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

ABSTRACT

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.

KEYWORDS:

• Chronic kidney disease
• chronic kidney disease-associated pruritus
• difelikefalin
• efficacy
• kappa opioid receptor
• opioids
• pruritus
• safety

1. Introduction

Chronic kidney disease-associated pruritus (CKD-aP) (previously referred to as uremic pruritus; however, due to the involvement of multiple factors in addition to uremic toxins, CKD-aP was found to be a more inclusive nomenclature) is a frequent and particularly bothersome symptom experienced by many patients with CKD receiving maintenance dialysis [1] [2]. Up to 40% of hemodialysis (HD) patients reported being ‘moderately’ to ‘extremely bothered’ by itching in the Dialysis Outcomes and Practice Patterns Study (DOPPS) [3]. However, the prevalence of CKD-aP is likely to be significantly underreported; data from DOPPS reported that approximately 1 in 6 HD patients with severe pruritus did not report their symptoms to a healthcare professional (HCP) [4]. A survey of recognition of symptoms and their severity in HD patients reported that nephrologists underestimated the severity of the majority of symptoms in their patients [5]. Underreporting is potentially due to a combination of patients not associating their symptoms with CKD and a lack of awareness by HCPs [6], as well as a lack of approved, effective treatments. This means that CKD-aP may also be undertreated when diagnosed [7,8]; more than two-thirds of HD unit medical directors surveyed by DOPPs underestimated the prevalence of CKD-aP among their patients [4]. Additionally, tools to identify and quantify the severity of CKD-aP are frequently not used in the clinical setting; there is currently no universally accepted method to quantify CKD-aP [9].

The importance of CKD-aP extends beyond the symptom itself because CKD-aP is associated with reduced quality of life (QoL), poor sleep quality, and depression among other outcomes [10,11]. Patients with severe pruritus are also more likely to withdraw from or miss dialysis sessions [3]. CKD-aP is also associated with worse clinical outcomes, including increased medication use (intravenous [IV] antibiotics, erythropoiesis-stimulating agents, and iron supplementation) infections, hospitalizations, and mortality [2,3,8].

The mechanism of chronic itch (lasting 6 weeks or longer) is markedly different from that of acute itch. Chronic itch develops from activation of pruriceptors after exposure to pruritogens or inflammatory mediators, enhancing the responsiveness of pruriceptive nerve fibers. Immune modulation results in further interactions with sensory fibers, transmitting both histamine-dependent and histamine-independent itch.

Several mechanisms appear to contribute to the occurrence of CKD-aP and is most likely multifactorial (Figure 1). These include activation of the non-histaminergic itch pathway, as well as the accumulation of uremic toxins [19]. A combination of these mechanisms results in opioid imbalance, peripheral neuropathy, or immune system dysregulation, with subsequent microinflammation and xerosis [9,20,21].

Figure 1. Pathophysiology of CKD-aP [2,12–18]. CKD-aP, chronic kidney disease-associated pruritus; IL, interleukin; KOR, kappa opioid receptor; MOR, mu opioid receptor.

CKD-aP is commonly thought to be driven by inadequate control of metabolic bone disease parameters such as phosphate, parathyroid hormone and calcium, or poor dialysis adequacy [3]. However, recent studies have not shown consistent associations between biochemical markers and pruritus [1,4,22–24]. Serum levels of inflammatory markers, including interferon gamma (IFNγ), interleukin (IL)-2, and granulocyte macrophage colony-stimulating factor (GM-CSF), were significantly correlated with itch intensity and markers of pruritus (e.g. IL-31) in HD patients with moderate-to-severe pruritus [25].

Until the approval of difelikefalin (CR845), there were no approved therapies for CKD-aP in the U.S.A or Europe (nalfurafine hydrochloride is approved in Japan for the treatment of resistant pruritus in HD patients). Various off-label treatments have therefore been used to treat CKD-aP, including moisturizers, antihistamines, ultraviolet light, corticosteroids, gabapentinoids, and opioids; however, these agents have not been studied in large-scale, high-quality randomized trials [26]. Besides doubtful efficacy, they might be associated with significant adverse events.

Difelikefalin is approved in both the U.S.A (as CR845/KORSUVA™) and Europe (as Kapruvia®) for the treatment of moderate-to-severe pruritus in adults undergoing HD [27].

Difelikefalin is a kappa opioid receptor (KOR) agonist, which acts mainly on peripheral neurons and cells of the immune system. The primary mode of action is therefore outside of the central nervous system [28,29].

In phase 3 clinical trials (KALM-1 and KALM-2) in HD patients with moderate-to-severe pruritus, treatment with difelikefalin resulted in significantly greater reduction in itch intensity and improvement in itch-related QoL, compared with placebo. Additionally, difelikefalin was shown to have an acceptable safety profile [30–32].

2. Overview of the treatment landscape

The underlying etiology of CKD-aP is distinct to other causes of itching seen within the general population [33]. Historically, toxin accumulation and deposition have been implicated in CKD-aP, particularly inadequate phosphate and calcium control [34–37]. Peripheral neuropathy, immune system dysregulation, or opioid dysregulation have also been suggested as pathways implicated in CKD-aP [9], or potentially a combination of these factors [38]. Therefore, control of phosphate and optimization of dialysis adequacy should be initially investigated: changing dialyzer type e.g. to polymethyl methacrylate, may also be beneficial, as this has shown reductions in ‘dialysis itchiness,’ potentially through the removal of inflammatory cytokines [22,39]). Current treatment algorithms then recommend a stepwise approach starting with emollients and topical anti-inflammatories, or alternatively systemic treatment with gabapentin or κagonists (difelikefalin, or nalfurafine in refractory cases), followed by drugs with an antiinflammatory action, then phototherapy, or acupuncture [40]. In addition, successful kidney transplantation will relieve patients from CKD-aP [12] (Table 1). However, until the recent approval of difelikefalin, no therapies were approved for CKD-aP in the U.S.A or Europe, and difelikefalin remains the only approved therapy within the treatment algorithm [80].

Table 1. Overview of CKD-aP treatments.

Treatment	Target	Mechanism of action	Efficacy/safety	Approved/off-label for treatment of CKD-aP?	References
Difelikefalin	Immune dysfunction	Activation of kappa opioid receptors on peripheral sensory neurons and immune cells	Robust clinical efficacy and safety data from large well-designed phase 3 randomized, controlled trials	Approved in the U.S.A and Europe for treatment of moderate-to-severe CKD-aP in patients undergoing HD	[27,30,41–44]
Nalfurafine hydrochloride		Antagonization of mu opioid receptors	Evidence of efficacy in short-term studies and a multicenter randomized controlled trial in 373 patients on HD, but no difference to placebo in a double-blind crossover study. Post-marketing surveillance suggests nalfurafine is a safe and effective treatment for CKD-aP	Approved in Japan only for treatment of CKD-aP	[40,45–47]
Nalbuphine		Antagonization of mu and kappa opioid receptors	Evidence of efficacy and tolerability in clinical studies	Not approved for CKD-aP, off-label treatment	[47]
Topical tacrolimus		Immunosuppression	Efficacy was demonstrated in a small case series; however, a randomized-controlled double-blind trial reported no benefit. Extensive use may increase risk of dermatologic malignancies	Not approved for CKD-aP, off-label treatment	[40,48]
Doxepin		Tricyclic antidepressant with anti-H1 receptor effect	Evidence of efficacy and tolerability of low doses in small clinical studies	Not approved for CKD-aP, off-label treatment	[49,50]
Naltrexone		Antagonism of endogenous opiates	Limited evidence of efficacy and safety for treating other forms of pruritus	Not approved for CKD-aP, off-label treatment	[51–53]
Antihistamines		Inhibition of the histaminergic-itch pathway	Limited evidence of efficacy for CKD-aP. Additionally, histamines are not a major pruritogen in CKD-aP	Not approved for CKD-aP, off-label treatment	[12,33]
Phototherapy		Immunomodulation, through inhibiting T-helper 1- and 2-mediated immune responses, decreasing proinflammatory cytokines and induction of mast cell apoptosis	Limited evidence of efficacy in some small, open-label trials. However, regular UVB therapy is time-consuming for patients, of limited availability, and may present an increased risk of skin cancer, particularly in immunosuppressed patients	Not approved for CKD-aP, off-label treatment	[14,54–56]
Thalidomide	Immune dysfunction and neuropathy	Immunomodulation and neuromodulation	Evidence of efficacy in small clinical studies. Adverse risk profile for long-term use	Not approved for CKD-aP, off-label treatment	[57,58]
Gabapentoids	Neuropathy	Gabapentoids modulate the action of the GABA synthetic enzyme, glutamic acid decarboxylase, and the glutamate-synthesizing enzyme, branched-chain amino acid transaminase	Effective for reduction of itch intensity. Risk of potentially serious adverse effects, particularly at higher doses, including altered mental status, falls and fractures	Not approved for CKD-aP, off-label treatment	[40,59–61]
Ketotifen		Immunomodulation through mast cell blockade	Evidence of efficacy and safety profile in small clinical studies	Not approved for CKD-aP, off-label treatment	[62,63]
Topical analgesics (e.g. pramoxine and capsaicin)	Inflammatory response	Blocking the conduction of nerve impulses from the skin	Efficacy has been reported in several small trials. Adverse events commonly reported include burning, stinging, and erythema, and it should not be used over large areas	Not approved for CKD-aP, off-label treatment	[40,64–66]
Cannabinoids		Inhibition of inflammation	Limited evidence of efficacy in small clinical studies. Limited evidence available on adverse events from long-term use	Not approved for CKD-aP, off-label treatment	[40,67]
Serotonin antagonists, e.g. sertraline		Reduction of inflammatory cytokines	Evidence of efficacy in small clinical studies. Known safety profile in other populations. No dosage adjustment is necessary in patients with renal impairment	Not approved for CKD-aP, off-label treatment	[68–70]
Acupuncture		Parasympathetic innervation and positive functional connectivity of the putamen-posterior midcingulate cortex	Limited evidence of efficacy in some small trials	Not approved for CKD-aP, off-label treatment	[40,71]
Fatty acid supplementation		Treatment of any underlying essential fatty acid deficiency and reduction of inflammation	Limited evidence of efficacy in a small double-blind, randomized study	Not approved for CKD-aP, off-label treatment	[72,73]
Emollients	Xerosis	Reduction of xerosis	Efficacy has been reported in several small, uncontrolled trials	Not approved for CKD-aP, off-label treatment	[40,74]
Optimization of dialysis	Biochemical regulation	Removal of uremic toxins	Optimizing dialysis has historically been shown to reduce itch in several studies; however, several recent studies have not reported a link between serum phosphorous/calcium and pruritus Changing dialyzer type (e.g. to polymethyl methacrylate) has shown reductions in ‘dialysis itchiness’	Not applicable	[4,22,24,26,40,75–79]

CKD-aP, chronic kidney disease-associated pruritus; HD, hemodialysis; UVB, ultraviolet B.

Oral, topical, or IV antihistamines are frequently prescribed as off-label treatments for pruritus [6], despite data indicating that histamines are not a major pruritogen in CKD-aP [12], with any efficacy likely contributed to by a combination of sedative and placebo effects.

Off-label treatment with gabapentin has shown efficacy in small clinical trials (14–54 patients) with relatively limited follow-up (1–8 weeks) [60], as well as following meta-analysis [7,60]. However, gabapentinoids require reduced doses in patients on HD because the risk of altered mental status, falls, and fractures increases in doses greater than 100 mg (the maximum recommended dose in post-dialysis patients is 300 mg) [61,81]. Gabapentin toxicity is a particular concern in patients with CKD because gabapentinoids are exclusively eliminated renally [82]. According to data from DOPPS, 5%, 19%, and 21% of medical directors use gabapentin as a first-, second-, or third-choice treatment in patients with CKD-aP; however, approximately 50% of medical directors never prescribe gabapentin for pruritus [4]. Non-pharmacological therapies include phototherapy with ultraviolet B light, which has demonstrated efficacy in some small, open-label trials [55,56]. However, regular ultraviolet B therapy is time-consuming for patients, of limited availability, and may present an increased risk of skin cancer, particularly in immunosuppressed patients [14], although a systematic review did not report an increased risk of skin cancer [13].

3. Introduction to the drug

3.1. Chemistry and pharmacokinetics

Difelikefalin has a unique pharmacology. It is a synthetic D-amino acid tetra-peptide with a single stereoisomer [44] (Figure 2) that was developed as an analogue of an endogenous opioid peptide, Dynorphin A, a neuromodulator of pruritus [41].

Figure 2. Chemical structure of difelikefalin.

Difelikefalin acetate is a white to off-white powder with a molecular weight of 0.68kDa (monoisotopic; free base). It is soluble in water, is not sensitive to light, and can be stored at room temperature. The chemical name of difelikefalin acetate is 4-amino-1-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)piperidine-4-carboxylic acid, acetate salt [44].

Difelikefalin is a hydrophilic peptide with very limited, if any, blood–brain barrier penetration, meaning it is peripherally restricted [41,42]. The mean volume of distribution of difelikefalin is approximately 238 mL/kg [44], and difelikefalin is non protein-bound (approximately 23–28% in plasma) [44]. Difelikefalin is not metabolized to any appreciable extent and is not a substrate for cytochrome P450 enzymes; therefore, interactions of difelikefalin with other medicinal products are unlikely [27,44]. Additionally, the structure of difelikefalin is not a substrate for drug uptake transporters and is not significantly metabolized [83,84]. Difelikefalin is renally excreted and is also removed by the dialyzer membrane during HD [27,44].

The half-life of difelikefalin in patients undergoing HD ranges between 23 and 31 hours; HD reduced plasma concentrations of difelikefalin by 70–80%, with difelikefalin undetectable in plasma following two dialysis cycles. For this reason, difelikefalin is administered via bolus IV injection at the end of HD treatment, during or after rinse back [44]; this also means dialysis efficiency will not impact the efficacy of difelikefalin. Clinically relevant pharmacokinetics of difelikefalin were not affected by age (25–80 years of age), sex, race/ethnicity, or mild-to-moderate hepatic impairment [44].

3.2. Pharmacodynamics and mechanism of action

The proposed mechanism of action of difelikefalin in alleviating itching is thought to be through selectively activating KORs on peripheral sensory neurons and immune cells, which are thought to play an important role in CKD-aP [41,42].

Difelikefalin is a selective and full agonist at the KOR, with no or negligible activity at mu or delta opioid receptors or other receptors, ion channels, or transporters (based on nonclinical studies conducted by Cara Therapeutics), with at least a 10,000 times greater affinity for KORs than mu opioid receptors [28]. The unique peptidic structure of difelikefalin differs significantly from the other small-molecule KOR agonists developed to date, which for the most part are active in the central nervous system, whereas difelikefalin was designed to activate KORs located primarily in the peripheral nervous system without producing side effects associated with the activation of mu opioid receptors, such as respiratory depression and abuse. Additionally, difelikefalin is a hydrophilic peptide with limited membrane permeability by passive diffusion, thereby limiting access of the drug to the central nervous system [41,42]. Consequently, difelikefalin is expected to have an improved safety and tolerability profile compared with other opioid agonists, including centrally acting KOR agonists.

To assess the abuse potential of difelikefalin, a double-blind, randomized, placebo-controlled, four-way crossover study of volunteers was carried out (n = 44; 18–55 years, mean = 28 years; 35 males). The study concluded that difelikefalin has a low risk for abuse potential in humans [85]. An additional single‐center, randomized, double‐blind, placebo‐controlled, three‐way crossover study also reported that difelikefalin did not produce respiratory depression [84].

Difelikefalin therefore has low abuse potential and is not categorized as a controlled substance according to the Controlled Substance Act Scheduling. Furthermore, no events of dysphoria or euphoria have been reported [44].

Reduction in itch intensity with DFK correlated with reductions in serum levels of inflammatory markers, including IFNγ, IL-2, and GM-CSF. These results identify a potential mechanism of action of DFK through significantly reducing markers of pruritus-associated inflammation [25]; however, elucidation of the mechanism of action requires further investigation in well-designed studies.

4. Clinical efficacy

4.1. Assessment of clinical efficacy in research settings

The clinical efficacy and safety profile of difelikefalin have been assessed through a large-scale clinical trial program, recruiting more than 1,400 HD patients who were treated for up to 64 weeks, with assessments of pruritus severity incorporating evaluations of both itch intensity and the impact of itch on patient QoL (Table 2) [86].

Table 2. Key clinical trial results of difelikefalin in moderate-to-severe pruritus associated with CKD in adults undergoing hemodialysis.

Study Publication	Design/Analyses	N	Treatment	Key efficacy results	Key safety results	Reference
Phase 2
NCT02858726 Fishbane 2020	Double-blind, controlled trial primary analysis	174	IV DFK (0.5, 1.0, or 1.5 μg/kg) or PBO TIW for 8 wks	1°: reduction at wk 8 from BL with DFK vs. PBO in WI-NRS score (P = 0.002) 2°: improvement Skindex-10, 5-D itch, and sleep disturbance scores with DFK vs. PBO (P ≤ 0.005)	TEAEs: 78% pts on DFK vs 42% on PBO ≥5% diarrhea, dizziness, nausea, somnolence, and fall	[86]
Phase 3
KALM-1 Fishbane 2020	Double-blind, PBO-controlled primary analysis	378	IV DFK (0.5 μg/kg) or PBO TIW for 12 wks	1°: ≥3-point reduction at wk 12 from BL in WI-NRS: 49.1% of pts on DFK vs. 27.9% on PBO (P < 0.001) 2°: improvement at wk 12 from BL in 5-D itch and Skindex-10 with DFK vs. PBO	Diarrhea, dizziness, and vomiting were more common in the DFK group than PBO group	[30]
KALM-1/2 Topf 2022	Randomized, PBO-controlled pooled efficacy and subgroup analyses	851	IV DFK (0.5 μg/kg) or PBO TIW for 12 wks	≥3-point reduction at wk 12 from BL in WI-NRS: 51.1% of pts on DFK vs. 35.2% on PBO (P < 0.001) Subgroups (age, sex, race, geographic region, BL use of anti-itch medication, medical conditions, and BL use of gabapentin or pregabalin): DFK favored vs. PBO At wk 12, complete WI-NRS response (≥80% of weekly scores equal to 0 or 1): 12.0% pts on DFK vs. 6.7% on PBO (P = 0.006) Decreases ≥15 points in Skindex-10 total score: 55.5% pts on DFK vs. 40.5% on PBO (P < 0.001); and ≥5 points in 5-D itch total score: 52.1% of pts on DFK vs. 42.3% on PBO (P = 0.012)	NA	[31]
KALM-1/2 Fishbane 2022	Randomized, PBO-controlled pooled long-term safety and 5-D itch	1306	IV DFK (0.5 μg/kg) or PBO TIW for 12 wks	NA	PBO-controlled cohort: Most common TEAEs in DFK and PBO groups, respectively: diarrhea (9.0% and 5.7%), dizziness (6.8% and 3.8%), nausea (6.6% and 4.5%), gait disturbance including falls (6.6% and 5.4%), hyperkalemia (4.7% and 3.5%), headache (4.5% and 2.6%), somnolence (4.2% and 2.4%), and mental status changes (3.3% and 1.4%) Mostly mild or moderate in severity, with few leading to study drug discontinuation Incidence rates of TEAEs, serious TEAEs, and TEAE-related study drug discontinuations did not increase with long-term exposure Incidence of death higher in the PBO than DFK group All-DFK-exposure cohort: Death rates aligned with mortality rates for pts undergoing HD in the USRDS 2020 report	[32]
KALM-1/2 Ahdoot 2021	Randomized, PBO-controlled post hoc analysis of pooled sleep quality data	850	IV DFK (0.5 μg/kg) or PBO TIW for 12 wks	Greater improvement in mean 5-D itch sleep disability question score from BL to wk 12 for pts with a ≥3-point (vs. <3-point) reduction in WI-NRS score: −1.5 vs. −0.6 (P < 0.0001, n = 709) Moderate correlation between WI-NRS and 5-D itch sleep disability question scores at wk 12 (r = 0.499, 95% CI 0.442–0.552) Greater improvement at first assessment of sleep quality (4 wks) for pts with a ≥3-point (vs. <3-point) reduction in WI-NRS score: −1.2 vs. −0.4 (P < 0.0001, n = 761)	NA	[87]
KALM-1/2 Fishbane 2021	Randomized, PBO-controlled pooled African American subgroup analysis	249	IV DFK (0.5 μg/kg) or PBO TIW for 12 wks	≥3-point improvement in WI-NRS: 48% of pts on DFK vs. 45% on PBO (OR 2.82; 95% CI 1.63–4.87; P < 0.001) ≥5-point improvement in WI-NRS: 36% of pts on DFK vs. 17% on PBO (OR 2.72; 95% CI 1.47–5.01; P = 0.001) ≥5-point improvement in 5-D itch: 55% of pts on DFK vs. 36% on PBO (OR 2.18; 95% CI 1.18–4.03; P = 0.013) ≥15-point improvement in Skindex-10: 49% of pts on DFK vs. 29% on PBO (OR 2.36; 95% CI 1.26–4.36; P = 0.006)	Most common TEAEs in DFK and PBO groups, respectively: diarrhea (10.4% and 6.2%), dizziness (10.4% and 2.7%), vomiting (7.4% and 4.4%), headache (5.2% and 0.9%), and hyperkalemia (5.2% and 2.7%) Serious AE incidence similar between groups	[88]
KALM-1/2 Fishbane 2022	Randomized, PBO-controlled pooled analysis of PGIC	800/851 with PGIC data	IV DFK (0.5 μg/kg) or PBO TIW for 12 wks	‘Very much’ or ‘much’ improved itch: 56% of pts on DFK vs. 39% on PBO (OR 1.94; 95% CI 1.45–2.60; P < 0.001)	NA	[89]
KALM-1/2 Csiky 2022	Randomized, PBO-controlled post hoc analysis of pooled WI-NRS score over time	851	IV DFK (0.5 μg/kg) or PBO TIW for 12 wks	WI-NRS response within 4 wks: ≥66% of pts on DFK vs. 44% PBO, and within 8 wks>90% DFK vs. 57% PBO	NA	[90]
3105 Weiner 2022	Open-label, multicenter, single-arm intervention trial/primary analysis	222	IV DFK (0.5 μg/kg) TIW for 12 wks	Clinically meaningful reduction in WI-NRS in 74% of pts Improvement in 5-D itch in 70% of pts Improvement in Skindex-10 in 63% of pts Sleep quality improvement (≥3-point reduction on NRS) in 66% of pts	Most common TEAEs related to study drug: somnolence (1.8%), hypoesthesia (1.4%), nausea (0.9%), and dizziness (0.9%) reported in 16 pts (7.2%) No deaths or serious TEAEs considered treatment-related	[91]
3105 Weiner 2021	Open-label, multicenter, single-arm intervention trial itch and sleep quality correlation analysis	222	IV DFK (0.5 μg/kg) TIW for 12 wks	≥3-point improvement in WI-NRS and SQQ score in 74% and 66% of pts at wk 12 Greater improvement in SQQ score from BL to wk 12 for pts with a ≥3-point (vs. <3-point) reduction in WI-NRS score (−5.22 vs. −1.53) and in 5-D itch sleep score (−1.83 vs. –‍0.78) From BL to wk 12, strong correlation between WI-NRS and SQQ scores (r = 0.78) and moderate correlation between WI-NRS and 5-D itch sleep disability scores (r = 0.48). Strong correlation between SQQ and 5-D itch sleep disability scores at wk 12 (r = 0.64)	NA	[92]
3105 Weiner 2022	Open-label, multicenter, single-arm intervention trial post hoc analysis on itch-related sleep disruption	222	IV DFK (0.5 μg/kg) TIW for 12 wks	At BL, 3.6%, 4.5%, 39.2%, and 52.7% pts reported no, mild, moderate, or severe itch-related sleep disruption, respectively, with 13.5% reporting the highest scores (9–10). 194 (87.4%) pts had sleep quality scores at wk 12, and 32.0%, 43.3%, 19.6%, and 5.2% reported no, mild, moderate, or severe itch-related sleep disruption, respectively, with no pts scoring >8	NA	[93]
KALM-1/2 and 3105 Weiner 2022	Open-label, multicenter, single-arm intervention trial post hoc analysis on CKD-aP severity	222	IV DFK (0.5 μg/kg) TIW for 12 wks	Mean improvement from BL to wk 12 was 51.7% for patients with moderate itch and 62.7% for severe itch. On average, itch severity improved to mild (WI-NRS <4) following 12 wks treatment with DFK, irrespective of baseline itch severity	NA	[94]

AE, adverse event; BL, baseline; CI, confidence interval; CKD, chronic kidney disease; CKD-aP, CKD-associated pruritus; DFK, difelikefalin; HD, hemodialysis; IV, intravenous; NA, not available; NRS, Numerical Rating Scale; OR, odds ratio; PBO, placebo; PGIC, Patient Global Impression of Change; pt, patient; SQQ, Sleep Quality Questionnaire; TEAE, treatment-emergent adverse event; TIW, three times per week; USRDS, United States Renal Data System; WI-NRS, Worst-Itch Numeric Rating Scale; wk, week.

Patient-reported outcomes (PROs) assessed during the trial program include (Table 3):

• Kidney Disease Quality of Life Instrument, a 36-item health-related QoL measure for dialysis patients [96].

• The Worst-Itch Numerical Rating Scale (WI-NRS), an 11-point scale ranging from 0 to 10, which was validated in patients with CKD-aP [17,22,95]. Clinically meaningful changes in itch intensity have been associated with a reduction of ≥ 3 points on the WI-NRS for patients with moderate-to-severe pruritus undergoing HD [95].

• The 5-D Itch scale, which utilizes five separate itch-related domains to assess itch-related QoL and itch intensity [39]. Clinically meaningful changes in itch intensity have been associated with a ≥ 5-point reduction from baseline in the total 5-D itch score [86].

• Skindex-10, a multidimensional tool evaluating itch-related QoL across three domains: Disease, Mood/Emotional Distress, and Social Functioning [22]. Clinically meaningful changes in itch intensity have been associated with a reduction from baseline of ≥ 15 points [86].

• Sleep quality, assessed by a Sleep Quality Numerical Rating Scale (NRS) with responses ranging from 0 (‘did not interfere’) to 10 (‘completely interfered’) to indicate how much itch interfered with sleep over the preceding 24 hours [91].

• The Patient Global Impression of Change, a global patient-reported outcome measure assessing overall perception of change in itch (ranging from ‘Very much improved’ to ‘Very much worse’) compared with the start of the study [97].

Table 3. Overview of itch-related patient-reported outcome measures.

Measure	Description	References
Worst-Itch Intensity Numerical Rating Scale (WI-NRS)	Evaluates itch intensity over the previous 24 hours on an 11-point scale (range 0 to 10). WI-NRS has been validated in patients with CKD-aP, with a clinically meaningful change associated with a reduction of ≥3 points in patients with moderate-to-severe pruritus undergoing HD.	[17,22,95]
Skindex-10	Evaluates itch-related QoL across three domains: Disease, Mood/Emotional Distress, and Social Functioning. A ≥15-point reduction from baseline in the total Skindex-10 score represented a clinically meaningful change in a phase 2 clinical trial in adult HD patients with moderate-to-severe pruritus.	[22,86]
5-D itch	Assesses itch-related QoL and itch intensity over the previous 2 weeks, using five domains (Duration, Degree, Direction, Disability, and Distribution). A ≥5-point reduction from baseline in the total 5-D itch score represented a clinically meaningful improvement in a phase 2 clinical trial.	[39,86]
Sleep Quality Numerical Rating Scale	Evaluates itch interference with sleep over the preceding 24 hours on an 11-point scale, ranging from 0 (‘did not interfere’) to 10 (‘completely interfered’).
Kidney Disease Quality of Life Instrument (KDQOL)	Assesses health-related QoL measure for dialysis patients through a 36-item health survey	[96]
Patient Global Impression of Change (PGI-C)	Assesses patients’ overall perception of change in itch relative to the start of the study (from ‘Very much improved’ to ‘Very much worse’)	[97]

CKD-aP, chronic kidney disease-associated pruritus; HD, hemodialysis; KDQOL, Kidney Disease Quality of Life Instrument; PGI-C, Patient Global Impression of Change; QoL, quality of life; WI-NRS, Worst-Itch Numerical Rating Scale.

4.2. Phase 2 studies

4.2.1. Difelikefalin phase 2 study: intravenous administration [86]

A randomized, double-blind, placebo-controlled trial in 174 HD patients with moderate-to-severe pruritus was the largest phase 2 clinical trial of difelikefalin. Participants were randomized to IV difelikefalin (0.5, 1.0, or 1.5 µg/kg) or placebo, following HD, three times per week for 8 weeks. The primary endpoint was the change from baseline to week 8 in the weekly mean of the 24-hour WI-NRS score, while secondary and other endpoints included change in itch-related QoL (measured by the Skindex-10 questionnaire and the 5-D itch scale), safety profile, and sleep quality.

Treatment with difelikefalin resulted in a significant reduction from baseline in WI-NRS scores at week 8 versus placebo (P = 0.002). Significant improvement with difelikefalin compared with placebo was also reported for Skindex-10, 5-D itch, and sleep disturbance scores (P < 0.005). Treatment-emergent adverse events (TEAEs) were reported in more patients receiving difelikefalin (78%), compared with 42% of patients receiving placebo. Diarrhea, dizziness, nausea, somnolence, and falls were the most commonly reported adverse events.

The overall conclusion of the trial was that difelikefalin effectively reduced itching intensity and improved sleep and itch-related QoL.

4.3. Phase 3 studies

The pivotal phase 3 trials of difelikefalin were the KALM-1 and KALM-2 double-blind, placebo-controlled studies (Figure 3), followed by the open-label 3105 single-arm study.

Figure 3. KALM trial design. *1 patient withdrew post-randomization and before first dose of placebo. HD, hemodialysis; IV, intravenous; U.S., United States; WI-NRS, Worst-Itch Numerical Rating Scale.

4.3.1. KALM-1 and KALM-2 studies [30]

KALM-1 was a double-blind, placebo-controlled, phase 3 trial. Hemodialysis patients with moderate-to-severe pruritus were randomly assigned to receive either IV difelikefalin (0.5 µg/kg) or placebo three times per week for 12 weeks, with an additional open-label extension of 52 weeks. The primary outcome of the double-blind treatment period was the proportion of patients with an improvement of at least 3 points from baseline at week 12 in the weekly mean of the 24-hour WI-NRS. Secondary outcomes included change from baseline in itch-related QoL, proportion of patients with an improvement in WI-NRS score ≥4 points at week 12, and safety profile.

The overall conclusion of the trial was that HD patients with moderate-to-severe pruritus treated with difelikefalin had a significant, clinically meaningful reduction in itch intensity and improved itch-related QoL compared with patients who received placebo.

The KALM-2 phase 3 study had an almost identical study design to KALM-1; however, KALM-1 was conducted in the U.S.A whereas KALM-2 was conducted in North America, Europe, and Asia-Pacific region (Australia, New Zealand, South Korea, Taiwan). Inclusion criteria differed slightly between the two trials, with KALM-1 requiring a weekly mean WI-NRS score of >4 during the run-in period, whereas KALM-2 required a WI-NRS weekly mean score of ≥5. The results of both the KALM studies have therefore been combined, with further publications reporting on the pooled population.

4.3.2. KALM-1 and KALM-2 pooled efficacy [31]

Overall, in KALM-1 and -2, 851 patients were randomized (426 patients received difelikefalin and 425 received placebo). Significantly more patients achieved a clinically meaningful (≥3-point) reduction in weekly mean WI-NRS score with difelikefalin versus placebo at week 12 (51.1% vs. 35.2%, P < 0.001). Difelikefalin also demonstrated greater improvements in itch intensity compared with placebo in patient subgroups based on age, sex, race, geographic region, medical conditions, and baseline use of anti-itch medication (including gabapentin or pregabalin). At week 12, significantly more patients reported complete WI-NRS response (≥80% of weekly scores equal to 0 or 1) with difelikefalin versus placebo (12.0% vs. 6.7%, P = 0.006). Significantly greater proportions of difelikefalin-treated patients also achieved clinically meaningful decreases in Skindex-10 total score (≥15 points; 55.5% vs. 40.5%, P < 0.001) and in 5-D itch total score (≥5 points; 52.1% vs. 42.3%, P = 0.012).

Overall, difelikefalin provided clinically meaningful improvements in itch intensity and QoL in patients with moderate-to-severe pruritus undergoing HD. Additionally, findings were consistent across diverse patient subgroups.

4.3.3. KALM-1 and KALM-2 pooled safety [32]

Pooled safety findings were reported for two separate cohorts: a placebo-controlled cohort from the 12-week pivotal studies, KALM-1 and KALM-2, and an all-difelikefalin-exposure cohort including subjects who received one or more IV doses of difelikefalin (0.5 µg/kg) for up to 64 weeks. Differences in TEAEs are descriptive only, as p values are generally not ascribed to AE data; AEs are already noted in the label and this study was not powered for safety data.

Total exposure in the all-difelikefalin-exposure cohort was 811.3 person-years (n = 1,306 subjects); exposure was ≥6 months in 711 patients, with 400 patients exposed for ≥12 months. In the placebo-controlled cohort, the most commonly reported TEAEs occurring in more patients in the difelikefalin group were diarrhea (9.0% and 5.7%), dizziness (6.8% and 3.8%), nausea (6.6% and 4.5%), gait disturbance including falls (6.6% and 5.4%), hyperkalemia (4.7% and 3.5%), headache (4.5% and 2.6%), somnolence (4.2% and 2.4%), and mental status changes (3.3% and 1.4%), in the difelikefalin and placebo groups, respectively. Adverse events were mostly mild to moderate in severity, with most patients continuing study drug. Long-term exposure did not increase incidence rates of TEAEs, serious TEAEs, or study drug discontinuations caused by TEAEs. The incidence of death was higher in the placebo group than in the difelikefalin group, and death rates in the all-difelikefalin-exposure cohort were consistent with those for patients undergoing HD documented in the US Renal Data System 2020 report [98].

Overall, IV difelikefalin demonstrated an acceptable safety profile and was generally well tolerated with long-term use. Difelikefalin therefore has the potential to address the unmet need for a safe and effective treatment for CKD-aP in patients undergoing HD.

4.3.4. Study 3105 [91]

Study 3105 was an open-label, multicenter, single-arm intervention trial of maintenance HD patients with moderate-to-severe CKD-aP (baseline WI-NRS ≥5). Patients received IV difelikefalin (0.5 µg/kg) after each HD session for 12 weeks. The primary outcome of the study was to assess the safety profile of difelikefalin, while secondary outcomes included the effectiveness of difelikefalin to reduce itch intensity (assessed by the WI-NRS); improving itch-related QoL (assessed by the 5-D itch and Skindex-10 scales); and improvement of sleep (assessed with the Sleep Quality NRS). Clinically meaningful thresholds for improvement in itch and QoL were previously established in this population as ≥3-point reduction in WI-NRS, ≥15-point reduction in Skindex-10, and ≥5-point reduction in 5-D itch. A clinically relevant reduction in Sleep Quality NRS score has not yet been validated.

Among 222 patients, mean [standard deviation] baseline WI-NRS was 7.6 [1.3], mean age was 58 years, 55% were male, and mean dialysis duration was 5.9 years. Treatment was completed by 197 patients (89%). Adverse events were reported in 7.2% of patients. The most common TEAEs related to study drug were somnolence (1.8%), hypoesthesia (1.4%), nausea (0.9%) and dizziness (0.9%); no deaths or serious TEAEs were considered related to treatment. Efficacy of difelikefalin was clearly demonstrated, with 74% of patients reporting clinically meaningful reductions in itch intensity, and 70% and 63% also reporting clinically relevant improvements in QoL (measured by 5-D itch and Skindex-10, respectively). Improvements in sleep quality (≥3-point NRS reduction) were reported in 66% of patients.

Study 3105 concluded that difelikefalin was well tolerated overall and resulted in clinically meaningful improvements in itch intensity, as well as improvements in itch-related QoL and sleep quality in HD patients who had moderate-to-severe CKD-aP. Additionally, Study 3105 provided evidence regarding the potential real-world effectiveness of difelikefalin.

4.3.5. Difelikefalin phase 3 study: oral administration [99]

An additional phase 3, multicenter, double-blind, randomized, placebo-controlled study in 400 patients of oral difelikefalin is currently underway in CKD patients with moderate-to-severe pruritus. The study aims to evaluate the safety and efficacy of oral difelikefalin (1 mg once-daily tablet) in reducing the intensity of itch compared with placebo in patients with advanced CKD with moderate-to-severe pruritus who are not on dialysis. The development of an oral formulation of difelikefalin will enable treatments of patients with CKD-aP who are not undergoing HD, or who are undergoing dialysis at home [99].

5. Regulatory status

In the U.S.A, difelikefalin is indicated for the treatment of moderate-to-severe pruritus associated with CKD in adults undergoing HD [44]. In Europe, a Pediatric Investigation Plan was agreed in May 2020 by the European Medicines Agency [100]. In May 2022, difelikefalin was also approved as the first therapy in Europe for the treatment of CKD-aP in HD patients [27]. Subsequent approvals followed in 2022 in Switzerland as part of an Access Consortium procedure, together with Canada, Australia and Singapore [101,102]. Additionally, a new drug application was submitted in Japan in September 2022.

6. Conclusion

CKD-aP is an underreported, underdiagnosed, and undertreated condition, which is common in patients with CKD, including those undergoing HD. CKD-aP is a particularly bothersome symptom, affecting patients’ QoL, as well as resulting in worse clinical outcomes for patients on HD, including higher rates of mortality.

Difelikefalin has demonstrated efficacy, tolerability, and safety profile in several large-scale clinical trials in more than 1,400 HD patients with CKD-aP, who were treated for up to 64 weeks.

Difelikefalin activates peripherally located KORs without producing adverse effects associated with the activation of mu opioid receptors, such as respiratory depression and abuse. Consequently, difelikefalin presents an improved safety profile compared with other opioid agonists, with limited potential for abuse and dependency.

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.

7. Expert opinion

Currently, CKD-aP is underreported [4], as well as undertreated [7,8]. This may partly be due to a previous lack of approved treatments, as well as a lack of standardized assessment and monitoring tools. However, difelikefalin, now approved in multiple countries worldwide [27,44,103,104], has demonstrated efficacy in a large-scale clinical-trial program in more than 1,400 HD patients with CKD-aP, who were treated for up to 64 weeks [31,86,91], and has a well-demonstrated safety profile, with no serious adverse events related to study drug reported even with up to triple the intended dose [32,86]. The most common TEAEs reported following difelikefalin treatment are mostly mild in nature and manageable; diarrhea, dizziness, somnolence, and vomiting are the most common adverse events reported, rarely requiring discontinuation of treatment [30,32,91]. Additionally, TEAEs of somnolence tended to subside with continued dosing [27]. Of particular note, unlike other opioid medications, difelikefalin has a low abuse potential [84,85]. Of further note, the lack of serious adverse events at higher concentrations may be relevant for assessing the efficacy of increased dosing more than three times per week in patients receiving dialysis more frequently, or those receiving at-home HD. An associated future development in the difelikefalin pipeline is the development of an oral formulation for non-dialysis and home-dialysis patients [99], which again is possible due to the safety profile and lack of abuse potential of difelikefalin [84,85].

Difelikefalin represents a potential step-change for patients with CKD-aP: other treatments for CKD-aP are only available as off-label treatments, and have limited evidence of efficacy in much smaller, shorter-term studies, with the safety profile and lack of toxicity not demonstrated in large-scales trials in this patient population (Table 1). Additionally, the clinical development program has demonstrated the importance of the use of validated PROs to diagnose and monitor the course of CKD-aP. Therefore, the combination of the availability of an approved, safe, and effective therapy along with increased recognition of the value of utilizing itch-specific PROs has the potential to dramatically increase both the recognition and treatment of this debilitating condition.

However, it is vital that HCPs change their view of CKD-aP as a mild or rare symptom associated with CKD, and understand that it has a significant impact on patients’ QoL [10,11], in addition to impacting clinical outcomes, such as attendance at dialysis sessions, hospitalizations, infections, and mortality [2,3,8]. The lack of recognition by HCPs that CKD-aP is a common, debilitating condition appears to be one of the major barriers to patient education regarding the association of their symptoms to CKD, so that patients are aware that treatments are available.

The importance of HCP awareness of the impact of symptoms associated with CKD on patient QoL and the prioritization of symptom management have recently been highlighted [105,106], including the importance of the use of PROs. The tools chosen for assessing itch intensity and impact on QoL in the clinical trial program are based on tools that can be applied in real-world clinics, in order to address the underreporting and undertreatment of CKD-aP. Further avenues of exploration therefore include whether increasing use of these tools (Figure 4), as well as the availability of an approved treatment with demonstrated efficacy and a tolerable safety profile, can reduce the underreporting and undertreatment of CKD-aP.

Figure 4. Assessment of patients with CKD-aP.

As the only approved treatment of CKD-aP in the U.S.A and Europe, difelikefalin has been recommended as first-line treatment for patients with moderate to severe pruritus (Figure 5). It is important that the treatment pathway includes screening, diagnosis, and assessment of itch severity, as well as treatment options. Gabapentinoids are also recommended as a first-line treatment; however as gabapentoids are not approved for this indication and their use is off-label, it may be preferable to reserve treatment with gabapentinoids to patients found to be refractory to difelikefalin. Other treatments such as phototherapy and selective serotonin reuptake inhibitors are recommended as third-line (again, off-label) treatments. Skin moisturization and barrier-function therapy with emollients, moisturizing ointments, and bath oils remain a universal approach to the management of xerosis related to CKD-aP, particularly for relief of mild disease.

Figure 5. Treatment algorithm for management of CKD-aP [2,3,30,107–110]. CKD-aP, chronic kidney disease-associated pruritus; PTH, parathyroid hormone; SSRI, selective serotonin reuptake inhibitor; UVB, ultraviolet B.

To improve implementation of difelikefalin within the CKD-aP treatment pathway, further research is required into real-world effectiveness and safety profile: the anticipated real-world effectiveness of difelikefalin has already been suggested through the open-label Study 3105 [91]; however, confirmation of the safety profile and effectiveness of treatment within a real-world population (without additional inclusion/exclusion criteria) will also be important. Additionally, the safety profile and efficacy of difelikefalin in patients undergoing HD more than three times per week remain to be confirmed (although given the tolerable safety profile observed at treble doses of difelikefalin [86], it is not expected that additional treatments at the current dose of difelikefalin will result in any additional safety signals).

Furthermore, although the clinical trial program included continued use of other itch therapies (approximately one-third of participants were receiving an anti-itch medication at baseline) [31,91], elucidation of any benefits of combination treatments will be beneficial. Further investigation of combining difelikefalin with other therapies may avoid the potential for additional adverse effects from additional treatments (particularly off-label treatments), if these do not substantially increase symptom relief, compared with the use of difelikefalin alone, as well as to ascertain any potential benefits of improving control of CKD-aP.

Elucidating the driving factors behind CKD-aP (e.g. predictors of disease severity and predictors of response to difelikefalin) is another exciting avenue of research, which will further improve QoL for patients.

Additionally, in real-world management of CKD-aP, many patients may be referred to dermatologists rather than nephrologists, and it is important to assess the real-world use of difelikefalin in this setting.

When these research queries have been answered, difelikefalin has the potential to significantly advance the treatment of CKD-aP, as well as utilizing the lessons learned through its clinical development program to advance the use of appropriate, validated PROs as part of routine clinical management of CKD.

Article highlights

• CKD-aP is quite prevalent in hemodialysis patients but is still underrecognized, underreported, underdiagnosed, and undertreated.

• The pathogenesis of CKD-aP is complex and likely to be multifactorial, with the dysregulated endogenous opioid pathway playing a significant role.

• Difelikefalin is the first and only approved therapy for CKD-aP in the U.S.A and Europe.

• Difelikefalin is a peripherally acting KOR agonist.

• Difelikefalin’s unique pharmacology contributes to its safety profile, efficacy, and tolerability.

• Difelikefalin has been studied widely and has not been found to be associated with any dependency or withdrawal.

Declaration of interest

A Rastogi reports advisory board participation and speakers bureau fees from AstraZeneca and Relypsa Inc, and research grants from AstraZeneca. E Lerma reports speaker/advisory board/steering committee involvements with Akebia, AstraZeneca, Bayer, Glaxo Smith Kline, Otsuka, Travere, and CSL Vifor. S Frisbane reports receipt of grants from Cara Therapeutics, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed involvement with CSL Vifor’s advisory board on difelikefalin. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

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Acknowledgments

Medical writing support was provided by AXON Communications (London, United Kingdom) and funded by CSL Vifor.

Additional information

Funding

This paper was funded by CSL Vifor.