Peptide education
Difelikefalin
Korsuva · Difelikefalin acetate
Difelikefalin is a prescription medicine for adults receiving hemodialysis who have moderate-to-severe itching related to chronic kidney disease. The approved U.S. product, Korsuva, is given through the dialysis circuit's venous line at the end of a session, after blood stops circulating through the dialyzer.
In KALM-1, an estimated 49.1% of participants receiving difelikefalin and 27.9% receiving placebo had at least a 3-point improvement on a 0-to-10 itch scale at week 12. These are imputed trial estimates, not a guarantee of individual response.
Overview
Quick answer
Korsuva is not approved for every cause of itching. The label says it has not been studied in people on peritoneal dialysis and is not recommended for them. Its restricted entry into the central nervous system does not mean neurological side effects are impossible.
What does difelikefalin do?
It activates kappa opioid receptors. The KALM-1 publication describes it as peripherally restricted, but the prescribing information says the connection between receptor activation and its therapeutic effect is not known.
Who is Korsuva for?
The U.S. label specifies adults undergoing hemodialysis who have moderate-to-severe itch associated with chronic kidney disease. It does not recommend Korsuva for peritoneal dialysis, where the drug has not been studied.
What dose and route appear in the label?
The label describes 0.5 mcg per kilogram, calculated from target dry body weight. It is given as an intravenous bolus through the dialysis circuit's venous line at the end of each hemodialysis treatment, after blood is no longer circulating through the dialyzer. This is label context, not an individualized treatment plan.
What did the main trial measure?
KALM-1 measured the share of participants whose weekly average worst-itch score improved by at least 3 points at week 12. Both groups improved, but the difelikefalin group had a higher response rate.
Can it cause sleepiness or falls?
Yes. The label reports dizziness, somnolence, changes in mental status, gait disturbances, and falls. Sedating antihistamines, centrally acting depressants, and opioid pain medicines can increase the likelihood of these effects.
Evidence
Evidence snapshot
The label covers moderate-to-severe chronic kidney disease-associated pruritus in adults undergoing hemodialysis.
Imputed proportions with at least a 3-point improvement in the weekly worst-itch score at week 12, difelikefalin versus placebo.
At week 12, the estimated shares with at least a 3-point improvement in weekly worst-itch scores were higher with difelikefalin than placebo. The pooled analysis included 851 randomized participants and imputed missing scores.
A Japanese phase 2 trial tested 0.25, 0.5, and 1.0 mcg/kg against placebo for 8 weeks. Only the middle dose matches the amount in the U.S. label.
Across the two controlled trials in the label, 17% on Korsuva versus 12% on placebo had at least one of the grouped dizziness, somnolence, mental status, or gait adverse reactions.
Claims
Common claims vs evidence
| Claim | Human evidence | Mechanistic evidence | Verdict |
|---|---|---|---|
| Difelikefalin can reduce kidney disease-associated itch during hemodialysis. | KALM-1 and the pooled phase 3 analysis found more participants reached a prespecified itch improvement with difelikefalin than with placebo. Measures of itch-related quality of life also improved. | The medicine activates kappa opioid receptors; the label says the relevance of that activation to the treatment effect is not known. | Supported for the studied adult hemodialysis population, with a meaningful placebo response and no promise that every patient will respond. |
| The drug is free of neurological effects because it is peripherally restricted. | The label reports dizziness, sleepiness, mental status changes, gait disturbances, and falls in treated patients. | Peripheral restriction describes drug distribution; it does not establish an absence of effects on alertness or balance. | False. The observed safety findings matter more than that inference. |
| The same evidence applies to all itch or peritoneal dialysis. | The main trials studied adults on hemodialysis with moderate-to-severe kidney disease-associated itch. The label says peritoneal dialysis has not been studied and does not recommend use in that population. | The approved use and trial population are narrower than a general anti-itch claim. | |
| Every dose tested in research is a labeled dose. | A phase 2 study included 0.25, 0.5, and 1.0 mcg/kg research arms. The U.S. label specifies 0.5 mcg/kg at the end of each hemodialysis treatment. | No. Trial arms describe what researchers tested, not alternate dosing advice. |
Bottom line
Main takeaway
Korsuva is a dialysis-clinic medicine for a particular kind of persistent itch, not a general skin or pain treatment.
KALM-1 measured a 3-point improvement on a 0-to-10 scale after 12 weeks. The placebo group improved too, and the result does not predict one person's response.
Keep the individual KALM-1 estimates separate from pooled KALM-1 and KALM-2 results, and distinguish the Japanese research doses from the U.S. label.
Identity
What it is
Difelikefalin is a synthetic peptide and kappa opioid receptor agonist. Korsuva is supplied as a sterile single-dose intravenous vial for use with hemodialysis.
The KALM-1 study used a 0-to-10 worst-itch rating to assess response. The trial evaluated 12 weeks of treatment, not a cure for kidney disease or a guarantee that itching would disappear.
Use context
Routes, doses, and cycle patterns
The label describes administration at the end of each hemodialysis session; the phase 3 trials studied three sessions per week. These doses are not individualized instructions.
Human studies and product labels
Korsuva U.S. label
- Purpose
- Moderate-to-severe CKD-associated itch in adults on hemodialysis
- Context
- Label-reported, prescription product
- Route
- Intravenous bolus through the dialysis circuit's venous line
- Amount
- 0.5 mcg/kg based on target dry body weight
- Frequency
- At the end of each hemodialysis treatment
- Duration
- Per the treatment plan and label, not a fixed trial course
The product is removed by the dialyzer, so the label describes administration after blood is no longer circulating through it, during or after rinseback. Peritoneal dialysis is not studied and is not recommended in the label.
KALM-1 phase 3 trial
- Purpose
- Itch intensity and itch-related quality of life
- Context
- Study-reported randomized comparison, not a recommendation
- Route
- Intravenous at the end of hemodialysis
- Amount
- 0.5 mcg/kg compared with placebo
- Frequency
- Three times weekly
- Duration
- 12-week blinded comparison
The primary outcome was at least a 3-point improvement in the weekly mean worst-itch score at week 12.
Japanese phase 2 dose-ranging trial
- Purpose
- Compare itch outcomes and safety across dose groups
- Context
- Study-reported research arms, not alternative labeled regimens
- Route
- Intravenous at the end of hemodialysis
- Amount
- 0.25, 0.5, or 1.0 mcg/kg compared with placebo
- Frequency
- Three times weekly
- Duration
- 8 weeks
Mean itch-score improvement was greater than placebo in the 0.5 and 1.0 mcg/kg groups, but not the 0.25 mcg/kg group. The U.S. label lists 0.5 mcg/kg, not all three research amounts.
What varies
- Population: adults on hemodialysis with moderate-to-severe CKD-associated itch.
- Route: the labeled injection is given through the dialysis circuit.
- Weight: the label uses target dry body weight to determine the amount.
- Schedule: the label says at the end of each treatment; the phase 3 trials used three treatments weekly.
- Safety: concurrent sedating medicines and balance problems need clinical attention.
Research
Research evidence
Two randomized phase 3 trials support an itch benefit in adults undergoing hemodialysis. KALM-1 also reported improved itch-related quality of life, while the placebo group had a substantial response. A separate phase 2 study explored several doses over a shorter period.
| Study / evidence area | Population | Design | Product context | Main outcome | Limitations | Weight |
|---|---|---|---|---|---|---|
| KALM-1 | 378 randomized patients on hemodialysis with moderate-to-severe itch | Randomized, double-blind, placebo-controlled phase 3 trial | Intravenous difelikefalin 0.5 mcg/kg or placebo, three times weekly | The imputed week-12 response rate for at least a 3-point improvement in worst-itch score was 49.1% with difelikefalin versus 27.9% with placebo. Itch-related quality-of-life measures also improved. | Placebo responses were substantial. The blinded comparison lasted 12 weeks and involved a specific dialysis population. | Strong |
| KALM-1 and KALM-2 pooled analysis | 851 randomized adults on hemodialysis with moderate-to-severe CKD itch | Pooled analysis of two randomized phase 3 studies | Intravenous difelikefalin 0.5 mcg/kg versus placebo | At week 12, the estimated rates of at least a 3-point improvement in the weekly worst-itch score were 51.1% with difelikefalin and 35.2% with placebo. Missing weekly scores were imputed. | Some subgroups were small. Trial scales and trial conditions may not predict routine-care results. | Strong |
| Japanese dose-ranging trial | 247 randomized patients on hemodialysis with moderate-to-severe itch | Randomized, double-blind, placebo-controlled phase 2 trial | Three intravenous dose groups versus placebo | At week 8, mean itch-score changes in the 0.5 and 1.0 mcg/kg groups were greater than placebo; the 0.25 mcg/kg group did not show the same difference. | The study lasted 8 weeks and was conducted in one population. Research dose groups do not define the approved U.S. schedule. | Moderate |
Use context
Reported use context
Korsuva is administered at the end of hemodialysis. In controlled trials, difelikefalin was given intravenously three times a week.
Study and label context
0.5 mcg/kg three times weekly for 12 weeks, compared with placebo.
Study-reported only, not a recommendation.0.25, 0.5, and 1.0 mcg/kg were tested three times weekly for 8 weeks.
Research arms, not three approved label doses.Cautions
Safety and unknowns
- Dizziness, somnolence, mental status changes, and gait disturbances, including falls, occurred with Korsuva. The label cautions against driving or operating dangerous machinery until the person's response is known.
- Centrally acting depressants, sedating antihistamines, and opioid analgesics may increase the likelihood of these effects. The label advises caution with them.
- The label also lists diarrhea, nausea, hyperkalemia, and headache among common adverse reactions. It does not recommend Korsuva for severe hepatic impairment.
- Safety and effectiveness are not established in pediatric patients. The label says peritoneal dialysis has not been studied and does not recommend that use.
Product quality
Product identity and quality
Korsuva is supplied as a sterile single-dose vial with a specified concentration for intravenous administration in the hemodialysis setting.
Another preparation carrying the same name cannot be assumed to have the same identity, concentration, or sterility.
Product and route
The evidence concerns a particular intravenous product given through the dialysis circuit, not an unverified preparation or another route.
Dialysis timing
The dialyzer removes difelikefalin, so the labeled timing is tied to the end of the hemodialysis session.
Mechanism
How it is proposed to work
Difelikefalin activates kappa opioid receptors. It is described as peripherally restricted, but the label does not establish exactly how receptor activation produces the observed reduction in itching.
In the phase 3 studies, the measured outcome was a patient-reported itch score. Receptor activity is not a substitute for that clinical comparison.
Hemodialysis removes difelikefalin from blood. The product label therefore specifies administration at the end of each hemodialysis treatment.
FAQ
Common questions
Is difelikefalin approved for all kinds of itching?
No. The Korsuva label is for moderate-to-severe chronic kidney disease-associated itch in adults on hemodialysis.
Can it cause sleepiness or falls?
Yes. The label reports sleepiness, dizziness, changes in mental status, gait disturbances, and falls, with added caution around sedating medicines.
Details
Technical details
Sources
References
- 1.
DailyMed. Korsuva prescribing information
- 2.
PubMed. KALM-1 phase 3 trial in hemodialysis patients with pruritus
doi:10.1056/NEJMoa1912770 PMID:31702883 NCT03422653
- 3.
PubMed. Pooled analysis of KALM-1 and KALM-2
PMID:36016762
- 4.
PubMed. Randomized dose-ranging trial in Japanese hemodialysis patients
doi:10.1001/jamanetworkopen.2022.10339 PMID:35511180 NCT03802617