A phase 2 study of oral difelikefalin in subjects with chronic kidney disease and moderate-to-severe pruritus.

INTRODUCTION/BACKGROUND: Chronic pruritus is burdensome for patients with chronic kidney disease (CKD). OBJECTIVE: We evaluated difelikefalin efficacy and safety in reducing itch in subjects with non-dialysis-dependent CKD and those undergoing hemodialysis (HD). METHODS: This phase 2, double-blind, randomized, placebo-controlled, dose-finding study enrolled non-dialysis-dependent CKD (stage 3-5) and HD subjects with moderate-to-severe pruritus. Subjects were equally randomized to oral difelikefalin (0.25, 0.5, or 1.0 mg) or placebo once daily for 12 weeks. The primary end point was the change in the weekly mean Worst Itching Intensity Numeric Rating Scale (WI-NRS) score at week 12. RESULTS: Two hundred sixty-nine subjects were randomized (mean [SD] baseline WI-NRS: 7.1 [1.2]). Difelikefalin 1.0 mg significantly reduced weekly mean WI-NRS scores versus placebo at week 12 (P = .018), with numerical reductions observed with difelikefalin 0.25 and 0.5 mg. At week 12, 38.6% of subjects receiving difelikefalin 1.0 mg achieved a complete response (WI-NRS 0-1) versus 14.4% receiving placebo. Difelikefalin resulted in ∼20% improvement in itch-related quality-of-life measures. The most common treatment-emergent adverse events were dizziness, fall, constipation, diarrhea, gastroesophageal reflux disease, fatigue, hyperkalemia, hypertension, and urinary tract infection. LIMITATIONS: Study duration was 12 weeks. CONCLUSIONS: Oral difelikefalin significantly reduced itch intensity in stage 3-5 CKD subjects with moderate-to-severe pruritus, supporting continued development for this condition.

Difelikefalin: A New κ-Opioid Receptor Agonist for the Treatment of Hemodialysis-Dependent Chronic Kidney Disease-Associated Pruritus.

OBJECTIVE: To review data for difelikefalin (Korsuva) intravenous solution for management of moderate-to-severe pruritus in hemodialysis (HD) patients. DATA SOURCES: Literature search of PubMed (January 1946-May 2022) and SCOPUS (January 1946-May 2022) was performed using the terms: Korsuva, CR845, and difelikefalin. Additional information sources include ClinicalTrials.gov, prescribing information, meeting posters, and references of identified articles. STUDY SELECTION AND DATA EXTRACTION: Clinical trials and articles evaluating difelikefalin for chronic kidney disease-associated pruritis (CKD-aP) in HD patients. DATA SYNTHESIS: Difelikefalin is a peripherally acting κ-opioid receptor agonist with antipruritic effects for HD patients with moderate-to-severe CKD-aP. A phase 3 study showed significant improvement of patient itch intensity and itch-related quality of life (QOL) when compared with placebo. More patients had decreased pruritus on the 24-hour Worst Itch Intensity Numerical Rating Scale with difelikefalin (49.1%) compared with placebo (27.9%, P < 0.001). A positive effect was seen with or without use of additional antipruritic agents. Common adverse events include diarrhea, dizziness, and vomiting; there were no signs of physical dependence or centrally acting opioid effects (euphoria, hallucinations). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Difelikefalin reduced itch intensity and improved QOL for patients with CKD-aP. Whether the benefit is continued long-term as well as how it compares with other effective agents is currently unknown. CONCLUSION: Difelikefalin is the only Food and Drug Administration-approved treatment for moderate-to-severe CKD-aP with additional research into its benefit in this and other types of pruritus ongoing.

An evaluation of difelikefalin as a treatment option for moderate-to-severe pruritus in end stage renal disease.

Introduction: Chronic kidney disease-associated pruritus (CKD-aP), or uremic pruritus, is a severely distressing condition that occurs in greater than 60% of patients undergoing dialysis. However, there are currently no FDA approved treatments for CKD-aP in the United States or Europe. Difelikefalin (DFK) is a kappa opioid receptor agonist with limited central nervous system (CNS) penetration that aims to fill this void by effectively and safely reducing itch in these patients.Areas covered: Through a review of the current literature (using PubMed and Google Scholar keyword searches of difelikefalin, CR845, pruritus, itch, opioids, hemodialysis, chronic kidney disease, uremic pruritus), the authors review DFK's mechanism of action and use published clinical trial data to evaluate its effectiveness in treating CKD-aP both individually and comparatively to other treatment alternatives.Expert opinion: DFK's IV formulation seems to provide safe, rapid-acting and effective itch reduction in hemodialysis patients without many of the negative mu opioid receptor (MOR)- or CNS- related side effects or drug-drug interactions of other currently available opioids. Its administration through IV bolus immediately after dialysis sessions at dialysis centers also increases availability to and ease of drug scheduling for this target population.

Randomized Controlled Trial of Difelikefalin for Chronic Pruritus in Hemodialysis Patients.

INTRODUCTION: There is an unmet medical need for pruritus associated with chronic kidney disease, a distressing complication characterized by generalized and persistent itch affecting 20% to 40% of patients undergoing hemodialysis. Here we report the results of a phase 2 trial evaluating the efficacy and safety of a novel peripherally restricted kappa opioid receptor agonist, difelikefalin, in adult patients undergoing hemodialysis with pruritus. METHODS: In this study, 174 hemodialysis patients with moderate-to-severe pruritus were randomly assigned to receive difelikefalin (0.5, 1.0, or 1.5 µg/kg) or placebo intravenously thrice weekly after each hemodialysis session for 8 weeks in a double-blind, controlled trial. The primary endpoint was the change from baseline at week 8 in the weekly mean of the 24-hour Worst Itching Intensity Numerical Rating Scale score. The secondary efficacy endpoint was the change in itch-related quality of life measured by the Skindex-10 questionnaire. Other endpoints included safety, sleep quality, and additional measures including the 5-D itch scale. RESULTS: A significant reduction from baseline in itch intensity scores at week 8 favored all difelikefalin doses combined versus placebo (P = 0.002). Difelikefalin also showed improvement over placebo in Skindex-10, 5-D itch, and sleep disturbance scores (P ≤ 0.005). Overall, 78% of patients receiving difelikefalin reported treatment-emergent adverse events versus 42% of patients given placebo, with diarrhea, dizziness, nausea, somnolence, and fall being the most frequent (≥5%). CONCLUSION: In this trial, difelikefalin effectively reduced itching intensity and improved sleep and itch-related quality of life.