Evidence Grade A — Regulatory approved. 115 published studies. 23 registered clinical trials.
Medically reviewed by a licensed medical professional
Loading...
Difelikefalin (sold as Korsuva) is the first targeted treatment for the severe itching that affects many people on dialysis for chronic kidney disease. This itching — called uraemic pruritus — can be intense enough to disrupt sleep and significantly reduce quality of life. Difelikefalin is given intravenously at the end of each dialysis session and relieves itching through opioid receptors in the body without causing sedation, euphoria, or addiction risk.
Difelikefalin is also known by these brand and alternate names:
115 published studies: 60 human, 5 animal, 1 in-vitro, 33 reviews
Difelikefalin is marketed as Korsuva (approved August 2021) for moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing haemodialysis. It is administered intravenously three times per week at the end of dialysis.
In the KALM-1 and KALM-2 trials, approximately 50–54% of patients on difelikefalin achieved a clinically meaningful reduction in itch severity compared to 31–42% on placebo. For patients suffering from uraemic pruritus — which can be severe enough to impair sleep and quality of life — this was the first approved targeted treatment. An oral formulation is in development, which could expand its use beyond the dialysis setting.
Chronic kidney disease causes severe, debilitating itch through a complex process involving inflammation and nerve sensitisation in the skin. Difelikefalin selectively activates kappa opioid receptors on peripheral nerve endings and immune cells in the skin, which suppresses the itch-signalling pathways and reduces the inflammatory mediators that drive the sensation. Its all-D-amino-acid structure plus a PEG attachment physically prevent it from crossing the blood-brain barrier, confining its effects to the periphery and avoiding the central nervous system effects of traditional opioids.
Two Phase III trials (KALM-1 and KALM-2) demonstrated that approximately half of patients on difelikefalin achieved a meaningful reduction in itch severity, compared to 31-42% on placebo. For a population that previously had no approved targeted treatment, this was a significant advance. The drug is specifically designed with all-D-amino acids (mirror-image building blocks) that prevent it from entering the brain, which is how it avoids the central nervous system effects of traditional opioids. The main limitation is that the IV formulation ties treatment to the dialysis schedule. An oral version is in Phase III trials for kidney disease patients not yet on dialysis, which could substantially expand the eligible population. Side effects include diarrhoea, dizziness, and nausea, but no significant abuse potential has been observed.
PeptideTrace tracks 23 registered clinical trials for Difelikefalin sourced from ClinicalTrials.gov.
Intermediate-Size Patient Population Expanded Access Program for Intravenous Difelikefalin
Safety and Tolerability of Difelikefalin in Adolescents on Haemodialysis With Moderate-to-Severe Pruritus
Difelikefalin for Itching in Hemodialysis Patients With Chronic Kidney Disease
Study to Evaluate the Efficacy and Safety of Oral Difelikefalin for Moderate to Severe Pruritus in Subjects With Notalgia Paresthetica
Pharmacokinetics of Intravenous Difelikefalin in Chinese Adult Subjects on Haemodialysis
FDA ORIG 1
EMA Marketing Authorisation
Health Canada Market Authorisation
FDA SUPPL 2
Difelikefalin is a synthetic D-amino acid tetrapeptide (D-Phe-D-Phe-D-Leu-D-Lys-[PEG4]), MW ~714 Da. All-D configuration resists proteolysis; PEG4 on D-Lys restricts CNS penetration. Peripherally selective kappa opioid receptor (KOR) agonist. IV 0.5 mcg/kg post-hemodialysis 3x/week. Half-life ~23-31 hours in dialysis patients.
Selective KOR agonist (Ki ~0.16 nM, >100-fold vs. MOR/DOR). KOR activation on peripheral neurons and immune cells: inhibits TRPV1 sensitization, reduces pruritogenic neuropeptides (substance P, CGRP), suppresses pro-inflammatory cytokines (IL-2, IL-4, IL-31). All-D backbone and PEG4 prevent BBB penetration, eliminating central KOR dysphoria/sedation.
Marketed as Korsuva. Approved August 23, 2021. KALM-1 (Phase III; N=378): >=3-point WI-NRS improvement 51.9% vs. 30.9% (P<0.001). KALM-2 (N=473): 54.0% vs. 42.2% (P=0.018). Oral formulation in development. Indication: moderate-severe pruritus in CKD patients on hemodialysis.
Linaclotide is marketed as Linzess (approved August 2012). It is taken as a daily oral capsule on an empty stomach, at least 30 minutes before the first meal. The recommended dose is 290 mcg for IBS-C and 72 or 145 mcg for chronic constipation. In clinical trials, approximately 34% of IBS-C patients met the composite improvement endpoint compared to 17% on placebo. Diarrhoea is the most common side effect (approximately 20%) and the leading reason for discontinuation. Linaclotide has a boxed warning against use in children under 6 years due to deaths in young mice, though no such events have been reported in humans. It competes with plecanatide (which targets the same pathway) and other IBS-C treatments.
Elamipretide (Forzinity) was approved by the FDA for Barth syndrome based on the TAZPOWER trial. The randomised crossover phase (12 patients) did not meet its primary endpoints, but the open-label extension (168 weeks) demonstrated durable improvements in walking distance and muscle strength that formed the basis for approval. Barth syndrome affects approximately 1 in 300,000–400,000 births. A larger Phase III trial in primary mitochondrial myopathy (218 patients, MMPOWER-3) did not meet its primary endpoint, and the drug was not approved for that broader indication. Elamipretide remains approved exclusively for Barth syndrome. See also SS-31 (#158) for the research compound context.
Palopegteriparatide is marketed as Yorvipath (Ascendis Pharma, approved August 2024). It is the first FDA-approved PTH replacement therapy for hypoparathyroidism, a condition that previously had no approved hormone replacement and was managed only with high doses of calcium supplements and active vitamin D — an approach that does not fully normalise calcium metabolism. In the PaTHway trial, 79% of patients achieved independence from calcium and active vitamin D supplements while maintaining normal blood calcium levels, compared to 5% on placebo. This represents a fundamental shift in managing hypoparathyroidism — from supplementation to actual hormone replacement. Patients also showed improvements in kidney function markers and bone metabolism parameters.
Comparisons
Evidence Reviews
Timelines
This content is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional before making decisions about your health.
