Efficacy and Safety of Difelikefalin for Moderate-to-Severe CKD-Associated Pruritus: A Global Phase 3 Study in Hemodialysis Patients (KALM-2)

Abstract

Background: Chronic kidney disease (CKD)-associated pruritus (CKD-aP) is a common and distressing condition in CKD patients (pts) and has a serious negative impact on quality of life (QoL). Difelikefalin (DFK), a novel, peripherally restricted and selective kappa opioid receptor agonist, demonstrated efficacy in a US phase 3 study (KALM-1) in hemodialysis (HD) pts with CKD-aP. Here we report primary results from the global phase 3 study of DFK in HD pts with CKD-aP (KALM-2; NCT03636269). Methods: HD pts with moderate-to-severe CKD-aP in the US, Europe, and Asia were randomized to receive intravenous DFK 0.5 mcg/kg (N=237) or placebo (PBO; N=236) after dialysis sessions. The primary endpoint was the proportion of pts who achieved ≥3-point improvement from baseline (BL) in the weekly mean of the daily Worst Itching Intensity Numerical Rating Scale (WI-NRS) score at wk 12. Secondary endpoints were the proportion of pts who achieved ≥4-point improvement in WI-NRS score and mean change in itch-related QoL scores (5-D Itch and Skindex-10) from BL to wk 12. Results: BL mean weekly WI-NRS scores were 7.3 and 7.1 in the DFK and PBO groups. The primary endpoint was met, with 54% of pts who received DFK achieving a ≥3-point improvement in WI-NRS score vs 42% in the PBO group (P=.020). The proportion of pts who achieved a ≥4-point improvement in WI-NRS score was also significantly greater with DFK vs PBO (41% vs 28%, P=.010). Itch reduction was evident at wk 1 and was sustained through wk 12. Improvement in itch-related QoL assessed by 5-D Itch and Skindex-10 was observed. Treatment-emergent AEs ≥5% with DFK vs PBO were 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 across the groups. Conclusions: In this second phase 3 study, IV DFK demonstrated rapid and sustained itch reduction in HD pts with CKD-aP in multiple regions of the world. DFK was generally well tolerated; safety was consistent with findings in prior studies. With no approved therapies for CKD-aP in the US or Europe, DFK is a potential therapeutic that may address this unmet need. Funding: Commercial Support - This study was funded by Cara Therapeutics

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