Korsuva IV (difelikefalin IV) / Maruishi Pharma, Chong Kun Dang, Kissei, CSL Behring - LARVOL DELTA

Uremic Pruritus in Hemodialysis: Mechanisms, Burden, and Emerging Therapies. (PubMed, J Clin Med) - "Sertraline, nalbuphine, and difelikefalin showed significant antipruritic effects in controlled trials. Emerging therapies, including AST-120, omega-3 fatty acids, and the biologic dupilumab, demonstrated promising but preliminary results. Management of uremic pruritus requires a multifaceted, individualized approach integrating skin-directed therapies, dialysis optimization, and targeted systemic treatments. Ongoing research is needed to identify reliable biomarkers and to develop safer, more effective, mechanism-based therapies."

Journal • Review • Dermatology • Nephrology • Pediatrics • Pruritus • Renal Disease

EXPLORING KAPPA OPIOID RECEPTOR MUTATIONS IN IBD: FROM MOLECULAR PHARMACOLOGY TO DRUG DISCOVERY (CCCongress 2026) - "A focused ligand panel will include FDA-approved therapeutics (e.g. difelikefalin, anrikefon, nalfurafine), experimental drug candidates (e.g., sialorphin), and in-house designed peptides (e.g. helianorphin-19, DNCP-β-NalA). Nat Commun. 2023 Dec 6;14(1):8064."

Addiction (Opioid and Alcohol) • Gastroenterology • Gastrointestinal Disorder • Immunology • Inflammation • Inflammatory Bowel Disease

MKOP002, a novel bifunctional μ-/κ-opioid decapeptide with G protein-biased μ-opioid agonism, exhibits antinociceptive and antipruritic activities. (PubMed, Biochem Pharmacol) - "Additionally, MKOP002 exhibited antipruritic effects comparable to CR845, mediated by both the peripheral and central KOR...Importantly, MKOP002 did not elicit MOR-associated adverse effects such as tolerance, constipation, respiratory depression, or addiction. These findings underscore the therapeutic potential of MKOP002 as a lead compound for antinociceptive and antipruritic therapy, supporting the development of bifunctional MOR/KOR agonists as a safer opioid strategy."

Journal • Addiction (Opioid and Alcohol) • Anesthesia • CNS Disorders • Constipation • Depression • Gastroenterology • Gastrointestinal Disorder • Neuralgia • Pain • Psychiatry

Reduction of pruritus and depression using longitudinal patient-reported outcome measures in hemodialysis: a quality improvement project. (PubMed, J Patient Rep Outcomes) - No abstract available

Journal • Chronic Kidney Disease • CNS Disorders • Depression • Dermatology • Mood Disorders • Nephrology • Pruritus • Psychiatry • Renal Disease

Rational design, synthesis and characterization of novel chimeric peptides containing the kappa-opioid agonists CR845 and dynorphin A-derived peptides. (PubMed, Eur J Med Chem) - "Additionally, subcutaneous administration of these 3 optimized analogues induced sedation without eliciting aversion or depressive-like side effects. Notably, analogue 4 was selected as the final candidate due to its high potency in KOR agonism and minimal sedative effects, making it the most promising drug candidate for the development of efficient and safe antinociceptive and antipruritic therapies."

Journal • Anesthesia • Dermatology • Pain • Pruritus

The efficacy and safety of intravenous difelikefalin for the treatment of pruritus in patients undergoing hemodialysis: a systematic review and meta-analysis of randomized controlled trials. (PubMed, Blood Purif) - "Difelikefalin is effective in reducing moderate-to-severe CKD-aP in HD patients, though it may increase non-serious adverse events. Limitations include limited evidence and short-term follow-up. Larger, multi-center RCTs are needed to confirm long-term safety and efficacy."

Journal • Retrospective data • Review • Chronic Kidney Disease • Dermatology • Nephrology • Pruritus • Renal Disease

Real-world effectiveness and tolerability of difelikefalin over 12 months for hemodialysis-associated pruritus. (PubMed, Int Urol Nephrol) - "In this real-world cohort of HD patients with refractory CKD-aP, 12 months of Difelikefalin treatment significantly reduced pruritus severity and associated sleep disturbance. Despite a 40% discontinuation rate, the safety profile was consistent with previous reports. These findings support Difelikefalin as a long-term therapeutic option, although larger studies are needed to confirm these results."

Journal • Real-world evidence • Alzheimer's Disease • Cardiovascular • Chronic Kidney Disease • CNS Disorders • Cognitive Disorders • Dermatology • Nephrology • Pruritus • Renal Disease • Sleep Disorder

Extemporaneous Preparation and Effectiveness of Low-Dose Naltrexone for the Treatment of Uremic Pruritus: A Literature Review and Case Report. (PubMed, Pharmacy (Basel)) - "Low-dose naltrexone provided symptomatic improvement in individuals with severe uremic pruritus when difelikefalin was inaccessible. While limited to a single case, this report highlights the potential role of naltrexone and underscores the need for further research to establish its safety and efficacy."

Journal • Chronic Kidney Disease • Dermatology • Nephrology • Pain • Pruritus • Renal Disease

CKD-Associated Pruritus: A Cross-Sectional Study (KIDNEY WEEK 2025) - "Difelikefalin(DFK) was taken by 21% of patients under medication, who complained about severe pruritus and had complete response (Graph 4,5)...This analysis confirms that DFK can effectively relieve severe CKD-aP. Further studies are required in order to understand the pathophysiology of CKD-aP and determine optimal treatment."

Observational data • Chronic Kidney Disease • CNS Disorders • Dermatology • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Pruritus • Renal Disease • Sleep Disorder • Type 2 Diabetes Mellitus

Identification of biomarkers associated with SUMO modification in heart failure. (PubMed, Medicine (Baltimore)) - "Subsequently, the results of drug prediction showed that CR845 might target CYLD in HF. PSME4 and CYLD were identified as SUMOylation-related biomarkers in HF, offering novel mechanism insights into the pathological underpinnings of HF."

Biomarker • Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Hepatology • Liver Failure • Targeted Protein Degradation

An Open-label, Single-arm Study to Evaluate the Safety and Tolerability of Intravenous Difelikefalin in Adolescents Aged 12 to 17 Years on Haemodialysis with Moderate-to-Severe Pruritus (ChiCTR) - P2 | N=18 | Not yet recruiting | Sponsor: Children's Hospital,Zhejiang University School of Medicine; Children's Hospital,Zhejiang University School of Medicine

New P2 trial • Chronic Kidney Disease • Dermatology • Nephrology • Pruritus • Renal Disease

Real-world safety of difelikefalin for chronic kidney disease-associated pruritus: initial insights from a European managed access programme. (PubMed, Clin Kidney J) - "No new safety signals were detected in this MAP analysis over a 3-year period. The overall safety results were consistent with the known safety profile for difelikefalin patients with moderate-to-severe CKD-aP receiving HD."

Journal • Real-world evidence • Chronic Kidney Disease • Dermatology • Nephrology • Pruritus • Renal Disease

Difelikefalin for CKD-aP: real world evidence of efficacy and safety in Italian patients. (PubMed, Clin Kidney J) - "Except for the two early therapy breaks, no other side effects were reported. In haemodialysis patients affected by CKD-aP, DFK is an effective and safe treatment that might clearly improve this distressing and overlooked condition."

HEOR • Journal • Real-world evidence • Chronic Kidney Disease • CNS Disorders • Depression • Dermatology • Nephrology • Pruritus • Psychiatry • Renal Disease

Meta-Analysis of Randomized Controlled Trials on Gamma-Aminobutyric Acid Analogues and Opioid-Based Therapies for CKD-Associated Pruritus. (PubMed, Kidney Int Rep) - "Our results suggest that GABA analogues and opioid-based therapies, particularly difelikefalin, have significant potential in alleviating itch intensity and improving the quality of life of patients with CKD-aP. However, opioid-based therapies, especially those involving μ-receptor antagonists such as naltrexone and nalbuphine, are associated with a higher incidence of AEs or ADRs. Given the substantial heterogeneity observed in most of the results, interpretation should be approached with caution."

Journal • Retrospective data • Chronic Kidney Disease • CNS Disorders • Dermatology • Nephrology • Pruritus • Renal Disease • Sleep Disorder

Phase 3 Study of Difelikefalin in Haemodialysis Chinese Adult Subjects With Moderate-to-Severe Pruritus (clinicaltrials.gov) - P3 | N=260 | Completed | Sponsor: Vifor Fresenius Medical Care Renal Pharma | N=184 ➔ 260

Enrollment change • Dermatology • Pruritus • Renal Disease

Pruritus in Uremic Patients: Approaches to Alleviating a Common Symptom in Chronic Kidney Disease. (PubMed, Life (Basel)) - "Difelikefalin, a κ-opioid receptor agonist, represents a breakthrough in systemic treatment, demonstrating efficacy with a favorable safety profile. Another opioid-based therapy, nalfurafine, has shown notable symptom relief in multiple clinical studies, with a low risk of abuse. Sertraline, an antidepressant, offers another alternative, although its delayed onset remains a limitation...Further research, including comparative and long-term studies, is essential to refine treatment algorithms and improve patient outcomes. By integrating new pharmacologic and nonpharmacologic options, CKD-aP management is shifting toward a more tailored and effective approach that addresses the individual needs of each patient."

Journal • Review • Chronic Kidney Disease • Dermatology • Inflammation • Nephrology • Pruritus • Renal Disease

Variation in Management of CKD-Associated Pruritus: Results From a Multinational Survey of Kidney Units. (PubMed, Kidney Med) - "Gabapentinoids (gabapentin or pregabalin) were the most widely used first-line systemic agent (49 units [47%]), followed by antihistamines (27 [26%])...Significant inter-country disparities were noted: doxepin, evening primrose oil, sertraline, and topical γ-linolenic acid were more frequently used in Australia than in NZ, and the UK, whereas hydroxyzine was preferentially used in UK units (P < 0.05). Units with a kidney supportive care service were more likely to use gabapentinoids, 5-hydroxytryptamine3 receptor antagonists, hydroxyzine, and topical therapies, and less likely to use promethazine (P < 0.05). Difelikefalin was not widely available during the survey period, which may limit generalizability. There is considerable variation in the management of CKDaP. Unexplained clinical variation suggests a need for the development of evidence-based guidelines and additional high-quality studies to inform care."

Journal • Chronic Kidney Disease • Dermatology • Nephrology • Pruritus • Renal Disease

Anti-inflammatory and renoprotective effects of difelikefalin, a kappa opioid receptor agonist, in a rat model of renal ischemia-reperfusion-induced acute kidney injury. (PubMed, BMC Nephrol) - "These findings indicate that difelikefalin has anti-inflammatory and renoprotective effects in a rat acute kidney injury model, with varying anti-inflammatory efficacy among KOR agonists."

Journal • Preclinical • Acute Kidney Injury • Cardiovascular • Inflammation • Nephrology • Renal Disease • Reperfusion Injury

Cost-Effectiveness of Difelikefalin for the Treatment of Moderate-to-Severe Chronic Kidney Disease-Associated Pruritus (CKD-aP) in UK Adult Patients Receiving In-Centre Haemodialysis. (PubMed, J Clin Med) - "Improved patient outcomes were achieved at an incremental cost of £7814 per person. Overall, at a price of £31.90/vial, difelikefalin was estimated to be a cost-effective treatment for moderate-to-severe CKD-aP at a willingness-to-pay threshold of £30,000/QALY, with conclusions robust to sensitivity analysis."

HEOR • Journal • Chronic Kidney Disease • Dermatology • Nephrology • Pruritus • Renal Disease • Transplantation

The efficacy and safety of kappa opioid receptor (KOR) agonists in patients with uraemic pruritus: a systematic review and network meta-analysis. (PubMed, Clin Kidney J) - "For the secondary endpoint, all four doses of difelikefalin were associated with higher rates of adverse events compared with placebo, while other interventions showed rates comparable to those of placebo and did not present statistically significant differences. In summary, difelikefalin at doses of 0.25 µg/kg and 0.5 µg/kg, along with nalfurafine at 0.25 µg/kg and 0.5 µg/kg, can be considered recommended therapeutic options for UP treatment."

Journal • Retrospective data • Addiction (Opioid and Alcohol) • Dermatology • Pruritus

Recurrence of CKD-associated pruritus after discontinuation of long-term difelikefalin: a national real-life study. (ERA 2025) - "Recurrence of CKD-associated pruritus affecting nearly half of patients within 3-months of discontinuation of DFK. Further studies are needed to determine the efficacy of intermittent use and the frequency of sustained remission according to patient characteristics. Figure 1: Event free survival:"

Clinical • Chronic Kidney Disease • Dermatology • Nephrology • Pruritus

Long-term efficacy and impact on quality of life of difelikefalin treatment in haemodialysed patients with moderate-to-severe chronic kidney disease associated pruritus (ERA 2025) - "Pruritus in our population was significantly associated with poorer QoL and higher psychological distress even though a lower prevalence (9.7%). Although the dropout rate was high in our study, the use of DFK, when well-tolerated, was associated with a dramatic response in pruritus scores and QoL improvement at 3 months which persisted up to 52 weeks of treatment. Those preliminary results obtained on a small sample size should be confirmed in further studies."

Clinical • HEOR • Chronic Kidney Disease • CNS Disorders • Depression • Dermatology • Mood Disorders • Nephrology • Pruritus • Psychiatry • Renal Disease • Sleep Disorder

Projections of infection-related cost savings associated with treating CKD associated pruritus (CKD-aP) with difelikefalin in five European countries through the combination of clinical trial data and real-world evidence (ERA 2025) - "CKD-aP is associated with significant infective hospitalization complications which translate into substantial costs. When modelling these estimates with the clinical effectiveness data of difelikefalin trials, national cost savings projections strongly advocate for the treatment of CKD- aP."

Clinical • HEOR • Real-world • Real-world evidence • Cardiovascular • Chronic Kidney Disease • Coronary Artery Disease • Dermatology • Heart Failure • Infectious Disease • Nephrology • Pruritus • Septic Shock

Subcutaneous Lignocaine for CKDaP in a Haemodialysis Patient – Time to revisit an old remedy (ERA 2025) - "In addition to skin emollients, treatments sequentially included pregabalin up to a daily dose of 75mg, Evening Primrose Oil oral capsules up to 2 daily, dialysis initiation with extended hours nocturnal HD to optimise clearance (>6hours, Kt/V >2), oral cetirizine 10mg daily, and topical compound ointment (menthol 5%, lignocaine 7%, and capsaicin 0.025%)... Thereafter, the patient developed an acute exacerbation of itch affecting her entire body, associated with severe sleep disturbance, ferocious scratching (Figure 1), and emotional distress, despite continuing her existing treatments of emollients, pregabalin, difelikefalin 1mcg/kg, and an empirical course of ivermectin (follow up of skin scraping for scabies were negative)... Case CKDaP is a challenging condition to manage and severe cases can be extremely distressing for patients. Lignocaine blocks sodium channels in neuronal cell membranes and is widely and safely administered by CSCI in palliative care..."

Clinical • Chronic Kidney Disease • CNS Disorders • Dermatology • Diabetic Nephropathy • Hematological Malignancies • Infectious Disease • Lymphoma • Nephrology • Oncology • Pain • Palliative care • Pruritus • Renal Disease • Sleep Disorder • T Cell Non-Hodgkin Lymphoma

The prevalence and disease burden of CKD associated pruritus in Danish dialysis patients and current treatment practices (ERA 2025) - "Gabapentinoids (gabapentin and pregabalin) were rated third choice by most, but nephrologist prescribed pregabalin more than residents as their first or second treatment choice ( P=0.03 X2-test). Difelikefalin was not chosen (90%) or rated as fourth choice by 4% of nephrologists in our survey... Roughly one out of five patients on chronic dialysis treatment suffers from CKD-aP. HRQoL is negatively affected by CKD-aP primarily manifested as sleep disturbance. Most physicians tend to overestimate CKD-aP prevalence and use dialysis and fatty cream as their preferred treatment."

Clinical • Chronic Kidney Disease • CNS Disorders • Dermatology • Nephrology • Pruritus • Sleep Disorder