Difelikefalin, an investigational intravenous (IV) drug for treating itch (pruritus) in patients with end-stage renal disease on hemodialysis, was safe and effective in two parallel pivotal trials in which 796 patients on dialysis received the drug.
In one analysis of the two trials, thrice-weekly treatment with IV bolus infusions of difelikefalin, administered at the end of each dialysis session, were “well-tolerated” and had an “acceptable safety profile.” The analysis also showed longer-term efficacy in a quality-of-life metric, Steven Fishbane, MD, and coauthors reported in a poster presented at the National Kidney Foundation’s Spring Clinical Meetings (SCM21).
A second poster at SCM21 presented combined efficacy data from the two trials that each began with a 12-week, randomized, placebo-controlled phase. The analysis showed that, after 12 weeks, roughly 50% of patients on active treatment achieved the primary efficacy endpoint of both studies — at least a 3-point improvement in the mean weekly score on a daily measure of pruritus intensity, the 24-hour Worst Itching Intensity Numerical Rating Scale (WI-NRS). Among patients who received placebo the response rate was about 30%, a significant difference favoring active treatment, reported Joel Topf, MD, medical director of St. Clair Nephrology Research in Detroit, Michigan, and coauthors.
Based on the results of the two trials and other clinical evidence, the two companies that are jointly developing difelikefalin (Korsuva) announced in March 2021 that the US Food and Drug Administration accepted their application for priority review for using the drug to treat moderate-to-severe pruritus in patients receiving hemodialysis. The agency will make a decision by August 2021 and does not plan to use an advisory committee for the decision.
“It Would Be Very Exciting if Difelikefalin Were Approved”
“It would be very exciting if difelikefalin were approved,” commented Holly M. Koncicki, MD, a nephrologist at Mount Sinai Hospital in New York City, who was not involved in the trials. In addition to its effectiveness in moderating itch, she highlighted three other ways routine availability of difelikefalin could benefit patients on dialysis who have intrusive pruritus that does not respond to topical moisturizers:
Because it’s administered at the end of each dialysis session under the supervision of a nephrologist, “I think this will start to open the eyes of providers who underestimate pruritus in this population,” she said during a talk at SCM21.
Delivery of the drug by IV bolus at a dialysis facility means no added pill burden for patients and guarantees good compliance.
Results from prior studies have documented the uremic pruritus that often occurs in patients on dialysis exacerbates other symptoms and worsens quality of life. Patients whose pruritus is mitigated with difelikefalin can expect to have improved symptoms and quality of life. “Patients will have better outcomes,” she predicted.
Two Parallel Trials
The two trials that supplied data for the combined analyses were KALM-1, which randomized 378 patients at any of 57 US sites, and KALM-2, which had a similar design and randomized 473 patients at any of 93 sites in the US and several other countries. In 2020, the KALM-1 results were published in The New England Journal of Medicine. Investigators presented the KALM-2 results during Kidney Week in October 2020, but the results have not yet been published.
In KALM-1, difelikefalin showed a significant benefit given at a dose of 0.5 μg/kg body weight for the primary efficacy endpoint — percentage of patients with an improvement (decrease) of at least 3 points from baseline in the weekly mean score on the 24-hour WI-NRS at week 12 — which occurred about 2.5-fold more often than in the placebo group. The results also showed significant benefits with difelikefalin for all three secondary efficacy endpoints examined.
The SCM21 poster presented by Fishbane included combined safety results from KALM-1 and KALM-2 during both the 12-week randomized phase and 52-week open-label extension phase. The combined 12-week data showed similar rates of treatment-emergent adverse events in the difelikefalin and placebo groups, which remained consistent during the 52-week extension phase, reported Fishbane, chief of the Division of Kidney Disease and Hypertension at Northwell Health in Manhasset, New York.
The only long-term efficacy data reported by these authors used the 5-D itch scale, a validated itch-related quality-of-life metric that assesses five dimensions of itch (degree, duration, direction, disability, and distribution) during a 2-week recall period.
The data showed that patients who switched from placebo to difelikefalin at the start of the open-label phase reached an average 5-D itch score after 4 weeks that matched the score maintained in patients who had received active treatment from the start. Both subgroups then maintained similar average 5-D itch scores for the balance of their time on the drug. Long-term results of the primary efficacy endpoint in the two trials were not reported.
Treating an Opioid-Receptor Imbalance
Difelikefalin is a peripherally restricted, selective kappa-opioid receptor agonist. This means that it produces no central neurologic effects and addresses the imbalance between mu and kappa receptors in the skin that seems to underlie uremic pruritus, also known as chronic kidney disease-associated pruritus, noted Koncicki.
Exclusively peripheral activity means that patients taking the drug show no evidence of altered mental state, abuse behaviors, or physical dependence, she added.
Even when difelikefalin becomes available for routine use, first-line treatment for pruritus in patients on dialysis will remain topical moisturizing agents, Koncicki emphasized.
Although no prescription agents are labeled for treating uremic pruritus, the current second-line agent is gabapentin, which has the “best evidence” for efficacy among currently available options but is limited by causing an altered mental state in a significant number of patients and has potential for abuse. Antihistamines are also often used to treatment uremic pruritus, but this drug class has never shown proven efficacy in this setting and is not recommended, she said.
Roughly a third of patients on hemodialysis develop moderate-to-severe pruritus.
KALM-1 and KALM-2 were sponsored by Cara Therapeutics, which is developing difelikefalin in partnership with Vifor Pharma. Fishbane and Topf have received research support from Cara Therapeutics and Topf is also an advisor to the company. Koncicki had no relevant disclosures.