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Phase II Success for Oral CKD-Related Pruritus Agent

— Novel drug activates kappa opioid receptors

MedpageToday

The investigational oral treatment difelikefalin (Korsuva) reduced pruritus in patients with chronic kidney disease (CKD) in a phase II trial.

Among 269 patients with moderate-to-severe CKD, 1 mg of difelikefalin significantly reduced itching intensity compared with placebo as measured by the daily 24-hour Worst Itching Intensity Numeric Rating Scale (-4.4 vs -3.3 placebo, P=0.018), reported Gil Yosipovitch, MD, of the University of Miami, and colleagues.

Meeting its primary efficacy endpoint, the was presented at the National Kidney Foundation's virtual Spring Clinical Meeting 2020.

A total of 37% of patients on 1 mg of difelikefalin achieved a complete treatment response versus only 14.3% of those on placebo by the end of the 12-week trial (P=0.006). And difelikefalin showed a statistically significant improvement in pruritus by only the second week of treatment, maintained through the end of the trial.

Difelikefalin works as a restricted, selective agonist at kappa opioid receptors to reduce pruritus.

"There is a significant unmet need in patients with chronic kidney disease-associated pruritus and there are no approved treatments in the U.S. and Europe," Yosipovitch and co-study author Ahmed Awad, DO, of Kansas City Kidney Consultants in Missouri, jointly explained to ֱ.

A phase III trial of an intravenous version of difelikefalin in hemodialysis patients already demonstrated significant reduction in itch intensity and improvement in itch-related quality of life, the pair noted.

"The goal of this study was to look beyond hemodialysis patients and evaluate an oral formulation of difelikefalin in a broader range of patients with stage 3-5 CKD including non-dialysis and dialysis patients with moderate to severe pruritus," they explained.

The trial included patients in these later stages of CKD with related moderate-to-severe pruritus, who were randomized equally to placebo or one of three doses of difelikefalin (0.25, 0.5, or 1 mg) once daily. Average baseline itching intensity scores were 7.1 and 7.0 in the active-drug groups and placebo group, respectively.

"The traditional thinking is that pruritus is more prevalent in severe CKD and patients undergoing hemodialysis. Surprisingly, about 60% of patients in this study had stage 3 CKD, confirming pruritus is prevalent across moderate to severe stages of CKD," Yosipovitch and Awad highlighted.

They noted that baseline itching scores were similar across patients with stage 3, 4, and 5 CKD, and was even similar between non-dialysis and dialysis patients. Of note, difelikefalin was efficacious at treatment pruritus regardless of CKD stage or dialysis status.

As for secondary endpoints, 72% of patients on 1 mg of difelikefalin were able to achieve at least a 3-point improvement in their weekly average itching score, only achieved by 58%. However, this difference wasn't statistically significant. And although more patients on 1 mg of treatment had greater quality-of-life improvements measured by the Skindex-10 and 5-D Itch scales when compared with placebo, this also wasn't statistically significant.

Among patients on difelikefalin, some of the most common adverse events that occurred in more than 5% of patients included dizziness (7.5% vs 0% of placebo), falling (6% vs 0%), diarrhea (6% vs 1.5%), and constipation (6% vs 3%).

"Although we need more data and further evaluation, difelikefalin is an emerging option which has shown promise in several clinical trials thus far," the trial authors concluded.

  • author['full_name']

    Kristen Monaco is a senior staff writer, focusing on endocrinology, psychiatry, and nephrology news. Based out of the New York City office, she’s worked at the company since 2015.

Disclosures

The trial was supported by Cara Therapeutics.

Primary Source

National Kidney Foundation

Yosipovitch G, 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 randomised, placebo-controlled, phase 2 trial" NKF 2020; Abstract 409.