FC 022AN OPEN-LABEL, MULTICENTER STUDY TO EVALUATE THE SAFETY AND EFFECTIVENESS OF INTRAVENOUS DIFELIKEFALIN IN PATIENTS WITH MODERATE-TO-SEVERE CKD–ASSOCIATED PRURITUS UNDERGOING HEMODIALYSIS
Authors: Weiner Daniel , Menzaghi Frederique , Wen Warren , Qian Jenny , Munera Catherine , Bhaduri Sarbani 
Published: May 2021

Abstract

Background and Aims
Chronic kidney disease–associated pruritus (CKD-aP) is a common and highly distressing condition in patients undergoing hemodialysis (HD). CKD-aP is associated with sleep disturbances, significant quality-of-life (QoL) impairment, and increased morbidity and mortality. Difelikefalin (DFK) is a selective kappa opioid receptor agonist in development for CKD-aP that has minimal central nervous system penetration. In placebo-controlled phase 3 trials of patients with moderate to severe CKD-aP undergoing HD, intravenous (IV) DFK had an acceptable safety profile and demonstrated significant reductions vs placebo in itch intensity. We report safety and effectiveness outcomes, including itch-related QoL and sleep measures, from a phase 3 open-label study of DFK in patients with moderate to severe CKD-aP.

Method
This multicenter, open-label study conducted in the United States and Europe enrolled patients with moderate to severe CKD-aP (mean baseline 24-hour Worst Itching Intensity Numerical Rating Scale [WI-NRS] score ≥5) undergoing HD for ≥3 months. Patients received IV DFK 0.5 mcg/kg 3 times/week at the end of each HD session for up to 12 weeks. Predefined effectiveness endpoints at week 12 included ≥3-point and ≥4-point improvement in the weekly mean of the 24-hour WI-NRS score (range from 0 [no itching] to 10 [worst itching imaginable]). Change from baseline in QoL at week 12 was assessed using the 5-D itch and Skindex-10, multidimensional itch-related questionnaires validated in CKD-aP (higher scores indicate worse QoL). The proportion of patients with no problems (score of 1) on the skin irritation and self-confidence domains of the EQ-PSO questionnaire was evaluated. Post hoc endpoints included complete resolution in WI-NRS (≥75% of week 12 scores 0 or 1) and Sleep Quality Questionnaire total score assessments (range of possible scores, 0 [did not interfere] to 10 [completely interfered]), including ≥3-point and ≥4-point improvement in weekly mean score and complete resolution (all scores of 0) at week 12. Safety assessments and adverse events (AEs) were evaluated. Data were summarized descriptively.

Results
Among 222 patients who received DFK, 197 (88.7%) completed the study. At baseline, mean ±SD age was 58.1 ±12.8 years and 54.5% of patients were male. Baseline mean ±SD WI-NRS score was 7.6 ±1.3, Sleep Quality score was 6.6 ±2.2, 5-D itch score was 17.1 ±3.5, and Skindex-10 score was 32.9 ±14.3. At week 12, the majority of patients achieved ≥3-point and ≥4-point improvement in WI-NRS (73.7% and 59.3%) and Sleep Quality score (66.0% and 56.7%). Complete resolution of WI-NRS and Sleep Quality score was observed in 29.4% and 19.1% of patients, respectively (Figure). DFK was associated with improvements in mean 5-D itch (−7.1 ±4.3) and Skindex-10 (−21.0 ±15.6) scores at week 12. The proportion of patients reporting no problems in the skin irritation EQ-PSO domain increased from 1.4% at baseline to 28.9% at week 12, and self-confidence EQ-PSO domain scores increased from 63.5% at baseline to 73.2% at week 12. Overall, 64.4% (143/222) of patients reported ≥1 treatment-emergent AE (TEAE). The most commonly reported TEAEs (≥4% of patients) were diarrhea (5.0% [11/222]), nausea (4.5% [10/222]), and hyperkalemia (4.1% [9/222]). Serious TEAEs were reported by 20.3% (45/222) of patients; no serious TEAEs were related to study drug.

Conclusion
In this phase 3 open-label study in patients with moderate to severe CKD-aP undergoing HD, DFK was generally well tolerated with an acceptable safety profile. DFK demonstrated effectiveness based on reduction of itch intensity, and improvements in sleep quality and itch-related QoL at week 12. The majority of patients reported ≥3-point or ≥4-point improvement in WI-NRS and Sleep Quality scores, with some reporting complete resolution. Findings from this open-label study provide insight into the potential real-world effectiveness of DFK in moderate to severe CKD-aP.