Summary

Difelikefalin (KDV-1000; brand name Korsuva) is a synthetic, selective kappa-opioid receptor (KOR) agonist peptide developed for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD-aP) in adults undergoing haemodialysis. It received FDA approval in August 2021 as an intravenous formulation. The compound is an 8-amino-acid D-amino acid peptide (a D-amino acid conformationally constrained analogue of dynorphin A) that selectively activates peripheral KORs without crossing the blood–brain barrier, thereby offering antipruritic and analgesic effects without the central side effects (euphoria, respiratory depression) associated with mu-opioid receptor agonists. For research and educational purposes only.

Mechanism

Difelikefalin is a full agonist at the kappa-opioid receptor (KOR/OPRK1), selectively activating peripheral KORs on sensory neurons and immune cells. Its exclusive D-amino acid composition makes it protease-resistant and prevents blood–brain barrier penetration, confining its activity to the periphery. KOR activation inhibits itch signal transmission and modulates neurogenic inflammation without producing the CNS effects (euphoria, respiratory depression) associated with mu-opioid receptor agonists.

Evidence base

Strong evidence — Two large Phase 3 RCTs (KALM-1: N=378; KALM-2: multinational) demonstrated statistically significant improvements in pruritus (WI-NRS ≥3-point improvement: 49–54% vs. 35–42% placebo). FDA-approved August 2021. EMA application withdrawn after negative CHMP opinion. Real-world data consistent with trial results.

Key trials:

  • KALM-1 (NCT03422653): Fishbane et al., NEJM 2020;382(3):222-232
  • KALM-2 (NCT03636269): Mathur et al., Kidney Int 2022;101(3):638-647

Protocols

Approved (IV, haemodialysis patients): 0.5 mcg/kg IV bolus into dialysis return line, 3×/week. Reduce to 0.25 mcg/kg in hepatic impairment.

Investigational (oral): 0.25–2 mg PO BID studied in Phase 2 for prurigo nodularis and atopic dermatitis.

Research use only — not medical advice.

UK Status: POM (Prescription-Only Medicine)

Difelikefalin is classified as a prescription-only medicine. It is not MHRA-licensed (EMA application withdrawn 2022). It is not a controlled substance under the Misuse of Drugs Act 1971. Research institutions may source non-clinical material for in vitro or animal research under appropriate licensing.

Vendor notes

Difelikefalin is a licensed pharmaceutical, not typically available from research peptide vendors. Source clinical-grade material through pharmaceutical supply chains. For non-clinical research, use certified chemical suppliers with COAs.

References

  1. 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(3):222-232.
  2. Mathur VS, Lindberg J, Germain M, et al. A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus: KALM-2. Kidney Int. 2022;101(3):638-647.
  3. Topf J, Wooldridge T, Yee J. Difelikefalin for the Treatment of Pruritus Associated with Chronic Kidney Disease in Patients Undergoing Hemodialysis. Drugs. 2022;82(1):69-81.
  4. Kumagai H, Ebata T, Takamori K, et al. Effect of a Novel Kappa-Receptor Agonist, Difelikefalin, on Severe Itch in 222 Haemodialysis Patients: A Phase 3, Randomised, Double-Blind, Placebo-Controlled Trial. Br J Dermatol. 2021;184(6):1095-1103.