Abstract
Difelikefalin (Korsuva™) is a synthetic peptide agonist of the kappa opioid receptor being developed by Cara Therapeutics for the treatment of pruritus. In August 2021, intravenous difelikefalin was approved in the USA for the treatment of moderate-to-severe pruritus associated with chronic kidney disease (CKD) in adults undergoing haemodialysis. Intravenous difelikefalin has also been evaluated for CKD-associated pruritus in patients undergoing haemodialysis in various other countries, with Marketing Authorization Application under regulatory review in the EU and a phase III trial ongoing in Japan. Clinical studies of an oral formulation of difelikefalin have also been completed or are underway in pruritus indications, including pruritus associated with atopic dermatitis, notalgia paraesthetica or primary biliary cholangitis. This article summarizes the milestones in the development of difelikefalin leading to this first approval for CKD-associated pruritus in adults undergoing haemodialysis.
Similar content being viewed by others
References
Phan NQ, Lotts T, Antal A, et al. Systemic kappa opioid receptor agonists in the treatment of chronic pruritus: a literature review. Acta Derm Venereol. 2012;92(5):555–60.
Aldrich JV, McLaughlin JP. Opioid peptides: potential for drug development. Drug Discov Today Technol. 2011;9(1):e23–31.
Albert-Vartanian A, Boyd MR, Hall AL, et al. Will peripherally restricted kappa-opioid receptor agonists (pKORAs) relieve pain with less opioid adverse effects and abuse potential? J Clin Pharm Ther. 2016;41(4):371–82.
Vadivelu N, Huang Y, Mirante B, et al. Patient considerations in the use of tapentadol for moderate to severe pain. Drug Healthc Patient Saf. 2013;5:151–9.
Pattinson KT. Opioids and the control of respiration. Br J Anaesth. 2008;100(6):747–58.
Al-Hasani R, Bruchas MR. Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology. 2011;115(6):1363–81.
Cara Therapeutics. Korsuva™ (difelikefalin) injection, for intravenous use: US prescribing information. 2021. https://korsuva.com. Accessed 25 Aug 2021.
Cara Therapeutics, Vifor Pharma. Vifor Pharma and Cara Therapeutics announce U.S. FDA approval of Korsuva™ injection for the treatment of moderate to severe pruritus in hemodialysis patients [media release]. 24 Aug 2021. https://www.viforpharma.com.
Unigene Laboratories Inc. Unigene announces manufacturing and clinical supply agreement with Cara Therapeutics for phase 1 study of novel kappa receptor agonist [media release]. 20 May 2011. http://www.unigene.com.
Cara Therapeutics Inc and Chong Kun Dang Pharmaceutical Corporation. Cara Therapeutics licenses novel kappa opioid agonist, CR845, to Chong Kun Dang Pharmaceutical Corporation for South Korean market [media release]. 3 May 2012. http://www.caratherapeutics.com.
Cara Therapeutics Inc and Maruishi Pharmaceutical Co Ltd. Cara Therapeutics enters Into development and commercial alliance with Maruishi for novel kappa opioid agonist, CR845, in Japan [media release]. 29 Apr 2013. http://www.caratherapeutics.com.
Enteris BioPharma. Enteris BioPharma oral formulation progresses into phase 2 study with Cara Therapeutics' CR845 [media release]. 14 Jul 2015. http://www.enterisbiopharma.com.
Kissei Pharmaceutical and Maruishi Pharmaceutical Co Ltd. Kissei and Maruishi to collaborate for development and sales/marketing of kappa opioid receptor agonist, "MR13A9", in Japan [media release]. 13 Mar 2017. http://www.kissei.co.jp.
Vifor Fresenius Medical Care Renal Pharma and Cara Therapeutics. VFMCRP and Cara Therapeutics to develop and commercialise CR845 injection for chronic kidney disease-associated pruritus [media release]. 23 May 2018. http://www.viforpharma.com.
Enteris BioPharma. Enteris BioPharma and Cara Therapeutics enter into licensing agreement for Peptelligence® to advance development of oral Korsuva™ [media release]. 21 Aug 2019. http://www.enterisbiopharma.com.
Vifor Pharma, Cara Therapeutics. Vifor Pharma and Cara Therapeutics sign US license agreement for i.v. Korsuva™* to treat dialysis patients with pruritus [media release]. 20 Oct 2020. www.viforpharma.com.
Cara Therapeutics. Securities and Exchange Commission: annual report on Form 10-K. 2020. https://ir.caratherapeutics.com/static-files/619cd29f-cdcc-4a47-be0b-ca3f3b7bb033. Accessed 30 Aug 2021.
Gardell LR, Spencer RH, Chalmers DT, et al. Preclinical profile of CR845: a novel, long-acting peripheral kappa opioid receptor agonist [poster]. In: International Association for the Study of Pain 2008.
Viscusi ER, Torjman MC, Munera CL, et al. Effect of difelikefalin, a selective kappa opioid receptor agonist, on respiratory depression: a randomized, double-blind, placebo-controlled trial. Clin Transl Sci. 2021. https://doi.org/10.1111/cts.13042.
Cara T. Cara Therapeutics announces summary data from phase 1 trial of oral CR845 in hemodialysis patients with chronic kidney disease [media release]. 12 Jul 2017. http://ir.caratherapeutics.com.
Fishbane S, Jamal A, Munera C, et al. A phase 3 trial of difelikefalin in hemodialysis patients with pruritus. N Engl J Med. 2020;382(3):222–32.
Wooldridge TD, McCafferty K, Schoemig M, et al. Efficacy and safety of difelikefalin for moderate-to-severe CKD-associated pruritus: a global phase 3 study in hemodialysis patients (KALM-2) [abstract FR-OR24 plus oral presentation]. J Am Soc Nephrol. 2020;31(Suppl):22–3.
Topf J, Wen W, Munera C, et al. Efficacy of difelikefalin in patients with moderate-to-severe chronic kidney disease–associated pruritus: pooled subgroup analysis of KALM-1 and KALM-2 [abstract and poster 233]. In: National Kidney Foundation 2021 Spring Clinical Meeting.
Fishbane S, Wen W, Munera C, et al. Long-term safety and efficacy of difelikefalin in patients with chronic kidney disease–associated pruritus: analysis from KALM-1 and KALM-2 [abstract and poster 207]. In: National Kidney Foundation 2021 Spring Clinical Meeting.
Weiner D, Menzaghi F, Wen W, et al. An open-label, multicenter study to evaluate the safety and effectiveness of intravenous difelikefalin in patients with moderate-to-severe CKD–associated pruritus undergoing hemodialysis [abstract no. FC022 and presentation]. Nephrol Dialysis Transplant. 2021;36(Suppl 1):i16–7.
Fishbane S, Mathur V, Germain MJ, et al. Randomized controlled trial of difelikefalin for chronic pruritus in hemodialysis patients. Kidney Int Rep. 2020;5(5):600–10.
Cara Therapeutics Inc. Cara Therapeutics announces positive results from phase 2 trial in uremic pruritus [media release]. 23 Jul 2015. http://www.caratherapeutics.com.
Yosipovitch G, Awad A, Spencer R, et al. Efficacy and safety of oral difelikefalin in stage 3–5 chronic kidney disease patients with moderate-to-severe pruritus: a response analysis from a randomized, placebo-controlled, phase 2 trial [abstract no. 4]. Am J Kidney Dis. 2020;75(5):820.
Cara Therapeutics. Cara Therapeutics announces topline results from KARE phase 2 dose-ranging trial of oral Korsuva™ in atopic dermatitis patients with moderate-to-severe pruritus [media release]. 29 Apr 2021. http://www.caratherapeutics.com.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Funding
The preparation of this review was not supported by any external funding.
Authorship and Conflict of interest
During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the authors on the basis of scientific completeness and accuracy. Emma Deeks is a contracted employee of Adis International Ltd/Springer Nature, and declares no relevant conflicts of interest. All authors contributed to the review and are responsible for the article content.
Ethics approval, Consent to participate, Consent to publish, Availability of data and material, Code availability
Not applicable.
Additional information
This profile has been extracted and modified from the AdisInsight database. AdisInsight tracks drug development worldwide through the entire development process, from discovery, through pre-clinical and clinical studies to market launch and beyond.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Deeks, E.D. Difelikefalin: First Approval. Drugs 81, 1937–1944 (2021). https://doi.org/10.1007/s40265-021-01619-6
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40265-021-01619-6