What Is Difelikefalin (Korsuva)? The Kappa Opioid Peptide for Dialysis Itch and What the KALM Trials Found

Difelikefalin, sold as Korsuva, is a synthetic peptide that treats itch in people on hemodialysis. The [FDA label on DailyMed](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0c7b81f2-0fd3-47cb-8b0f-185e07f19c87) lists an initial U.S. approval in 2021, and the indication is narrow: moderate to severe pruritus associated with chronic kidney disease (often shortened to CKD-aP) in adults undergoing hemodialysis. You would never inject difelikefalin at home, because it is given as an intravenous injection into the dialysis circuit at the end of each dialysis session.

Difelikefalin is interesting to anyone following peptide research for a second reason, which is that it works on kappa opioid receptors and yet was designed to stay out of the brain. The KALM-1 investigators ([Fishbane, New England Journal of Medicine, 2020](https://doi.org/10.1056/NEJMoa1912770)) describe it as "a peripherally restricted and selective agonist of kappa opioid receptors." This article covers what difelikefalin is, what its two phase 3 trials found, how it is dosed, what the label says about side effects and where research on the oral form stands. It is educational content about published research, not medical advice.

Chronic kidney disease associated pruritus is a persistent itch that affects people with advanced kidney disease, and it is especially common in people on hemodialysis. The itch is not a rash, since it often has no visible skin cause, and it can disrupt your sleep and daily life.

The researchers who pooled the phase 3 trials ([Topf, Kidney Medicine, 2022](https://doi.org/10.1016/j.xkme.2022.100512)) open their paper by stating that CKD-aP in patients treated by hemodialysis "impairs quality of life." Before difelikefalin, there was no FDA approved drug for this specific itch, and that gap is a large part of why a narrowly targeted peptide made it through approval.

Difelikefalin activates kappa opioid receptors, a different opioid receptor family from the mu receptors that drugs like morphine target. The KALM-1 paper notes that kappa opioid receptors "are considered to be important in modulating pruritus in conditions such as chronic kidney disease."

The Korsuva label is more cautious. Its mechanism section says only that the drug is a kappa opioid receptor agonist and that "the relevance of KOR activation to therapeutic effectiveness is not known." In other words, the receptor target is clear, but exactly why hitting it calms dialysis itch has not been fully worked out in humans.

Difelikefalin was designed to act on kappa receptors outside the central nervous system, and the KALM-1 investigators describe the peptide as peripherally restricted for that reason. Peripheral restriction is not perfect protection, though, because the label still lists dizziness, somnolence and mental status changes among its warnings, which are covered further down.

Difelikefalin is a short synthetic peptide made from D amino acids, which are the mirror image forms of the amino acids your body normally uses. According to the label, the chain is built from phenylalanine, phenylalanine, leucine and lysine in their D forms, attached to a piperidine carboxylic acid and supplied as an acetate salt, with a molecular weight of 679.4 g/mol for the free base.

The label also reports that, in laboratory studies with human liver cells, difelikefalin was not metabolized by the main cytochrome P450 enzymes that break down many drugs.

KALM-1 showed that more than half of hemodialysis patients on difelikefalin had a clinically meaningful itch improvement, compared with about 3 in 10 on placebo. The trial was published by [Fishbane and colleagues in the New England Journal of Medicine in 2020](https://doi.org/10.1056/NEJMoa1912770).

In KALM-1, 378 patients on hemodialysis with moderate to severe itch were randomly assigned to intravenous difelikefalin 0.5 µg per kilogram or placebo three times per week for 12 weeks. Itch was measured on the Worst Itching Intensity Numerical Rating Scale (WI-NRS), which runs from 0 to 10. By the observed data, 51.9% of patients on difelikefalin (82 of 158) had a drop of at least 3 points, compared with 30.9% on placebo (51 of 165).

Difelikefalin also improved itch related quality of life on the 5-D itch scale and the Skindex-10 scale. The trial reported that diarrhea, dizziness and vomiting were more common with difelikefalin than with placebo.

KALM-2 was the second phase 3 trial, and it confirmed the KALM-1 result with a smaller gap between drug and placebo. The FDA label reports both trials side by side, calling them Trial 1 and Trial 2, and uses at least a 4 point WI-NRS improvement at week 12 as the outcome.

The label adds that itch reduction was seen by Week 4 and sustained through Week 12. Placebo responses were large in both trials, which is common in itch studies, where people often improve simply from being in a trial and tracking their symptoms.

When the two trials were combined, difelikefalin improved both itch intensity and itch related quality of life compared with placebo. [Topf and colleagues](https://doi.org/10.1016/j.xkme.2022.100512) pooled 851 participants (426 on difelikefalin, 425 on placebo) in Kidney Medicine in 2022, and at least a 4 point itch reduction occurred in 38.7% on difelikefalin versus 23.4% on placebo.

The pooled paper reported efficacy beginning at week 1 and 5-D Itch effects sustained up to 64 weeks, a window that includes the 52 week open label extension that followed the 12 weeks of blinded treatment. The authors also listed honest limits, noting that subgroup samples were small and that the itch scales used in the trials "are not used in routine clinical care of dialysis patients," so the trial results may not match real world effectiveness.

Itch relief with difelikefalin was associated with better sleep quality in a post hoc analysis, but that analysis was not a separate trial of sleep. [Weiner and colleagues (Nephrology Dialysis Transplantation, 2024)](https://doi.org/10.1093/ndt/gfad245) looked at the pooled KALM data and an open label study called Study 3105, which enrolled 222 patients.

Patients whose itch improved by at least 3 points had larger sleep gains than those who did not. In Study 3105, the sleep quality score changed by -5.2 points in the responders versus -1.5 in the nonresponders, and in the pooled KALM data the 5-D Itch sleep question changed by -1.8 versus -0.8. Because the comparison splits patients by how well they responded, it shows an association between itch relief and sleep rather than proof that difelikefalin directly improves sleep.

Korsuva is dosed at 0.5 mcg/kg of target dry body weight, given as an intravenous bolus into the venous line of the dialysis circuit at the end of each hemodialysis treatment. Your dialysis care team gives the dose, so you never handle the vial yourself.

Several details in the label follow from how dialysis works. Korsuva is removed by the dialyzer membrane, so it must be given after blood is no longer circulating through the dialyzer, and hemodialysis reduced difelikefalin plasma concentrations by 70% to 80%. The label reports a half life between 23 and 31 hours in hemodialysis patients before dialysis, which is why a dose given at the end of each session carries a patient through to the next one.

The most common side effects of difelikefalin in the phase 3 trials were gastrointestinal and nervous system effects, and most were mild or moderate. [Fishbane and colleagues](https://doi.org/10.1016/j.xkme.2022.100513) pooled safety data from 848 people in the placebo controlled trials (424 in each group) and 1,306 people across all difelikefalin exposure in Kidney Medicine in 2022, and the same rates appear in Table 2 of the label.

According to the label, 2.6% of people on Korsuva stopped treatment because of an adverse reaction, compared with 0.7% on placebo, and serious adverse reactions occurred in 4.5% versus 2.8%. Dizziness occurred within the first 3 weeks of treatment and was generally transient. The pooled safety paper found that adverse event rates did not rise with long term exposure, and it reported deaths in 3 participants (0.7%) on difelikefalin and 5 participants (1.2%) on placebo during the studies.

The Korsuva label lists no contraindications, but it warns that dizziness, somnolence, mental status changes and gait disturbances, including falls, have occurred. It advises caution with centrally acting depressant medications, sedating antihistamines and opioid analgesics, and it warns that Korsuva may impair your ability to drive or operate machinery.

The label also says Korsuva is not recommended in severe hepatic impairment, because its effects in that group have not been studied, and it is not recommended in peritoneal dialysis, where it has not been studied at all.

Oral difelikefalin has been tested in other itch conditions, but the results are mixed and no oral form is approved. The 2021 first approval review in Drugs ([Deeks](https://doi.org/10.1007/s40265-021-01619-6)) noted that oral difelikefalin studies were completed or underway in atopic dermatitis, notalgia paresthetica and primary biliary cholangitis itch.

In notalgia paresthetica, the KOMFORT trial ([Kim, New England Journal of Medicine, 2023](https://doi.org/10.1056/NEJMoa2210699)) randomized 126 patients to oral difelikefalin 2 mg twice daily or placebo for 8 weeks. From a baseline itch score of 7.6, itch changed by -4.0 points on difelikefalin versus -2.4 on placebo, a difference of -1.6 points, and the authors called the benefit modest, said the secondary outcomes generally did not support the primary result and called for larger and longer trials. In atopic dermatitis, [Guttman-Yassky and colleagues (Journal of Allergy and Clinical Immunology, 2023)](https://doi.org/10.1016/j.jaci.2023.06.023) tested oral doses of 0.25, 0.5 and 1.0 mg in 401 people, and while all doses reduced itch versus placebo, the results were not statistically significant at week 12.

If you are reading about difelikefalin outside dialysis, the honest summary is that the evidence is limited and has not established a benefit in these other conditions.

Difelikefalin is a prescription drug given by dialysis teams, and it is not a self administered research peptide. The approved product is an intravenous injection dosed by weight and timed to the end of a hemodialysis session, and its safety data come from people on hemodialysis under medical supervision.

There is no human evidence for difelikefalin outside the populations studied in its trials, and no trial supports using it for general itch, pain or recovery. If you or someone you care for lives with kidney disease related itch, the nephrology team is the right place to ask whether Korsuva fits the treatment plan.

Difelikefalin shows how a carefully designed peptide can fill a real gap, since it became the first FDA approved treatment for a miserable and often overlooked symptom of kidney failure. Its two phase 3 trials show a consistent benefit over placebo, with at least a 4 point itch reduction in 38.7% versus 23.4% when pooled, and its side effects are mostly mild, although dizziness, sleepiness and falls deserve attention. Outside hemodialysis, the oral form has not yet proven itself, so the evidence supports difelikefalin for one setting and one setting only.