Korsuva
Evidence Grade A — Regulatory approved. 109 published studies. 22 registered clinical trials.
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.
109 published studies: 59 human, 4 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.
Intermediate-Size Patient Population Expanded Access Program for Intravenous Difelikefalin
Safety and Tolerability of Difelikefalin in Adolescents on Haemodialysis With Moderate-to-Severe Pruritus
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
Phase 3 Study of Difelikefalin in Haemodialysis Chinese Adult Subjects With Moderate-to-Severe Pruritus
FDA ORIG 1
EMA Marketing Authorisation
Health Canada Market Authorisation
FDA SUPPL 2
Exenatide was the first GLP-1 receptor agonist approved anywhere, reaching the market as Byetta in April 2005. The once-weekly formulation Bydureon followed in 2012. Clinical trials showed blood sugar reductions (HbA1c) of 1.6–1.9% and modest weight loss of 2–4 kg. The EXSCEL cardiovascular outcomes trial, involving over 14,700 patients, showed a trend toward cardiovascular benefit but narrowly missed statistical significance. While exenatide was groundbreaking as the first in its class, it has been largely overtaken by newer GLP-1 treatments that offer greater efficacy, less frequent dosing, and proven cardiovascular benefits. It remains available and in clinical use, particularly in combination products.
Lixisenatide was marketed as Adlyxin in the US (approved July 2016), though it has since been discontinued in the US market. The ELIXA cardiovascular trial, involving over 6,000 patients, was the first cardiovascular outcomes trial for any GLP-1 medication to report results. It showed a neutral cardiovascular profile — neither harmful nor beneficial — meeting safety requirements but not demonstrating the heart benefits later shown by semaglutide and liraglutide. Lixisenatide found its primary clinical role in combination with basal insulin, marketed as Soliqua (lixisenatide plus insulin glargine). This combination addresses both fasting blood sugar (via insulin) and post-meal spikes (via lixisenatide) in a single daily injection. As a standalone treatment, it has been largely superseded by more potent GLP-1 medications.
Pramlintide is marketed as Symlin (approved March 2005) and remains the only approved amylin-based treatment. It is used alongside mealtime insulin in both type 1 and type 2 diabetes. Clinical trials showed modest blood sugar improvements (HbA1c reductions of 0.2–0.6%) and approximately 2.3 kg of weight loss — less dramatic than GLP-1 treatments but meaningful as an add-on therapy. Symlin carries a boxed warning for severe hypoglycaemia, particularly when combined with insulin, and requires careful dose adjustment. Practical uptake has been limited by the need for separate injections at each meal alongside existing insulin injections. Despite its modest clinical impact, pramlintide remains the only medication that addresses the amylin deficiency in diabetes, filling a distinct biological role that GLP-1 treatments do not cover.
