A phase 3 randomized controlled trial has demonstrated that anrikefon, a novel selective peripherally restricted kappa opioid receptor agonist, significantly reduces itch severity and improves quality of life in patients with chronic kidney disease-associated pruritus undergoing hemodialysis. The multicenter study, conducted across 50 centers in China from June 2022 to June 2024, represents a major advancement in treating this challenging condition affecting dialysis patients.
Primary Efficacy Results
The trial enrolled 652 patients with moderate to severe chronic kidney disease-associated pruritus, with 545 patients ultimately randomized to receive either intravenous anrikefon (0.3 μg/kg) or placebo three times weekly for 12 weeks. At the primary endpoint of week 12, 37% of patients receiving anrikefon achieved at least a 4-point reduction in weekly mean 24-hour worst itching intensity numerical rating scale scores compared with 15% in the placebo group (P<0.001).
Secondary efficacy measures further supported anrikefon's therapeutic benefit. More than half (51%) of patients in the anrikefon group achieved at least a 3-point reduction in itch scores compared with 24% of placebo recipients (P<0.001). Improvements were observed as early as the second week of treatment and continued through the 12-week study period.
Quality of Life Improvements
Quality-of-life measures consistently favored anrikefon treatment. The anrikefon group showed significant improvements in itch-related quality of life, with mean changes from baseline in the 5-D itch scale of -5.3 versus -3.1 for placebo (P<0.001) and in the Skindex-10 scale of -15.2 versus -9.3 for placebo (P<0.001).
Long-term Efficacy Data
In a 40-week open-label extension phase, patients from both groups could continue with anrikefon treatment. At week 40, 356 of 443 participants showed persistent improvement in quality-of-life scores on the 5-D itch scale. The researchers noted that the change from baseline during the double-blind phase was -7.8 points among the 176 patients originally assigned to anrikefon and -7.6 points among the 180 patients originally assigned to placebo, demonstrating sustained therapeutic effects.
Superior Pharmacological Profile
According to the study authors led by Jiang-Hua Chen, MD, of Zhejiang University School of Medicine, anrikefon's enhanced efficacy stems from its unique structural modifications. "Notably, anrikefon has a spiral ring structural modification, which improves the binding affinity of kappa opioid receptor, providing stronger agonistic activity," the researchers wrote. An in vitro study revealed that anrikefon's agonistic activity was more than 12 times higher than that of difelikefalin, while requiring a lower treatment dose (0.3 μg/kg versus 0.5 μg/kg).
The phase 3 trial demonstrated that anrikefon's efficacy with the lower treatment dose was comparable to that of difelikefalin, with 37.2% versus 37.1% of patients achieving the primary endpoint in treating pruritus in hemodialysis patients.
Safety Profile
The safety profile of anrikefon was generally favorable. Adverse events occurred in 83% of patients who received anrikefon and 82% of those who received placebo during the double-blind phase. Severe events were reported in 18% and 21%, respectively. Mild to moderate dizziness was the most common drug-related event with anrikefon but was generally well-tolerated without evident clinical consequences.
Importantly, no dysphoria or hallucination events occurred, which are well-documented adverse effects with centrally acting kappa opioid receptor agonists. Three deaths occurred in the anrikefon group and five in the placebo group during the double-blind phase. In the 40-week open-label extension, adverse events occurred in 93% of patients, with drug-related adverse events in 21%, and 20 deaths (4%) were reported overall.
Study Design and Limitations
The multicenter, double-blind, randomized placebo-controlled trial used a 1:1 randomization ratio stratified by baseline itch severity. Anrikefon was administered intravenously at 0.3 μg/kg three times weekly within one hour following dialysis. The trial permitted stable doses of antipruritic medications but prohibited initiation of new therapy following screening.
Study limitations included the single-country setting, which may affect generalizability, and the potential for bias in adverse-event reporting during the open-label extension phase. The researchers noted that because only patients with end-stage renal disease undergoing hemodialysis were enrolled, the safety and efficacy of anrikefon in non-dialysis-dependent chronic kidney disease requires further evaluation. They also emphasized the need for active-controlled trials comparing anrikefon with approved treatments.
The researchers concluded that "the sustained therapeutic effect and low incidence of central opioid adverse reactions make anrikefon a promising new treatment option for patients with CKD associated pruritus."
