Difelikefalin

A synthetic all-D-amino-acid tetrapeptide that selectively activates peripheral kappa-opioid receptors, FDA approved since 2021 as Korsuva, an intravenous injection given at the end of hemodialysis for moderate-to-severe chronic kidney disease-associated itch.

Also referenced as: Difelikefalin acetate, CR845, CR-845, Korsuva, Kapruvia, MR13A9

Also appears in: Dermal

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What is Difelikefalin?

Difelikefalin (development code CR845) is a synthetic tetrapeptide built entirely from D-amino acids, designed as a peripherally restricted analog of the endogenous kappa-opioid peptide dynorphin A. The D-configuration resists proteolysis, and the molecule’s charge and polarity keep it largely out of the central nervous system, so it engages kappa-opioid receptors on peripheral sensory neurons and immune cells without the sedation and dysphoria associated with brain-penetrant kappa agonists. It reached the clinic as Korsuva, an intravenous injection approved by the FDA in August 2021 for moderate-to-severe pruritus associated with chronic kidney disease in adults on hemodialysis; it appears in research-compound catalogs mainly as a reference kappa-opioid ligand.

How it works

• Selective kappa-opioid receptor agonism — difelikefalin is a high-affinity, highly selective KOR agonist with no meaningful activity at mu or delta opioid receptors; the FDA label states plainly that the relevance of KOR activation to its therapeutic effectiveness is not known (Korsuva prescribing information, revised July 2025; Deeks, Drugs, 2021)
• Peripheral restriction — its all-D-amino-acid, hydrophilic structure limits blood-brain-barrier penetration, so activity is concentrated on KORs expressed by peripheral nerve terminals and immune cells rather than central circuits (Fishbane et al., Kidney International Reports, 2020; Albert-Vartanian et al., Journal of Clinical Pharmacy and Therapeutics, 2016)
• Rebalancing the opioid axis in uremic itch — chronic kidney disease is associated with a relative excess of mu-opioid tone over kappa tone that is thought to sensitize itch pathways; kappa activation on sensory neurons and keratinocytes is proposed to dampen pruriceptive signaling (Deeks, Drugs, 2021)
• Anti-inflammatory signaling on immune cells — KOR activation on monocytes and macrophages reduces release of pro-inflammatory cytokines in preclinical systems, a second proposed contribution to itch relief in inflammatory contexts (Fishbane et al., Kidney International Reports, 2020)

Research status

Difelikefalin has a completed, successful Phase 3 program in one indication and a string of negative or abandoned programs elsewhere.

Hemodialysis-associated pruritus (approved indication). A Phase 2 trial of 174 hemodialysis patients established that an end-of-session intravenous bolus reduced worst-itch scores over 8 weeks (Fishbane et al., Kidney International Reports, 2020, 5(5):600–610). KALM-1 (NCT03422653) randomized 378 hemodialysis patients to 0.5 µg/kg IV difelikefalin or placebo three times weekly; at week 12, 49.1% of difelikefalin patients versus 27.9% on placebo achieved at least a 3-point improvement on the 24-hour Worst Itching Intensity Numerical Rating Scale (Fishbane et al., New England Journal of Medicine, 2020, 382(3):222–232). KALM-2 (NCT03636269; 473 patients) replicated the design internationally, and a pooled analysis of 851 randomized patients across both trials reported 51.1% versus 35.2% responders (Topf et al., Kidney Medicine, 2022, 4(8):100512). These trials supported FDA approval of Korsuva in August 2021, EU approval as Kapruvia on April 25, 2022, and Japanese approval of a prefilled-syringe presentation (partner code MR13A9, developed by Maruishi and marketed by Kissei) in September 2023. Korsuva has been commercialized from the outset by Cara’s licensee CSL Vifor (through Vifor Fresenius Medical Care Renal Pharma); in the 2025 wind-down described below, Cara sold its remaining difelikefalin rights to CSL Vifor for a nominal sum.

Oral difelikefalin (all programs discontinued). Cara pursued oral tablets in three late-stage itch indications, and none survived; an earlier Phase 2 proof-of-concept in primary biliary cholangitis pruritus (NCT03995212) was also terminated without a positive readout.

• Atopic dermatitis: the Phase 2 KARE trial (401 adults) missed its primary endpoint in the overall population and reported a benefit only in an itch-dominant, low-body-surface-area subgroup. On December 18, 2023, the 287-patient dose-finding Part A of the Phase 3 KIND 1 study found no meaningful benefit of oral difelikefalin added to topical corticosteroids versus corticosteroids alone, and the program was terminated.
• Advanced chronic kidney disease (non-dialysis): the Phase 3 KICK 1 and KICK 2 trials (NCT05342623, NCT05356403) were stopped in January 2024 as a portfolio decision, before readout, alongside a roughly 50% workforce reduction to concentrate resources on notalgia paresthetica.
• Notalgia paresthetica: the Phase 2 KOMFORT trial (NCT04706975; 126 randomized, 125 treated) met its primary endpoint, with a 4.0-point versus 2.4-point reduction in weekly worst-itch score at week 8, although secondary endpoints were largely unsupportive (Kim et al., New England Journal of Medicine, 2023, 388(6):511–517). The confirmatory Phase 2/3 KOURAGE-1 study’s dose-finding Part A (214 patients; 0.25 mg, 1 mg, or 2 mg twice daily versus placebo) then showed no meaningful clinical benefit at any dose, and Cara discontinued the program on June 12, 2024.

Corporate status. After winding down oral development, Cara Therapeutics merged with Tvardi Therapeutics; the merger closed on April 15, 2025, the combined company trades as Tvardi Therapeutics (Nasdaq: TVRD), and its STAT3-inhibitor pipeline is unrelated to difelikefalin. The only active regulatory activity on the intravenous product since then is geographic expansion of the approved indication: licensee WinHealth completed a Chinese Phase 3 (KOR-CHINA-301) and announced acceptance of its NMPA filing in September 2025. As of November 2026, no sponsor has announced late-stage development of difelikefalin in any new indication.

Common dosage forms

The approved product is a single-dose glass vial containing 65 mcg in 1.3 mL (50 mcg/mL) of difelikefalin as a clear solution for intravenous bolus into the venous line of the dialysis circuit; it is supplied to dialysis units, not to patients, and is not self-administered. Oral tablets (0.25 mg to 2 mg strengths) existed only as clinical trial material and were never commercialized. Research-compound catalogs list difelikefalin acetate as lyophilized powder or small-volume solution for in vitro receptor pharmacology.

Key considerations

• FDA-approved, but in a narrow, clinic-administered setting. The FDA Approved status reflects Korsuva’s August 2021 approval for CKD-associated pruritus in adults on hemodialysis. Korsuva is indicated only for adults on hemodialysis with moderate-to-severe CKD-associated pruritus, dosed by the dialysis unit at the end of each session; it has not been studied in peritoneal dialysis, is not recommended there, and the label does not support any other route or population.
• Central-type adverse effects still occur. Despite peripheral restriction, the label carries warnings for dizziness, somnolence, mental status changes, and gait disturbances including falls (any of these in 17.0% versus 12.0% on placebo in the pooled pivotal trials), with somnolence more frequent in patients 65 and older (7.0% versus 2.8% in younger patients) and additive risk alongside sedating antihistamines, opioid analgesics, and other CNS depressants.
• The oral story is a cautionary one. Positive or partial Phase 2 signals in atopic dermatitis and notalgia paresthetica did not reproduce in larger dose-finding studies; three late-stage oral programs were discontinued between December 2023 and June 2024, so claims of broad anti-itch utility beyond hemodialysis are not supported by late-stage evidence.
• Mechanism-to-benefit link is incomplete. Even the FDA label notes the relevance of kappa-receptor activation to the drug’s effectiveness in uremic pruritus is not known, and the biology of CKD-associated itch remains multifactorial.
• Naming. CR845, difelikefalin, Korsuva (US, Japan), Kapruvia (EU), and MR13A9 (Japan partner code) all refer to the same molecule.