The efficacy and safety of difelikefalin for pruritus in hemodialysis patients: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Chronic kidney disease-associated pruritus (CKD-ap) is a common complication that negatively affects the quality of life. Difelikefalin has emerged as a novel FDA-approved drug to manage CKD-ap. This systematic review and meta-analysis will assess the efficacy and safety of Difelikefalin versus placebo to manage CKD-ap. METHODS: PubMed, Scopus, WOS, Central, and Embase were systematically searched until November 2023. RevMan was used to perform meta-analysis. Quality assessment was conducted using the Cochrane RoB 2.0 tool. Results were reported as risk ratio (RR) and mean difference (MD) with a 95% confidence interval (CI). PROSPERO ID: (CRD42023485979). RESULTS: Five RCTs with a total of 896 participants were included. Difelikefalin significantly decreased the weekly mean WI-NRS score (MD: -0.99 [-1.22, -0.75], p ˂ .00001), 5-D itch scale total score (MD: -1.51 [-2.26, -0.76], p > .0001), and Skindex-10 total score (MD: -7.39 [-12.51, -2.28], p = .005), but showed significantly higher adverse events (RR: 1.26 [1.03, 1.55], p = .03), versus placebo. However, there was no significant difference between both groups in serious adverse events (RR: 1.42 [0.78, 2.57], p = .25) or death (RR: 0.81 [0.19, 3.34], p = .77). CONCLUSION: Difelikefalin appears to be a promising agent for the management of CKD-induced pruritus in patients with end-stage renal disease. However, evidence is still underpowered due to the paucity of the current data; therefore, more robust RCTs are required to confirm the benefit of Difelikefalin.

Difelikefalin and treatment of severe pruritus associated with chronic kidney disease - Real-life retrospective study in a dialysis center / Difélikéfaline et traitement du prurit modéré à sévère associé à la maladie rénale chronique - Étude rétrospective en vie réelle dans un centre de dialyse.

Introduction: Difelikefalin is to date the first and only specific treatment to be approved for the treatment of moderate-to-severe chronic kidney disease-associated pruritus (CKD-aP) in adult patients on hemodialysis. Patients and methods: This was a retrospective, single-center, real-life study in hemodialysis patients with CKD-aP treated with difelikefalin. The primary objective was to evaluate the evolution of the intensity of pruritus during treatment with difelikefalin using the Worst Itch Intensity-Numerical Rating Scale (WI-NRS). Adult patients were included if they had been on hemodialysis for at least 3 months and were suffering from moderate to severe CKD-aP (objectified by the WI-NRS score) for which difelikefalin had been prescribed. Results: 11 patients (7 men and 4 women; mean age, 63.8 years) with a mean (SD) weekly dialysis time of 13 h (2.4) were included. The mean hemodialysis duration was 5 (3.6) years and the mean pruritus duration was 4.3 (3.2) years. At inclusion, on-going treatments of CKD-aP were emollients in all patients and antihistamines in 9 patients. The mean WI-NRS score was 7.4 (1.1) at initiation of difelikefalin. At last assessment after a median follow-up of 9.0 months, the mean change of WI-NRS score was -5.1 (2.9) and 82% of patients had a decrease ≥ 3 points. Mild to moderate adverse reactions to difelikefalin were reported in 4 patients, all of whom recovered without sequelae. Conclusion: These results show that difelikefalin, prescribed according to its therapeutic indication, is effective in the treatment of CKD-aP under real-life conditions, outside the controlled conditions of a clinical trial.

Introduction: La difélikéfaline est à ce jour le premier et le seul traitement spécifique approuvé pour le traitement du prurit d'intensité modérée à sévère associé à la maladie rénale chronique (Pa-MRC) chez les patients adultes hémodialysés. Patients et méthodes: Il s'agit d'une étude rétrospective, monocentrique, en vie réelle, chez des patients hémodialysés souffrant de Pa-MRC et traités par difélikéfaline. L'objectif principal était d'évaluer l'évolution de l'intensité du prurit au cours du suivi à l'aide de l'échelle WI-NRS (Worst Itch Intensity-Numerical Rating Scale). Les patients adultes ont été inclus s'ils étaient hémodialysés depuis au moins trois mois et souffraient d'un Pa-MRC modéré à sévère (objectivé par le score WI-NRS) pour lequel la difélikéfaline avait été prescrite. Résultats: Onze patients (7 hommes et 4 femmes ; âge moyen : 63,8 ans) avec un temps de dialyse hebdomadaire moyen (SD) de 13 h (2,4) ont été inclus. La durée moyenne d'hémodialyse était de 5 ans (3,6) et la durée moyenne de prurit de 4,3 ans (3,2). À l'inclusion, les traitements du prurit en cours étaient des émollients pour tous les patients et des antihistaminiques pour 9 d'entre eux. Le score WI-NRS moyen était de 7,4 (1,1) au début du traitement par la difélikéfaline. À la dernière évaluation, après un suivi médian de 9 mois, la variation moyenne du score WI-NRS était de -5,1 (2,9) et 82 % des patients avaient une diminution ≥ 3 points. Des effets indésirables d'intensité légère à modérée liés à la difélikéfaline ont été rapportés chez 4 patients, tous rétablis sans séquelles. Conclusion: Ces résultats montrent que la difélikéfaline, prescrite conformément à son indication thérapeutique, est efficace en vie réelle dans le traitement du Pa-MRC, en dehors des conditions contrôlées d'un essai clinique.

Difelikefalin in Black/African American Hemodialysis Patients with Moderate-to-Severe Pruritus: Post hoc Analysis of KALM-1 and KALM-2.

INTRODUCTION: Black and African American (AA) people are over-represented in the kidney failure population; therefore, the safety and efficacy of difelikefalin in Black/AA patients was evaluated. METHODS: This was a post hoc, pooled exploratory subgroup analysis of the Phase 3 KALM-1 and -2 studies. Patients undergoing hemodialysis (HD) who had moderate-to-severe chronic kidney disease-associated pruritus (CKD-aP) at enrollment were stratified into self-reported Black/AA or White subgroups. Patients were randomized (1:1) to receive intravenous (IV) difelikefalin 0.5 µg/kg or placebo for 12 weeks. Difelikefalin efficacy was assessed with validated patient-reported outcome questionnaires: 24-h Worst Itch Numerical Rating Scale (WI-NRS), 5-D itch, and Skindex­10. RESULTS: There were 249 (29.3%) patients from the KALM studies that self-identified as Black/AA (n = 135 difelikefalin; n = 114 placebo). Clinically meaningful (≥3-point) reduction in WI-NRS score was achieved by 47.9% of Black/AA patients with difelikefalin versus 24.6% with placebo (p < 0.001). More Black/AA patients achieved a ≥5-point 5-D itch total improvement (54.9% vs. 35.7%; p = 0.013) and a ≥15-point Skindex-10 score improvement with difelikefalin versus placebo (49.0% vs. 28.9%; p = 0.006) compared with White patients. Incidence of treatment-emergent adverse events (TEAEs) was higher for Black/AA patients (difelikefalin: 78.5%; placebo: 70.8%) versus White patients (difelikefalin: 64.8%; placebo: 61.8%). CONCLUSION: In this post hoc analysis, difelikefalin was efficacious in the Black/AA population and had an acceptable safety profile.

Intravenous difelikefalin for the treatment of hemodialysis pruritus.

INTRODUCTION: Patients with chronic kidney disease (CKD) undergoing hemodialysis often experience significant itch secondary to their condition and a subsequent reduction in their overall quality of life. Current treatments are underwhelming, necessitating the search for new, effective therapeutic options to combat itch in this population. AREAS COVERED: The purpose of this review is to explore the available data for the use of intravenous difelikefalin in patients with CKD undergoing hemodialysis. The pathophysiology of CKD-associated itch is multifactorial, with one proposed mechanism involving an imbalance in the endogenous opioid system, favoring upregulation of itch-activating µ-opioid receptors (MORs) and downregulation of itch-inhibiting κ-opioid receptors (KORs). Dysregulation of the immune system is also involved. Difelikefalin is a recent FDA approved treatment that functions as peripherally acting KOR agonist, targeting this imbalance in the endogenous opioid system seen in CKD patients with itch and having an anti-inflammatory effect on immune cells. Clinical data on intravenous difelikefalin is promising regarding its ability to reduce itch in CKD patients on hemodialysis and improve patient quality of life, with few, mild adverse side effects. EXPERT OPINION: As intravenous difelikefalin becomes more widely used in the clinical setting, further studies assessing long-term efficacy and safety will be needed.

Kappa opioid agonists in the treatment of itch: just scratching the surface?

Chronic pruritus is a debilitating condition affecting 23-44 million Americans. Recently, kappa opioid agonists (KOAs) have emerged as a novel class of potent antipruritic agents. In 2021, the Food and Drug Administration approved difelikefalin (Korsuva) for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis. Difelikefalin is a potent, peripherally restricted KOA that is intravenously available. Although promising, difelikefalin is currently available as an intravenous composition only, limiting the scope of use. Oral formulations of difelikefalin did not meet the primary endpoint criteria in recent phase 2 clinical trials; however, additional clinical studies are ongoing. The future for KOAs in the treatment of pruritus is encouraging. Orally active pathway-biased KOAs, such as triazole 1.1, may serve as viable alternatives with broader applications. Extended-release compositions, such as the TP-2021 ProNeura subdermal implant, may circumvent the pharmacokinetic issues associated with peptide-based KOAs. Lastly, dual-acting kappa opioid receptor agonist/mu opioid receptor antagonists are orally bioavailable and may be useful in the treatment of various forms of chronic itch. In this review, we summarize the results of KOAs in clinical and preclinical trials and discuss future directions of drug development.

Difelikefalin improves itch-related sleep disruption in patients undergoing haemodialysis.

BACKGROUND: Poor sleep quality is associated with increased mortality and lower quality of life in patients with chronic kidney disease-associated pruritus (CKD-aP). Difelikefalin reduces itch in patients with CKD-aP undergoing haemodialysis. This post hoc analysis of Phase 3 studies (3105 and the pooled dataset from KALM-1 and KALM-2) evaluated whether itch reduction in CKD-aP improved sleep quality. METHODS: Itch intensity was assessed in patients undergoing haemodialysis, who had moderate-to-severe CKD-aP treated with intravenous difelikefalin (0.5 µg/kg, three times weekly) (N = 222, Study 3105; N = 426, KALM-1/-2) or placebo (N = 425, KALM-1/-2) for 12 weeks, using the Worst Itch Intensity Numerical Rating Scale (WI-NRS). Sleep quality was assessed using the sleep disability question of the 5-D itch scale (5­D SDQ) in all studies and, in Study 3105, with the Sleep Quality Numeric Rating Scale (SQ-NRS). RESULTS: Greater improvements in sleep quality were observed in patients with ≥ 3-point, versus < 3-point WI-NRS improvement using SQ-NRS in Study 3105 (mean [95% confidence interval]: -5.2 [-5.6, -4.8] vs -1.5 [-2.0, -1.0]) and 5-D SDQ in KALM-1/-2 (-1.8 [-2.1, -1.6] vs -0.8 [-1.1, -0.4]). SQ-NRS and WI-NRS scores correlated strongly at baseline and Week 12 in Study 3105 (Spearman correlation coefficient: 0.77 and 0.84, respectively). Correlations were also observed between 5-D SDQ and WI-NRS scores in Study 3105 and KALM­1/­2. CONCLUSIONS: In patients undergoing haemodialysis with moderate-to-severe CKD-aP, itch reduction with intravenous difelikefalin was associated with improved sleep quality. As disturbed sleep may contribute to mortality and morbidity in CKD-aP, difelikefalin may help to address a major clinical burden by improving sleep quality, secondary to itch relief.

Difelikefalin suppresses itch and reduces scratching independent of inflammation in a murine model of atopic dermatitis.

BACKGROUND: Therapies specifically targeting nonhistaminergic pruritus are largely lacking. Difelikefalin (DFK) has been found to reduce itch in various chronic pruritic conditions, including atopic dermatitis (AD). OBJECTIVE: We sought to investigate the ability of DFK to impact scratching behavior, inflammatory mediators, and neuronal signaling in a murine model of AD. METHODS: The ears of C57BL/6 mice were topically treated with MC903 for 12 consecutive days to induce AD-like inflammation and itch. Before MC903 treatment, mice were treated with either DFK (0.5 mg/kg, intraperitoneal injection twice daily) or vehicle (saline). Skin ear thickness, histological analysis, flow cytometry, RNA-sequencing, and differential gene expression analyses of mouse ear skin were used to examine the effect of DFK on skin inflammation. Scratching behavior was quantified to measure itch behavior in mice that were topically treated with MC903 for 6 consecutive days; then, mice received a single injection of either DFK (1.0 mg/kg, intraperitoneal injection) or saline. Calcium imaging and single-cell RNA-sequencing were used in mouse dorsal root ganglia neurons to determine the size of the neurons activated with DFK treatment. Statistical significance was determined by Mann-Whitney test, unless otherwise noted. RESULTS: DFK rapidly suppressed itch without altering AD-like skin inflammation in MC903 (calcipotriol)-treated mice. In vitro Ca2+ influx trace of dorsal root ganglia suggested that a major target for DFK is the larger-diameter mechanoreceptors (eg, Aꞵ-fibers), rather than small-diameter pruriceptive C-fibers. CONCLUSIONS: These studies support a potential neuromodulatory role of DFK for reducing itch associated with AD in mice.

Difelikefalin for the treatment of moderate-to-severe pruritus associated with chronic kidney disease on hemodialysis.

INTRODUCTION: Chronic kidney disease-associated pruritus (CKD-aP) is often experienced by patients with CKD receiving dialysis. Approximately 40% of hemodialysis patients are 'moderately' to 'extremely bothered' by itching, associated with reduced quality of life, poor sleep quality, and depression as well as worse clinical outcomes, including increased medication use, infections, hospitalizations, and mortality. AREAS COVERED: This review covers the pathophysiology and treatment landscape of CKD-aP, and the development, clinical efficacy, and safety profile of difelikefalin. We summarize the existing evidence, and discuss both the position of difelikefalin in the treatment pathway and potential future developments. EXPERT OPINION: Difelikefalin is a kappa opioid receptor agonist, with a primary mode of action that is outside of the central nervous system and provides an improved safety profile compared with other opioid agonists, with limited potential for abuse and dependency. Difelikefalin has demonstrated efficacy, tolerability, and safety profile in several large-scale clinical trials in more than 1,400 hemodialysis patients with CKD-aP treated for up to 64 weeks. Difelikefalin is the only approved treatment for CKD-aP in the U.S.A and Europe; other treatments are used off-label, have limited proof of efficacy in large-scale clinical trials in this patient population, and may present an increased risk of toxicity in patients with CKD.

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.

Alleviating symptoms in patients undergoing long-term hemodialysis: a focus on chronic kidney disease-associated pruritus.

Since the breakthrough of kidney replacement therapy, increases in life expectancy for patients with end-stage kidney disease have been limited. However, patients have become increasingly vocal that, although mortality and life expectancy matter to them, the quality of their life, and particularly the relief of symptoms associated with their treatment, are in many cases more important. The majority of dialysis-associated symptoms and adverse effects do not currently have any approved treatments in this patient population, with the few treatments that are available used off-label, frequently without proven efficacy, yet still potentially adding further adverse effects to patients' current symptom burden. This article will illustrate how understanding the pathophysiology of a single, particularly burdensome symptom of dialysis (chronic kidney disease-associated pruritus) resulted in the design, development and regulatory approval of a treatment for that symptom. The pathway described here can be applied to other symptoms associated with dialysis, meaning that if we cannot add years to patients' lives, we can at least add life to their remaining years.

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.

Safety and Effectiveness of Difelikefalin in Patients With Moderate-to-Severe Pruritus Undergoing Hemodialysis: An Open-Label, Multicenter Study.

Rationale & Objective: Individuals with chronic kidney disease frequently suffer from chronic kidney disease-associated pruritus (CKD-aP), impacting sleep quality and quality of life (QoL) and increasing the likelihood of depression. Difelikefalin is a kappa-opioid receptor agonist recently approved in the United States for the treatment of moderate-to-severe CKD-aP in hemodialysis patients. Study 3105 was conducted to further assess the safety of difelikefalin and the effects on pruritus and QoL. Study Design: Open-label, multicenter, single-arm intervention trial. Setting & Participants: Maintenance hemodialysis patients with moderate-to-severe CKD-aP at enrollment. Intervention: Intravenous difelikefalin 0.5 µg/kg after each hemodialysis session for 12 weeks. Outcomes: The primary outcome was safety of difelikefalin. Secondary outcomes included: effectiveness of reducing itch intensity, assessed by the Worst Itching Intensity Numerical Rating Scale (WI-NRS); improving itch-related QoL, assessed with 5-D itch and Skindex-10 scales; and improvement of sleep, assessed with the Sleep Quality Numerial Rating Scale. Clinically meaningful thresholds for improvement in itch and QoL were previously established in this population. Results: Among 222 participants with baseline WI-NRS ≥5, mean [standard deviation] WI-NRS was 7.6 [1.3], mean age 58 years, 55% were male, and mean dialysis duration was 5.9 years; 197 participants (89%) completed treatment. Treatment-related treatment-emergent adverse events were reported in 16 participants (7.2%); those most commonly reported were somnolence (1.8%), hypoesthesia (1.4%), nausea (0.9%), and dizziness (0.9%). No deaths or serious treatment-emergent adverse events were considered treatment-related. Clinically meaningful reduction in itch intensity (≥3-point improvement) was reported by 74% of participants, with 70% and 63% also reporting a clinically relevant improvement in QoL as measured by 5-D itch and Skindex-10. Sleep quality improvement (≥3-point reduction on the Numerical Rating Scale) was reported in 66% of participants. Limitations: No placebo control group. Conclusions: Difelikefalin was well tolerated, and treatment was associated with clinically meaningful improvements in itch intensity and itch-related QoL measures as well as improvements in sleep quality among individuals receiving hemodialysis who had moderate-to-severe CKD-aP, providing important insights into expected real-world effectiveness. Funding: Cara Therapeutics. Trial Registration: NCT03998163.

Difelikefalin, a peripherally restricted KOR (kappa opioid receptor) agonist, produces diuresis through a central KOR pathway.

Difelikefalin is a peripherally restricted kappa opioid receptor (KOR) agonist that was recently approved by the FDA to treat pruritis in dialysis patients. Here, we investigated the cardiovascular and renal responses to difelikefalin, and using the KOR antagonist norbinaltorphimine (norBNI), examined whether any difelikefalin-induced changes in the renal excretion of water and/or electrolytes were mediated through a central or peripheral KOR pathway. The effects of norBNI pretreatment on nalfurafine, a KOR agonist that crosses the blood-brain barrier, were also examined. We hypothesized that difelikefalin would alter urine output differently than nalfurafine, given that KOR agonists produce diuresis via activating central KORs to inhibit vasopressin release. Following catheterization, conscious Sprague-Dawley rats were infused i.v. with isotonic saline and pretreated with norBNI centrally via an intracerebroventricular (ICV) cannula or peripherally via an intravenous catheter. After stabilization, difelikefalin or nalfurafine was administered i.v. and urine output, heart rate and mean arterial pressure (MAP) were recorded for 90 min. Difelikefalin produced a significant increase in urine output, and significant decrease in urinary sodium and potassium excretion, urine osmolality, and MAP. ICV norBNI pretreatment markedly attenuated the increase in urine output caused by difelikefalin and nalfurafine but did not inhibit the electrolyte effects. However, IV norBNI pretreatment prevented all responses to difelikefalin and nalfurafine. Together, these findings demonstrate that difelikefalin and nalfurafine utilize central KOR pathways to elicit diuresis and a decrease in MAP but enhance renal tubular electrolyte reabsorption through a peripheral KOR pathway, providing important insight into two clinically useful KOR agonists.

Pruritus in dialysis patients. Review and new perspectives.

Uremic pruritus (UP) is one of the most uncomfortable symptoms for patients in dialysis. UP has a great impact on dialysis patients' quality of life and has a great prevalence between those (28-70%). Physiopathology of UP is unknown and usually is unnoticed for most nephrologists (in more than 65% of centers is underdiagnosed). This lack of awareness drives to the unsuccessful treatment of this symptom. Moreover, the fact that most studies have been carried out on small populations and the difficulty assessing UP complicates a correct therapeutical approach. For this reason, we have designed treatment algorithms based on the efficacy of the drugs but also its safeness to avoid adverse effects.

Difelikefalin for pruritus associated with renal disease.

Chronic kidney disease-associated pruritus (CKD-aP) has been recognized for over a century. The complex pathophysiology of CKD-aP makes it challenging to find an effective treatment; the proposed therapeutic options come from anecdotal reports and small clinical trials, which at best compare the test drug against placebo. Gabapentinoids have shown relevant efficacy but there are serious safety concerns about their possible central nervous system toxicity. Recently difelikefalin, a κ-opioid receptor agonist, has been the first Food and Drug Administration (FDA)-approved drug for moderate-severe CKD-aP treatment. Approval from other regulatory agencies is expected in 2022. In this article, preclinical, pharmacokinetic and safety studies on difelikefalin are reported, but a great part of the data derive from meeting abstracts and non-peer-review communications and this is a possible cause for concern regarding bias in publication. A review of published and unpublished studies about difelikefalin in CKD-aP treatment is provided. Currently, two published large trials show that difelikefalin offers a new therapeutic opportunity to treat CKD-aP, a condition that leads to both worse survival and quality of life in hemodialysis patients.

Efficacy of Difelikefalin for the Treatment of Moderate to Severe Pruritus in Hemodialysis Patients: Pooled Analysis of KALM-1 and KALM-2 Phase 3 Studies.

Rationale & Objective: Chronic kidney disease-associated pruritus (CKD-aP) in patients treated by hemodialysis (HD) impairs quality of life (QoL). Difelikefalin, a selective κ-opioid receptor agonist, decreased the intensity of CKD-aP in patients undergoing HD. This pooled analysis evaluated difelikefalin's efficacy and the itch-related QoL overall and in subgroups defined by demographics or disease characteristics. Study Design: In KALM-1 and KALM-2, participants were randomized (1:1) to receive intravenous difelikefalin or placebo 3 times/wk for 12 weeks, followed by a 52-week open-label extension. Setting & Participants: Adults with moderate to severe CKD-aP treated by HD in North America, Europe, and the Asia-Pacific region. Intervention: Intravenous difelikefalin at 0.5 mcg/kg or placebo. Outcomes: Itch intensity (Worst Itching Intensity Numerical Rating Scale [WI-NRS]) and itch-related QoL (Skindex-10 and 5-D Itch questionnaires). Results: 851 participants were randomized (difelikefalin, n = 426; placebo, n = 425). This pooled analysis demonstrated early     (week 1), sustained difelikefalin efficacy, with significantly greater achievement of ≥3-point WI-NRS reduction with difelikefalin (51.1%) versus placebo (35.2%; P < 0.001). Achievement of a ≥4-point WI-NRS reduction was significantly greater with difelikefalin (38.7%) versus placebo (23.4%; P < 0.001). Difelikefalin reduced itch intensity in subgroups based on age, sex, anti-itch medication use, the presence of specific medical conditions, and gabapentin or pregabalin use. More participants receiving difelikefalin versus placebo achieved clinically meaningful decreases of ≥15 points on the Skindex-10 scale (55.5% vs 40.5%, respectively; P < 0.001) and ≥5 points on the 5-D Itch scale (52.1% vs 42.3%, respectively; P = 0.01), with sustained 5-D Itch effects up to 64 weeks. Limitations: Subgroup samples were small. The WI-NRS, Skindex-10, and 5-D Itch are not used in routine clinical care of dialysis patients; therefore, findings may not reflect the real-world effectiveness of difelikefalin. Conclusions: Difelikefalin demonstrated rapid, sustained efficacy, with consistent results in diverse populations of patients treated by HD. Funding: Cara Therapeutics, Inc. Trial Registration: The KALM-1 trial is registered as NCT03422653 and the KALM-2 trial is registered as NCT03636269.

Safety and Tolerability of Difelikefalin for the Treatment of Moderate to Severe Pruritus in Hemodialysis Patients: Pooled Analysis From the Phase 3 Clinical Trial Program.

Rationale & Objective: We report a pooled safety analysis of intravenous difelikefalin in participants with moderate to severe chronic kidney disease-associated pruritus (CKD-aP) treated by hemodialysis in 4 phase 3 clinical studies. Study Design: KALM-1 and KALM-2 were randomized, double-blind, placebo-controlled, pivotal phase 3 studies; CLIN3101 (52 weeks) and CLIN3105 (12 weeks) were open-label studies. Setting & Participants: Adults with moderate to severe CKD-aP treated by hemodialysis in North America, Europe, and the Asia-Pacific region. Intervention: At least 1 intravenous placebo or difelikefalin dose of 0.5 mcg/kg for up to 64 weeks. Outcomes: Safety. Results: Safety analyses were conducted with 848 participants in the placebo-controlled cohort (424 participants each in the difelikefalin and placebo groups) and in 1,306 participants in the all-difelikefalin-exposure cohort. In the placebo-controlled cohort, the most commonly reported treatment-emergent adverse events (TEAEs), occurring in ≥2% of participants receiving difelikefalin and with a ≥1% higher incidence than placebo, were diarrhea (9.0% and 5.7%, respectively); dizziness (6.8% and 3.8%, respectively); nausea (6.6% and 4.5%, respectively); gait disturbances, including falls (6.6% and 5.4%, respectively), hyperkalemia (4.7% and 3.5%, respectively); headache (4.5% and 2.6%, respectively); somnolence (4.2% and 2.4%, respectively); and mental status changes (3.3% and 1.4%, respectively). These were mostly mild or moderate, with few leading to discontinuation. Incidence rates of TEAEs, serious TEAEs, and discontinuations because of TEAEs did not increase with long-term exposure. Three participants (0.7%) in the difelikefalin group and 5 participants (1.2%) in the placebo group died during the study. Limitations: Pooled data from studies with different designs. Conclusions: Intravenous difelikefalin demonstrated an acceptable safety profile, was generally well tolerated with long-term use, and may address the unmet treatment need for patients with CKD-aP treated by hemodialysis. Funding: Cara Therapeutics, Inc. Trial Registration: KALM-1 is registered as NCT03422653, KALM-2 as NCT03636269, CLIN3101 as NCT03281538, and CLIN3105 as NCT03998163.

Difelikefalin in the Treatment of Chronic Kidney Disease-Associated Pruritus: A Systematic Review.

Chronic kidney disease-associated pruritus (CKD-aP) is a chronic condition that significantly reduces the quality of life of patients with end-stage renal disease. The etiology is not fully understood, but imbalance in the activity of the opioid pathways, including downregulation of the kappa-opioid receptor, may contribute to itching sensation. Difelikefalin is a selective, peripherally acting kappa-opioid receptor (KOR) agonist. Recently, difelikefalin has been approved as a first drug for the treatment of pruritus associated with chronic kidney disease (CKD) in adult hemodialysis patients. A systematic review of currently available clinical trials was performed to assess the efficacy and safety of difelikefalin in patients with uremic pruritus. A literature review was conducted in May 2022 based on the PRISMA 2020 guidelines. The analyzed clinical trials showed that difelikefalin was effective in reducing pruritus in patients as assessed by the Worst Itching Intensity Numerical Rating Scale. Improvement in quality of life assessed on the basis of the Skindex score and the 5-D itch scale was also noticed. The most commonly reported side effects were mild and included nausea, vomiting, dizziness, and diarrhea. Due to its proven efficacy and good safety profile, difelikefalin is a promising drug for the treatment of pruritus in patients with chronic kidney disease.

Modulation of the kappa and mu opioid axis for the treatment of chronic pruritus: A review of basic science and clinical implications.

Introduction: Treating chronic pruritus is challenging for dermatologists due to the lack of therapeutic options. We review the effects of κ-opioid receptor (KOR) and µ-opioid receptor (MOR) in the modulation of itch, summarize evidence supporting the efficacy and safety of opioid receptor-targeting agents in chronic pruritus, and address clinical considerations. Results: Preclinical studies have found neural pathways underlying detection, transmission, and modulation of itch signaling and spotlighted the importance of neuronal KOR and MOR in itch perception. Clinical reports suggest that opioid axis modulation may be the basis for the successful treatment of chronic itch. Several agents (MOR antagonist naltrexone; KOR agonists nalfurafine and difelikefalin; dual-acting KOR agonists/MOR antagonists butorphanol and nalbuphine) have been evaluated for treating chronic pruritus in case series, small studies, and clinical trials; nalbuphine has progressed through preliminary (phase II/III) studies in uremic pruritus and prurigo nodularis. The antipruritic efficacy of these agents has been observed across multiple disorders with disparate etiologies, suggesting the potential utility of this class to provide a unified approach to chronic pruritus treatment. Conclusions: The relative safety of these agents, including a reduced potential for dependence versus MOR-agonist analgesics, should help overcome resistance to the use of opioid receptor-targeting agents in chronic pruritus treatment.