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A four-residue opioid peptide built entirely from D-amino acids so it stays outside the brain — the first drug of its kind for dialysis itch.
Also known as: CR845 · CR-845 · MR13A9 · Korsuva (brand)
Part of the Neuropeptides & signaling cluster
Overview
Difelikefalin (Korsuva) is a synthetic tetrapeptide of D-amino acids that selectively activates κ-opioid receptors in the periphery without entering the central nervous system. Approved by the FDA in August 2021 and the EMA in 2022 for moderate-to-severe pruritus in haemodialysis patients, it roughly doubled the proportion of patients with a meaningful reduction in itch versus placebo in the phase 3 KALM-1 trial.
Source & context
Biological / chemical source: Synthetic tetrapeptide of D-amino acids (D-Phe-D-Phe-D-Leu-D-Lys) with a 4-aminopiperidine-4-carboxylic acid cap
Primary research or clinical context: Approved (FDA August 2021, EMA 2022) for moderate-to-severe pruritus in adults with chronic kidney disease on haemodialysis
What difelikefalin is
Difelikefalin is a first-in-class, peripherally acting, highly selective peptide agonist of the κ-opioid receptor developed for chronic itch (IUPHAR ligand 9044). Chemically it is 4-amino-1-(D-phenylalanyl-D-phenylalanyl-D-leucyl-D-lysyl)piperidine-4-carboxylic acid — a tetrapeptide of D-amino acids capped by a non-natural amino acid — with development codes CR845, MR13A9, FE202845 and CKD-943 (Pilla et al., StatPearls 2024). The FDA approved intravenous difelikefalin in August 2021 for patients with chronic kidney disease who develop haemodialysis-associated moderate-to-severe pruritus, on the basis of the KALM-1 and KALM-2 trials (IUPHAR clinical-use record; Deeks, Drugs 2021).
Mechanism: κ-opioid receptors outside the brain
Difelikefalin is believed to activate κ receptors on peripheral nerve cells, inhibiting afferent nerve activity and pain signalling, and on immune cells, inhibiting release of pro-inflammatory mediators such as cytokines and prostaglandins (IUPHAR mechanism record). Because it is peripherally selective, it is unlikely to cause the lethal central nervous system effects of conventional opioids such as respiratory depression (Pilla et al., 2024). In a mouse model of atopic dermatitis, difelikefalin suppressed itch and reduced scratching independently of inflammation (Tamari et al., Journal of Allergy and Clinical Immunology 2023).
Structure: why all-D
Natural peptides are made of L-amino acids and are cleaved by proteases within minutes. Building difelikefalin from D-amino acids makes it resistant to those enzymes, and its polar, charged structure limits passage across the blood–brain barrier — the two properties that let a four-residue peptide act as a durable, peripherally restricted drug. Its molecular formula, C36H53N7O6, and average mass of about 680 Da (PubChem CID 24794466) place it among the smallest peptides in this directory.
Clinical evidence: KALM-1
In the phase 3 KALM-1 trial, 378 haemodialysis patients with moderate-to-severe pruritus received intravenous difelikefalin 0.5 μg per kilogram or placebo three times per week for 12 weeks. A decrease of at least 3 points on the 24-hour Worst Itching Intensity Numerical Rating Scale (WI-NRS) occurred in 51.9% of the difelikefalin group versus 30.9% on placebo (imputed 49.1% vs 27.9%, P<0.001); a decrease of at least 4 points occurred in 37.1% versus 17.9%. Itch-related quality of life improved on the 5-D itch and Skindex-10 scales. Diarrhoea, dizziness and vomiting were more common with difelikefalin (Fishbane et al., New England Journal of Medicine 2020).
| Endpoint | Difelikefalin | Placebo |
|---|---|---|
| ≥3-point WI-NRS improvement (observed) | 51.9% | 30.9% |
| ≥3-point WI-NRS improvement (imputed) | 49.1% | 27.9% |
| ≥4-point WI-NRS improvement | 37.1% | 17.9% |
Other indications and the oral form
Difelikefalin was earlier evaluated intravenously as an analgesic after abdominal surgery (NCT02542384) and orally in osteoarthritis (NCT02524197) (IUPHAR record). Oral programmes in notalgia paresthetica (NCT05978063) and in pruritus with advanced chronic kidney disease not on dialysis (NCT05342623) were terminated. A phase 3 trial in Chinese haemodialysis patients completed in 2023 (NCT05885737), and a phase 2 study in adolescents on haemodialysis is recruiting (NCT06593392). It has not been associated with liver injury (LiverTox, NIDDK). A rat model reported anti-inflammatory and renoprotective effects in ischaemia–reperfusion injury (Takeuchi et al., BMC Nephrology 2025).
Related peptides and what this page is not
Difelikefalin is the only peptide opioid in this directory that is an approved medicine; the endogenous opioid peptides (endomorphins, β-endorphin, dynorphin) act centrally and are covered on their own profiles. This page is educational and not guidance on treatment.
Structure & chemistry
Molecular identity & reference confidence
Source-supported reference
Reference values are taken from the cited molecular record or curated profile. A database match is not independent laboratory verification; modifications, counter-ions, and formulations can change the measured mass.
- Molecular form
- D-Phe-D-Phe-D-Leu-D-Lys with a 4-amino-1-piperidine-4-carboxylic acid C-terminal cap (all-D configuration resists proteolysis)
- Species
- Not established by this molecular identity audit
- Termini (N / C)
- Not specified / Not specified
Average reference mass
Reference policy updated: 2026-10-05
- IUPHAR/BPS source snapshot · 2026-10-01
- PubChem molecular record · 2026-10-01
- Molecular formula
- C36H53N7O6
- Average reference mass
- ≈ 679.8
- Receptors
- κ-opioid receptor (selective agonist), peripherally restricted — activates receptors on peripheral sensory nerves and immune cells
- Backbone
- D-Phe-D-Phe-D-Leu-D-Lys with a 4-amino-1-piperidine-4-carboxylic acid C-terminal cap (all-D configuration resists proteolysis)
- Status
- Approved: FDA (August 2021), EMA (2022) for CKD-associated pruritus in haemodialysis patients; oral programmes in other indications terminated
- PubChem CID: 24794466
- IUPHAR ligand: 9044
- CAS RN: 1024828-77-0
- UNII: NA1U919MRO
Chemistry values: curated profile, PubChem, IUPHAR/BPS Guide to Pharmacology · fetched 2026-10-01.
Clinical development snapshot
ClinicalTrials.gov lists 23 registered studies with “Difelikefalin” as an intervention (snapshot 2026-09-07). A registry footprint is not evidence of efficacy or approval.
| NCT | Title | Phase | Status | Updated |
|---|---|---|---|---|
| NCT06593392 | Safety and Tolerability of Difelikefalin in Adolescents on Haemodialysis With Moderate-to-Severe Pruritus | Phase 2 | recruiting | 2026-09-01 |
| NCT07526324 | Difelikefalin for Itching in Hemodialysis Patients With Chronic Kidney Disease | Not applicable | not yet recruiting | 2026-04-13 |
| NCT05885737 | Phase 3 Study of Difelikefalin in Haemodialysis Chinese Adult Subjects With Moderate-to-Severe Pruritus | Phase 3 | completed | 2025-09-12 |
| NCT05885763 | Pharmacokinetics of Intravenous Difelikefalin in Chinese Adult Subjects on Haemodialysis | Phase 1 | completed | 2025-02-14 |
| NCT05978063 | Study to Evaluate the Efficacy and Safety of Oral Difelikefalin for Moderate to Severe Pruritus in Subjects Wi | Phase 3 | terminated | 2024-06-21 |
| NCT05342623 | A Study to Evaluate the Safety and Efficacy of Difelikefalin in Advanced Chronic Kidney Disease Patients With | Phase 3 | terminated | 2024-05-07 |
Difelikefalin — reconstitution calculator
Enter how much peptide is in the vial and how much diluent (e.g. bacteriostatic water) is added. The tool returns the resulting solution concentration — and, for any amount you type, the volume it corresponds to. This is educational arithmetic, not a dosing recommendation.
Reference form: D-Phe-D-Phe-D-Leu-D-Lys with a 4-amino-1-piperidine-4-carboxylic acid C-terminal cap (all-D configuration resists proteolysis)Average reference mass: 679.8 Da
Enter an amount to see the volume it corresponds to.
Educational concentration mathematics only. This tool does not recommend a dose, amount, or protocol, and nothing here is medical advice. Many peptides are not authorized by Health Canada for human use — see our reconstitution and bacteriostatic-water guides for context.
Change log
Dated observations from the data pipeline (registry flags, trial footprints, identifiers) and editorial reviews of this profile.
- ChemistryPubChem formula updated to C36H53N7O6.
- IdentifiersCross-linked to IUPHAR ligand 9044 and PubChem CID 24794466.
- TrialsClinicalTrials.gov snapshot added: 23 registered studies, highest phase 3.
- EditorialProfile content reviewed and updated by the editorial team.
FAQ about Difelikefalin
What is Difelikefalin?+
Difelikefalin (Korsuva) is a synthetic tetrapeptide of D-amino acids that selectively activates κ-opioid receptors in the periphery without entering the central nervous system. Approved by the FDA in August 2021 and the EMA in 2022 for moderate-to-severe pruritus in haemodialysis patients, it roughly doubled the proportion of patients with a meaningful reduction in itch versus placebo in the phase 3 KALM-1 trial.
What Canadian product status is recorded for Difelikefalin?+
Canadian product status for Difelikefalin has not been verified in this profile. No verified record here does not mean no authorization exists. Status depends on the product, formulation and use; consult Health Canada's product records.
What is the typical length of Difelikefalin?+
Difelikefalin is commonly described as approximately 4 amino acids (Synthetic D-amino-acid tetrapeptide (κ-opioid agonist)).
What is difelikefalin?+
A synthetic four-residue peptide of D-amino acids that selectively activates peripheral κ-opioid receptors. Sold as Korsuva, it is approved for moderate-to-severe itch in haemodialysis patients (FDA 2021, EMA 2022).
How does difelikefalin work?+
It activates κ-opioid receptors on peripheral sensory nerves and immune cells, dampening itch signalling and inflammatory mediator release, without entering the brain.
Is difelikefalin an opioid?+
Yes, a κ-opioid receptor agonist — but peripherally restricted, so it is unlikely to cause respiratory depression or the central effects of conventional opioids.
How effective was difelikefalin in trials?+
In KALM-1, 51.9% of patients had at least a 3-point drop in itch score versus 30.9% on placebo over 12 weeks.
Related peptides
References & further reading
- 1.Fishbane et al. (2020). A Phase 3 Trial of Difelikefalin in Hemodialysis Patients with Pruritus. New England Journal of Medicine
- 2.Deeks (2021). Difelikefalin: First Approval. Drugs
- 3.Pilla et al. (2024). Difelikefalin. StatPearls
- 4.Tamari et al. (2023). Difelikefalin suppresses itch and reduces scratching independent of inflammation in a murine model of atopic dermatitis. Journal of Allergy and Clinical Immunology
- 5.Ko et al. (2023). Uremic pruritus: pathophysiology, clinical presentation, and treatments. Kidney Research and Clinical Practice
- 6.PubChem — compound summary for Difelikefalin (CID 24794466)