Clinically Recommended Difelikefalin Dose for Uremic Pruritus

Patients with end-stage kidney disease undergoing dialysis frequently develop uremic pruritus. There are direct associations between pruritus and reduced quality of life (QoL), depression, poor sleep quality, and increased mortality. The most common treatments for pruritus are antihistamines, antiallergic agents, topical moisturizers, and corticosteroids. However, despite the use of these medications, moderate to severe pruritus persists in 40% of patients undergoing hemodialysis.

In Japan, nalfurafine, an oral k-opioid receptor (KOR), is approved for the treatment of moderate to severe pruritus. However, the oral formulation is problematic for many patients undergoing dialysis.

Difelikefalin is a selective KOR agonist with low membrane permeability and limited transfer to the central nervous system. It is expected to have a more favorable safety profile and improved tolerability compared with other KOR agonists. The intravenous formulation of difelikefalin allows direct administration at the end of the dialysis session.

Ichiei Narita, MD, PhD, and colleagues in Japan conducted a randomized, double-blind, placebo-controlled, four-arm phase 2 trial to identify the clinically recommended dose of difelikefalin based on efficiency, dose response, safety, and pharmacokinetics. Results were reported in JAMA Network Open [doi:10.1001/jamanetworkopen.2022.10339].

The trial was conducted from February 1, 2019, to October 22, 2019, at 94 sites in Japan. The study population included patients with moderate to severe pruritus receiving hemodialysis. The study intervention was difelikefalin (0.25, 0.5, and 1.0 µg/kg) or placebo administered intravenously three times a week at the end of each hemodialysis session for 8 weeks.

The primary end point was the change from baseline in the weekly mean Worst Itching Intensity Numerical Rating Scale (NRS) score at week 8. Secondary outcomes included measured changes in itch-related QoL score using the Skindex-16 and 5-D itch scale. Safety outcomes were assessed using adverse events, laboratory test results, vital signs, body weight, and 12-lead electrocardiogram.

A total of 311 Japanese patients provided informed consent. Of those, 247 (75% [n=186] male; mean age 64.5 years) were randomized and received at least one dose of the study drug: placebo (n=63), 0.25 µg/kg of difelikefalin (n=61), 0.5 µg/kg of difelikefalin (n=61), and 1.0 µg/kg of difelikefalin (n=62). Of those patients, 225 completed the study treatment: 59 in the placebo group; 59 in the 0.25 µg/kg of difelikefalin group; 53 in the 0.5 µg/kg of difelikefalin group; and 54 in the 1.0 µg/kg of difelikefalin group. In the full analysis set, baseline characteristics were similar across treatment groups. Treatment adherence in all groups was more than 98%.

The change from baseline in the weekly mean NRS score at week 8 was –2.86 in the placebo group, –2.97 in the 0.25 µg/kg of difelikefalin group; –3.65 in the 0.5 µg/kg of difelikefalin group; and ­–3.64 in the 1.0 µg/kg of difelikefalin group. Compared with the placebo group, there were significant differences for 0.5 µg/kg of difelikefalin (adjusted mean difference, –0.80; 95% CI, –1.55 to –0.04; P=.04) and for 1.0 µg/kg of difelikefalin (adjusted mean difference, –0.78; 95% CI, –1.54 to –0.03; P=.04). Sensitivity analyses revealed similar results.

Throughout the study, compared with placebo, there were significant reductions in weekly mean NRS score in the 0.5- and 1.0-µg/kg difelikefalin groups. At week 2, the difference in change from baseline in the weekly mean NRS score was –0.06 for the 0.25 µg/kg of difelikefalin group, –0.69 for the 0.5 µg/kg of difelikefalin group, and –0.95 for the 1.0 µg/kg of difelikefalin group. At week 8, the differences were –0.11 in the 0.25 µg/kg of difelikefalin group. –0.80 in the 0.5 µg/kg of difelikefalin group, and –0.78 in the 1.0 µg/kg of difelikefalin group and –0.78.

For the secondary end points, the Skindex-16 overall score and the 5-D itch scale total score indicated improvement with treatment with 0.5 and 1.0 µg/kg of difelikefalin ( adjusted weekly mean Skindex-16 overall score at week 8, –27.79 (95% CI, –31.83 to –23.74) for 0.5 µg/kg of difelikefalin and –22.69 (95% CI, –26.71 to –18.68) for 1.0 µg/kg of difelikefalin. The adjusted weekly mean 5-D itch scale total score at week 8 was –6.5 (95% CI, –7.2 to –5.8) for 0.5 0.25 µg/kg of difelikefalin and –6.8 (95% CI, –7.5 to –6.2) for 1.0 µg/kg of difelikefalin.

Analysis of safety outcomes identified adverse events in 42 of 63 patients in the placebo group (67%), in 44 of 61 patients in the 0.25 µg/kg of difelikefalin group (72%), in 47 of 61 patients in the 0.5 µg/kg of difelikefalin group (77%), and in 53 of 62 patients in the 1.0 µg/kg of difelikefalin group (85%). The incidence of adverse events increased in a dose-dependent manner, and the incidence was significantly higher in the 1.0 µg/kg of difelikefalin group compared with the placebo group (85% vs 67%, respectively; P=.02).

Adverse events related to the central nervous system (CNS), including somnolence and dizziness, were more frequent in the 1.0 µg/kg of difelikefalin group; the incidence of CNS adverse events in the 0.5 µg/kg of difelikefalin group and in the 0.25 µg/kg of difelikefalin group was similar to that in the placebo group. Most adverse events were mild and occurred relatively early in treatment, and patients improved or received without discontinued or suspended use of the study drug.

There were no deaths reported in any group. Serious adverse events occurred in three patients in the 0.25 µg/kg of difelikefalin group (5%), in eight patients in the 0.5 µg/kg of difelikefalin group (13%), and in five patients in the 1.0 µg/kg of difelikefalin group (8%).

The authors cited some limitations to the study findings, including the relatively large placebo effect due to the subjective symptoms of itching being evaluated based solely on patient-reported outcomes, not including depression and anxiety in the analyses, not evaluating objective end points such as skin findings, and the small sample size.

In conclusion, the researchers said, “This phase 2 trial in Japanese patients with pruritus receiving hemodialysis demonstrated that, compared with placebo, 0.5 µg/kg of difelikefalin significantly improved moderate to severe pruritus and this dose can be considered to be the clinically recommended dose. Difelikefalin at a dose of 0.5 µg/kg is expected to be a new option for the treatment of moderate to severe pruritus in patients receiving hemodialysis.”

Takeaway Points

1. Researchers in Japan conducted a phase 2 trial in patients on hemodialysis with pruritus to determine the clinically recommended dose of difelikefalin based on efficacy, dose response, safety, and pharmacokinetics.
2. At 8 weeks of treatment with difelikefalin (0.5 to 1.0 µg/kg), there was significant reduction in weekly mean Worst itching Intensity Numerical Rating Scale from baseline.
3. Difelikefalin at 0.5 µg/kg is expected to be a new option for the treatment of pruritus in patients receiving hemodialysis, with high adherence, safety, and tolerability.