Long-term efficacy and safety of difelikefalin in moderate-to-severe pruritus in Japanese hemodialysis patients: a 52-week open-label extension period of a phase 3 trial
Authors: Narita Ichiei , Tsubakihara Yoshiharu , Takahashi Naoko , Ebata Toshiya , Uchiyama Takuma , Marumo Masaya , Okamura Shota , Gejyo Fumitake ,   MR13A9-5 trial investigators, Fukaya Yasuo , Yajima Takahiro , Hamamoto Yukihiro , Hagiwara Noriyasu , Itami Noritomo , Komeda Masami , Kim Jong Il , Hattori Hideaki , Ishii Sakae , Imanishi Masahito , Funakoshi Satoshi , Ohsawa Isao , Degawa Noriyuki , Endo Toko , Toyoda Mariko , Akamatsu Yorihiro , Ito Sadayoshi , Sato Takashi , Udagawa Takashi , Otsuka Masakazu , Sato Masatsugu , Oguchi Tomomasa , Yano Shintaro , Saka Yosuke , Shimizu Hiroyuki , Ogura Haruyuki , Kagawa Toru , Senga Yutaka , Kawaguchi Yuji , Fujisaki Kiichiro , Shimizu Hideaki , Aizawa Nobuyuki , Shigehara Tetsuya , Nishio Toshiki , Matsukawa Hideki , Masakane Ikuto , Kikuchi Hiroshi , Okada Noriyuki , Obayashi Hiroaki , Yoshitomi Ryota , Oka Harumichi , Ito Kyoko , Kimura Naoaki , Ando Shigeki , Shibata Toshiro , Shimada Hisaki , Yanase Masahiro , Isono Motohide , Shibuya Kouji , Sasagawa Isoji , Sugiyama Satoshi , Ogawa Hiroshi , Motonishi Shuta , Hiraiwa Nozomu , Taniguchi Masatomo , Yoshida Yuichi , Kurosawa Akira , Oguchi Kenichi , Omata Momoyo , Oura Masaharu , Kinuno Hiroyuki , Ohishi Akira , Watanabe Makoto , Toyoyama Takayuki , Fujita Yoshiro , Hirayama Kouichi , Maruyama Yasuyuki , Obunai Suguru , Yamagishi Takashi , Takaeda Chikako , Hayashi Daiki 
Published: July 2024

Abstract
Background
Difelikefalin, a potent and highly selective agonist of kappa opioid receptors, is used to treat moderate-to-severe pruritus in hemodialysis patients.

Methods
This was a 52-week, open-label phase 3 trial following a 6-week randomized double-blind placebo-controlled treatment period to investigate the efficacy and safety of difelikefalin in Japanese hemodialysis patients. Having completed the 6-week double-blind period, patients received difelikefalin 0.5 μg/kg three times per week intravenously for 52 weeks. Efficacies were assessed using numerical rating scale (NRS) scores, proportion of patients whose NRS score improved by ≥ 3 points and ≥ 4 points, Shiratori severity score, proportion of patients with a nighttime Shiratori severity score of ≤ 2, the Skindex-16 score, 5-D itch scale score, and patient global impression of change (PGIC). Safety was assessed on the basis of adverse events, clinical laboratory tests, vital signs, body weight, 12-lead electrocardiography, and dependency.

Results
The number of patients who entered the extension treatment period from the difelikefalin (MR–MR) and placebo (P-MR) groups was 85 and 83, respectively. The weekly mean NRS scores (mean ± SD) in the MR–MR group at baseline, week 6, and week 58 were 6.57 ± 1.32, 4.04 ± 2.24, and 2.36 ± 1.86, respectively. The weekly mean scores in the P-MR group, at baseline, week 6, and week 58 were 6.42 ± 1.29, 4.85 ± 1.90, and 2.73 ± 2.14, respectively. In patients receiving difelikefalin, there was a decline in the score from treatment initiation, and this decline continued until week 58. Similarly, improvements were seen until week 58 in the proportion of responders, Shiratori severity score, proportion of responders based on the Shiratori severity score, the Skindex-16 score, 5-D itch scale score, and PGIC. A correlation was seen between the change in NRS and itch-related quality of life (QOL), including the Shiratori severity score, Skindex-16 score, 5-D itch scale score, and PGIC. Difelikefalin was well tolerated and safe even when used long term.

Conclusions
Difelikefalin improved itching and itch-related quality of life during long-term treatment in hemodialysis patients with moderate-to-severe pruritus whose response to conventional medications had been inadequate. It also demonstrated excellent safety and tolerability.
Trial registration: ClinicalTrials.gov; NCT04711603. Registered 15 January 2021, https://www.clinicaltrials.gov/study/NCT04711603?term=NCT04711603&rank=1.