91.1%)
Grade ≥ 3 TEAEs	7 (10.4%)	7 (8.9%)
TEAEs leading to temporary discontinuation of study drug	2 (3.0%)	2 (2.5%)
TEAEs leading to study discontinuation	1 (1.5%)	0
COVID-19	15 (22.4%)	23 (29.1%)
COVID-19 pneumonia	3 (4.5%)	2 (2.5%)
Upper respiratory tract infection	8 (11.9%)	6 (7.6%)
Constipation	3 (4.5%)	2 (2.5%)
Hypotension	5 (7.5%)	5 (6.3%)
Hypoglycemia	3 (4.5%)	1 (1.3%)
Dizziness	2 (3.0%)	2 (2.5%)
Fatigue	1 (1.5%)	1 (1.3%)
Metabolic acidosis	1 (1.5%)	2 (2.5%)
Hypoproteinemia	1 (1.5%)	1 (1.3%)
Sleep disorder	1 (1.5%)	0
Muscle cramps	1 (1.5%)	3 (3.8%)
Dialysis related hypotension	1 (1.5%)	1 (1.3%)
Hypoalbuminemia	0	2 (2.5%)
Chest pain	0	1 (1.3%)
Diarrhea	0	1 (1.3%)
Hyperkalemia	0	1 (1.3%)

TEAEs = treatment emergent adverse events. *Preferred terms in the Medical Dictionary for Regulatory Activities, version 27.0, were used for the documentation of adverse events

Discussion

This post hoc analysis of data from the phase 3 Anrikefon-302 trial aimed to investigate whether anrikefon ameliorates CKD-aP in patients with DKD condition. Interestingly, in diabetic hemodialysis patients with moderate to severe pruritus, anrikefon resulted in a noticeable reduction in itch intensity and an improvement in itch related quality of life.

Diabetes, the most common metabolic disorder frequently progressing to DKD, predisposes patients to pruritus, which is usually neglected and frequently underdiagnosed [17]. Previously, multiple studies demonstrated that hyperglycemia was associated with development and severity of pruritus [18, 19]. Indeed, diabetic pruritus is considered a dermatometabolic condition. Impaired skin elasticity and decreased cutaneous sebaceous gland activity were one of the charactered features of patients with diabetes [20]. Although the pathogenesis of pruritus in diabetes is not fully understood, multifactorial mechanisms may be involved, such as peripheral neuropathy, immune system dysregulation, and imbalances in the endogenous opioid system. Diabetic patients with disease of peripheral or small nerves represent about 40% of the dialysis population worldwide. Notably, peripheral neuropathic itching is thought to result when primary afferent sensory neurons or interneurons are activated out of proportion to or independent of any pruritogens [21]. Furthermore, a high prevalence of peripheral sensorimotor neuropathy and dysautonomia has been found in diabetic patients, which may explain their itching [22, 23]. These findings suggest that peripheral nerve dysfunction represents a pivotal pathogenic driver of diabetic pruritus.

Currently, non-specific targeted strategies aimed at symptom relief, such as anesthetics, antihistamines, emollients, cooling agents, corticosteroids, and phototherapy, are a mainstay for CKD-aP [24]. It has been found efficacy in relieving pruritus among diabetic hemodialysis patients [25, 26]. However, the limited efficacy and/or considerable side effects hinder their widespread use. Therefore, the clinical need for effective therapy of pruritus remains unmet. Interestingly, anrikefon, a novel selective peripherally restricted KOR agonist, possesses a hydrophilic small peptide and spirocyclic structure that enhances its binding affinity to the KOR, resulting in minimal penetration of the blood-brain barrier [27]. However, the efficiency of anrikefon in patients with DKD has not been investigated. Here, this post hoc analysis found that significantly more patients reported a clinically meaningful ≥ 4-point (29.9% versus 15.2%) and ≥3-point (41.8% versus 20.3%) reduction from baseline to week 12 in WI-NRS for the diabetes group with anrikefon versus placebo, indicating that anrikefon is considered for pruritus associated with DKD.

It is well-known that diabetes profoundly impacts patients’ overall health by significantly increasing their risk of developing a range of complications and comorbidities, which severely diminish quality of life across multiple dimensions—including physical health, and mental well-being [28, 29]. Notably, pruritus, a frequent and distressing problem, also leads to a plethora of problems including sleep impairment, anxiety, and depression [30]. Consequently, this imposes a heavy burden on individuals and health systems. Interestingly, besides alleviating pruritus, anrikefon can critically improve the quality of life in individuals with DKD. Accordingly, the post hoc analysis indicated that compared with the placebo, the mean changes from baseline in the Skindex-10 and 5-D itch score at week 12 were significantly greater in the anrikefon group. Thus, exploring effective therapeutic strategies for diabetic pruritus holds profound clinical significance that extends far beyond alleviating patients’ physical discomfort.

Moreover, scratching behavior induced by pruritus could result in skin barrier damage, secondary infections, and ulceration [31], which not only exacerbate the disease burden but also increase the risk of diabetic foot—a life-threatening complication requiring costly clinical interventions. Thus, targeted treatments for this condition may not only relieve pruritic symptoms but also reduce the incidence of potentially life-threatening complications. Additionally, optimizing therapeutic regimens for diabetic pruritus can reduce the frequency of hospital readmissions and healthcare expenditures [32]. Collectively, advancing the treatment of pruritus is pivotal for improving the comprehensive management and prognosis of DKD patients in clinical practice.

There are limitations to this analysis. Notably, because this is a post hoc subgroup analysis, results should be interpreted with caution. This conclusion needs to be validated by large-sample randomized controlled trials.

In conclusion, it was found that anrikefon resulted in a noticeable reduction in itch intensity and an improvement in itch related quality of life in diabetic hemodialysis patients with pruritus.

Author contributions

Z-L L and B-C L designed the study, analyzed data, and wrote and edited the paper. M-M P and Z-Y L analyzed and interpreted the data. All authors read and approved the final paper.

Funding

This work was supported by the National Natural Science Foundation of China (82570816); the Natural Science Foundation of Jiangsu Province (BK20240212); and the ZhiShan Scholar Program of Southeast University (2242025RCB0054).

Data availability

Previously published data were used for this study.

Declarations

Ethical approval

This is a post hoc analysis of data collected in a randomized, placebo-controlled phase 3 study, which was conducted in accordance with the principles of the Declaration of Helsinki. Institutional review boards or independent ethics committees reviewed and approved the protocols before studies were commenced (the ethics committee of the Clinical Research of the First Affiliated Hospital to Zhejiang University School of Medicine [approval No 2022–177], Zhongda Hospital Affiliated to Southeast University School of Medicine [approval No 2021ZDSYLL318-Y01], and all other participating centers). Informed consent was obtained from each patient.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.