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

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.

Acknowledgments

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

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.

Information resources

Sukul, N., et al., Self-reported Pruritus and Clinical, Dialysis-Related, and Patient-Reported Outcomes in Hemodialysis Patients. Kidney Med, 2021. 3(1): p. 42–53.e1. - Describes self-reported pruritus severity from the DOPPS study.

Shirazian S, et al., Chronic kidney disease-associated pruritus: impact on quality of life and current management challenges. Int J Nephrol Renovasc Dis, 2017. 10: p. 11–26. - Reviews the quality-of-life instruments available, recent studies examining the prevalence, characteristics and outcomes of CKD-aP, current treatments and clinical trials.

Rayner, H.C., et al., International Comparisons of Prevalence, Awareness, and Treatment of Pruritus in People on Hemodialysis. Clin J Am Soc Nephrol, 2017. 12(12): p. 2000–2007. - Describes the prevalence of CKD-aP in over 35,000 patients from the DOPPS study.

Fishbane, S., et al., A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus. New England Journal of Medicine, 2020. 382(3): p. 222–232. - Describes the key placebo-controlled phase 3 clinical trial of difelikefalin efficacy and safety.

Topf, J., et al., 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. Kidney Medicine, 2022: p. 100512. - Describes the pooled efficacy data from the key placebo-controlled phase 3 clinical trials of difelikefalin.

Fishbane, S., et al., 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. Kidney Medicine, 2022: p. 100513. - Describes the pooled safety data from the key placebo-controlled phase 3 clinical trials of difelikefalin.

Agarwal, R., et al., Alleviating symptoms in patients undergoing long-term hemodialysis: a focus on chronic kidney disease-associated pruritus. Clinical Kidney Journal, 2022: p. sfac187. - Describes the proposed treatment algorithm for difelikefalin and positioning within the treatment pathway, as well as the pathway to development and regulatory approval of difelikefalin.

Weiner, D.E., et al., Safety and Effectiveness of Difelikefalin in Patients With Moderate-to-Severe Pruritus Undergoing Hemodialysis: An Open-Label, Multicenter Study. Kidney Medicine. - Describes the safety and efficacy data from the key open-label phase 3 clinical trial of difelikefalin, providing important insights into expected real-world safety and effectiveness.

US Food and Drug Administration. Korsuva Prescribing Information. 2021; Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214916s000lbl.pdf.

Agency, E.M. European Medicines Agency decision. 2020; Available from: https://www.ema.europa.eu/en/documents/pip-decision/p/0172/2020-ema-decision-13-may-2020-agreement-paediatric-investigation-plan-granting-deferral-granting_en.pdf.

Additional information

Funding

This paper was funded by CSL Vifor.