Treatment with difelikefalin (DFK), an investigational medication, is associated with rapid and sustained itch reduction and improvement in itch-related quality of life among patients on hemodialysis suffering from moderate to severe chronic kidney disease (CKD)-associated pruritus, according to phase 3 study results presented at the American Society of Nephrology’s Kidney Week 2020 Reimagined virtual conference.1

The medication, a novel peripherally restricted and selective kappa opioid receptor agonist that is administered intravenously, was generally well tolerated, and safety was consistent with findings from prior studies, according to Thomas D. Wooldridge, MD, of Nephrology and Hypertension Associates, Ltd, in Tupelo, Mississippi, and colleagues.

The latest results are from the KALM-2 trial, in which investigators randomly assigned 473 patients on hemodialysis (HD) in the United States, Europe, and Asia to receive DFK 0.5 mcg/kg (237 patients) or placebo (236 patients). The patients had moderate to severe CKD-associated pruritus.

The primary endpoint was the proportion of patients who achieved a 3-point or greater improvement (that is, a decrease in score) from baseline in the weekly mean of the daily Worst Itching Intensity Numerical Rating Scale (WI-NRS) score at week 12. The scale ranges from 0 (no itch) to 10 (worst itching imaginable).


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At baseline, the mean weekly WI-NRS scores were 7.3 and 7.1 in the DFK and placebo arms, respectively. Results showed that 54% of patients who received DFK achieved at least a 3-point improvement in WI-NRS compared with 42% of the placebo group. The proportion of patients who achieved a 4-point or higher improvement also was significantly greater with DFK than placebo (41% vs 28%).

Itch reduction was evident at week 1 and was sustained through week 12, according to the investigators. They also observed improvement in itch-related quality of life (QoL) among DFK recipients as measured using the 5-D Itch and Skindex-10 questionnaires.

Treatment-emergent adverse events (AEs) that occurred in 5% or more of patients occurred more frequently in DFK-treated patients than placebo recipients: diarrhea (8.1% vs 5.5%), fall (6.8% vs 5.1%), dizziness (5.5% vs 5.1%), vomiting (6.4% vs 5.9%), and nausea (6.4% vs 4.2%). The incidence of serious AEs was similar between the study arms.

The new findings follow publication of the results from the phase 3 KALM-1 trial in the New England Journal of Medicine.2 In that trial, investigators randomly assigned 378 patients on HD who had moderate to severe pruritus to receive DFK 0.5 mcg/kg or placebo. The primary outcome was the proportion of patients with a 3-point or greater improvement in WI-NRS score from baseline to week 12. A significantly higher proportion of patients in the DFK-treated patients than placebo recipients achieved the primary endpoint (51.9% vs 30.9%). The proportion of patients achieving a 4-point or greater improvement in WI-NRS score also was significant higher in the DFK group (40.5% vs 21.2%). DFK recipients also experienced a significant improvement in itch-related QoL as assessed by the 5-D itch scale and Skindex-10 scale.

Disclosure: The study was funded by Cara Therapeutics, which is developing the drug.

References

  1. Wooldridge TD, Mccafferty K, Schoemig M, et al. Efficacy and safety of difelikefalin for moderate-to-severe CKD-associated pruritus: A global phase 3 study in hemodialysis patients (KALM-2). Presented at: Kidney Week 2020 Reimagined, October 19-25. Abstract FR-OR24.
  2. Fishbane S, Jamal A, Munera C, et al. A phase 3 trial of difelikefalin in hemodialysis patients with pruritus. N Engl J Med. 2020;382:222-232. doi:10.1056/NEJMoa1912770