Difelikefalin for pruritus associated with chronic kidney disease

Approved indication: treatment of moderate to severe pruritus associated with chronic kidney disease in adult patients on haemodialysis
Korsuva (Seqirus)
vials containing difelikefalin acetate 50 micrograms in 1 mL solution for intravenous injection

Patients with chronic kidney disease commonly suffer from intense itch, which can impair quality of life.¹ Medicines such as antihistamines, gabapentinoids and corticosteroids have been used for pruritus associated with chronic kidney disease, with varied success.² Difelikefalin is the first drug approved in Australia specifically for the treatment of moderate to severe pruritus associated with chronic kidney disease in adults undergoing haemodialysis.³

Pruritus associated with chronic kidney disease is likely linked to immune system dysregulation and endogenous opioid imbalance, characterised by downregulation of kappa opioid receptors and overexpression of mu opioid receptors.⁴ Difelikefalin is a selective kappa opioid receptor agonist that is thought to exert antipruritic and anti-inflammatory effects by its action on peripheral sensory neurons and immune cells; it has limited central nervous system (CNS) penetration.⁵

The efficacy and safety profile of difelikefalin was informed by 2 pivotal randomised, double-blind, placebo-controlled phase 3 trials (KALM-1 and KALM-2).^6,7

In these trials, the primary endpoint for efficacy of difelikefalin was the proportion of participants who achieved a clinically meaningful reduction in itch intensity. This was defined as at least a 3-point reduction in the weekly mean of daily Worst Itching Intensity Numerical Rating Scale (WI-NRS) scores at 12 weeks, compared with baseline.⁶ The WI-NRS score can range from zero to 10, with higher scores indicating worse itch. Secondary endpoints included the proportion of patients with at least a 4-point reduction in the weekly mean WI-NRS score after 12 weeks, and improvement in itch-related quality of life over 12 weeks.

The efficacy of difelikefalin was assessed using pooled data from the 2 trials in 851 patients on haemodialysis (426 treated with difelikefalin and 425 with placebo, mean age 59 years).⁶ More than one-third of participants reported using an anti-itch medication at baseline. A significantly greater proportion of patients achieved at least a 3-point reduction in mean WI-NRS score at week 12 with difelikefalin compared with placebo (51.1% versus 35.2%, p<0.001). Similarly, there was a greater proportion of patients who achieved at least a 4-point reduction in mean WI-NRS score with difelikefalin compared with placebo (38.7% versus 23.4%, p<0.001). Clinically meaningful improvements in itch-related quality of life were observed with difelikefalin over the 12-week placebo-controlled phase of the trials and the further 52-week open-label extension phase.

The reported adverse effects that were higher in the difelikefalin group compared with the placebo group were diarrhoea, dizziness, nausea, gait disturbance (including falls), hyperkalaemia, headache, somnolence, mental status change and back pain.^5,7 The incidence of somnolence was higher in participants aged over 65 years and those who used anti-itch medications (predominantly sedating antihistamines). Most of these adverse effects were mild or moderate in severity.

In patients who experienced somnolence, this occurred within the first 3 weeks of treatment, while dizziness occurred within the first 9 weeks; both effects tended to subside over time.⁵ Patients receiving difelikefalin should be cautioned about driving, especially at the start of treatment. They should also be counselled on the potential risks of using sedating antihistamines, opioid analgesics or other CNS depressants concurrently, as this may increase the likelihood of dizziness and somnolence.

Difelikefalin should be used with caution in patients with potentially impaired permeability of the blood–brain barrier (e.g. primary brain malignancies, CNS metastases, multiple sclerosis, advanced Alzheimer disease) as there is a risk of difelikefalin crossing the blood–brain barrier and causing CNS effects.⁵

Difelikefalin is not recommended for use in people with severe hepatic impairment, or in pregnancy and breastfeeding, because of limited safety data in these groups.⁵ The drug undergoes minimal hepatic metabolism and is not a substrate of major cytochrome P450 enzymes; however, there have been no clinical studies exploring drug interactions.

Difelikefalin is administered by intravenous injection 3 times a week into the venous line of a dialysis circuit at the end of haemodialysis, during or after rinse-back (where sodium chloride solution is used to push the remaining blood in the haemodialysis machine back into the patient). The recommended dosage is difelikefalin acetate 0.5 micrograms per kilogram of dry body weight (i.e. the patient’s target post-dialysis weight). If administered after rinse-back, at least 10 mL of sodium chloride 0.9% solution should be used to flush the line after difelikefalin injection.⁵

In summary, difelikefalin serves as an alternative treatment option to relieve itching in patients with chronic kidney disease undergoing haemodialysis.

This new drug comment was finalised on 9 July 2024.

🅃 🅃 manufacturer provided additional useful information. The Transparency Score is explained in New drugs: transparency, Vol 37 No 1, Aust Prescr 2014;37:27.

At the time the comment was prepared, information about this drug was available on the websites of the Food and Drug Administration in the USA, the European Medicines Agency and the Therapeutic Goods Administration.

 

References

1. Sukul N, Karaboyas A, Csomor PA, Schaufler T, Wen W, Menzaghi F, et al. Self-reported Pruritus and Clinical, Dialysis-Related, and Patient-Reported Outcomes in Hemodialysis Patients. Kidney Med 2021;3:42-53 e1.
2. Hercz D, Jiang SH, Webster AC. Interventions for itch in people with advanced chronic kidney disease. Cochrane Database Syst Rev 2020;12:CD011393.
3. Therapeutic Goods Administration. Australian Public Assessment Report for Korsuva. Department of Health and Aged Care; 2023. [cited 2024 May 28]
4. Agarwal R, Burton J, Gallieni M, Kalantar-Zadeh K, Mayer G, Pollock C, et al. Alleviating symptoms in patients undergoing long-term hemodialysis: a focus on chronic kidney disease-associated pruritus. Clin Kidney J 2023;16:30-40.
5. Therapeutic Goods Administration. Australian Product Information - Korsuva (difelikefalin [as acetate]) solution for injection. Department of Health and Aged Care; 2024. [cited 2024 May 28]
6. Topf J, Wooldridge T, McCafferty K, Schomig M, Csiky B, Zwiech R, 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 Med 2022;4:100512.
7. Fishbane S, Wen W, Munera C, Lin R, Bagal S, McCafferty K, 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 Med 2022;4:100513.

 The new drug commentaries in Australian Prescriber are prepared by the editors and reviewed by the Editorial Advisory Committee. Some of the views expressed on newly approved products should be regarded as preliminary, as there may be limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Advisory Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.